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Sample records for metastatic castrate-resistant prostate

  1. Enzalutamide for patients with metastatic castration-resistant prostate cancer

    Science.gov (United States)

    Ramadan, Wijdan H; Kabbara, Wissam K; Al Basiouni Al Masri, Hiba S

    2015-01-01

    Objective To review and evaluate current literature on the US Food and Drug Administration (FDA)-approved drug enzalutamide (XTANDI®) in metastatic castration-resistant prostate cancer. Data sources Literature search was done through PubMed using the terms enzalutamide, MDV3100, abiraterone, and castration-resistant prostate cancer. Data from FDA product labels were also used. Study selection and data extraction Recent and relevant studies were included in the review. Collected clinical trials were screened and evaluated. Data synthesis Enzalutamide is an androgen receptor (AR) inhibitor with high selectivity and affinity to the AR. It was approved by the FDA to treat metastatic castration-resistant prostate cancer in patients previously treated with docetaxel, after a Phase III trial (AFFIRM) that showed a 4.8-month survival benefit in this population. Recently, the FDA expanded the approval of enzalutamide as first-line therapy for metastatic castration-resistant prostate cancer (mCRPC) who did not receive chemotherapy. Moreover, enzalutamide is shown to be associated with an acceptable safety profile. Conclusion Enzalutamide has been shown to be both safe and effective in improving overall survival in metastatic castration-resistant prostate cancer postchemotherapy with docetaxel and as a first line treatment before initiation of chemotherapy. However, additional studies and head-to-head trials are needed. PMID:25945058

  2. Metastatic castration-resistant prostate cancer: time for innovation.

    Science.gov (United States)

    Tucci, Marcello; Scagliotti, Giorgio Vittorio; Vignani, Francesca

    2015-01-01

    Androgen deprivation is the mainstay of advanced prostate cancer treatment. Despite initial responses, almost all patients progress to castration-resistant prostate cancer (CRPC). The understanding of the biology of CRPC and the evidence that CRPC still remains driven by androgen receptor signaling led to the discovery of new therapeutic targets. In the last few years, large Phase III trials showed improvements in survival and outcomes and led to the approval of a CYP17 inhibitor (abiraterone), an androgen receptor antagonist (enzalutamide), the taxane cabazitaxel, an α-emitter (radium-223), the bone resorption-targeting drug denosumab and an immunotherapy (sipuleucel-T). This article describes the molecular mechanisms underlying castration resistance, discusses recent and ongoing trials and offers some insights into identifying the best sequence of new drugs.

  3. Annotating MYC Status in Treatment-Resistant Metastatic Castration-Resistant Prostate Cancer With Gallium-68 Citrate PET

    Science.gov (United States)

    2017-09-01

    which avidly binds to circulating transferrin) labeled transferrin (Tf) can detect MYC-positive prostate cancer tumors, since the transferrin receptor ...Castration-Resistant Prostate Cancer with Androgen Receptor - Axis Imaging. Journal of nuclear medicine : official publication, Society of Nuclear...AWARD NUMBER: W81XWH-16-1-0469 TITLE: Annotating MYC Status in Treatment-Resistant Metastatic Castration- Resistant Prostate Cancer With

  4. Enzalutamide in Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer

    DEFF Research Database (Denmark)

    Beer, Tomasz M; Armstrong, Andrew J; Rathkopf, Dana

    2017-01-01

    Enzalutamide significantly improved radiographic progression-free survival (rPFS) and overall survival (OS) among men with chemotherapy-naïve metastatic castration-resistant prostate cancer at the prespecified interim analysis of PREVAIL, a phase 3, double-blind, randomized study. We evaluated...

  5. Abiraterone acetate for patients with metastatic castration-resistant prostate cancer progressing after chemotherapy

    DEFF Research Database (Denmark)

    Sternberg, Cora N; Castellano, Daniel; Daugaard, Gedske

    2014-01-01

    , development of sustained side-effects, or abiraterone acetate becoming available in the respective country. The primary outcome was the number of adverse events arising during study treatment and within 30 days of discontinuation. Efficacy measures (time to prostate-specific antigen [PSA] progression and time......BACKGROUND: In the final analysis of the phase 3 COU-AA-301 study, abiraterone acetate plus prednisone significantly prolonged overall survival compared with prednisone alone in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy. Here, we present the final...... analysis of an early-access protocol trial that was initiated after completion of COU-AA-301 to enable worldwide preapproval access to abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy. METHODS: We did a multicentre, open-label, early...

  6. Safety of cabazitaxel in senior adults with metastatic castration-resistant prostate cancer

    DEFF Research Database (Denmark)

    Heidenreich, Axel; Bracarda, Sergio; Mason, Malcolm

    2014-01-01

    BACKGROUND: Cabazitaxel/prednisone has been shown to prolong survival versus mitoxantrone/prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) that has progressed during or after docetaxel. Subsequently, compassionate-use programmes (CUPs) and expanded-access progra......-CSF, especially at cycle 1 and in men aged > or =75 years, is important and improves tolerability in senior adults treated with cabazitaxel....

  7. Docetaxel, Carboplatin, and Rucaparib Camsylate in Treating Patients With Metastatic Castration Resistant Prostate Cancer With Homologous Recombination DNA Repair Deficiency

    Science.gov (United States)

    2018-02-20

    ATM Gene Mutation; BRCA1 Gene Mutation; BRCA2 Gene Mutation; Castration Levels of Testosterone; Castration-Resistant Prostate Carcinoma; Homologous Recombination Deficiency; Prostate Carcinoma Metastatic in the Bone; PSA Level Greater Than or Equal to Two; PSA Progression; Stage IV Prostate Adenocarcinoma AJCC v7

  8. Update on options for treatment of metastatic castration-resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Prakash Vishnu

    2010-03-01

    Full Text Available Prakash Vishnu, Winston W TanDivision of Hematology Oncology, Mayo Clinic, Jacksonville, FL, USABackground: Prostate cancer is one of the most common cancers in men in US and European countries. Despite having a favorable prognosis, the incidence of incurable metastatic disease and mortality in the US is about 28,000 per year. Although hormone-based androgen deprivation therapies typically result in rapid responses, nearly all patients eventually develop progressive castration-resistant disease state. With readily available prostate-specific antigen (PSA testing, most of these patients are asymptomatic and manifest progression simply as a rising PSA. In patients with castration-resistant prostate cancer (CRPC, the median survival is about 1–2 years, with improvements in survival seen mostly with docetaxel-based regimens. The purpose of this article is to review the recent developments in the treatment of advanced CRPC.Recent findings: Since the two landmark trials (TAX-327 and Southwest Oncology Group 99–16 in CRPC, several newer cytotoxic drugs (epothilones, satraplatin, targeted agents (abiraterone, MDV3100 and vaccines have been tested in phase II and III setting with promising results.Conclusions: The role of newer agents in the treatment of CRPC still needs to be validated by phase III trials, which are currently ongoing. Whilst the novel biomarkers, ‘circulating tumor cells’, have been shown to provide important prognostic information and are anticipated to be incorporated in future clinical decision-making, their exact utility and relevance calls for a larger prospective validation.Keywords: castration-resistant prostate cancer, novel therapies, mechanisms of resistance, circulating tumor cells

  9. Radiographic progression with nonrising PSA in metastatic castration-resistant prostate cancer

    DEFF Research Database (Denmark)

    Bryce, A H; Alumkal, J J; Armstrong, A

    2017-01-01

    monitoring alone to determine disease status on therapy. This approach has not been adequately tested. METHODS: Chemotherapy-naive asymptomatic or mildly symptomatic men (n=872) with metastatic castration-resistant prostate cancer (mCRPC) who were treated with the androgen receptor inhibitor enzalutamide......BACKGROUND: Advanced prostate cancer is a phenotypically diverse disease that evolves through multiple clinical courses. PSA level is the most widely used parameter for disease monitoring, but it has well-recognized limitations. Unlike in clinical trials, in practice, clinicians may rely on PSA...... treated with enzalutamide. As restaging in advanced prostate cancer patients is often guided by increases in PSA levels, our results demonstrate that disease progression on enzalutamide can occur without rising PSA levels. Therefore, a disease monitoring strategy that includes imaging not entirely reliant...

  10. Update on options for treatment of metastatic castration-resistant prostate cancer.

    Science.gov (United States)

    Vishnu, Prakash; Tan, Winston W

    2010-06-24

    Prostate cancer is one of the most common cancers in men in US and European countries. Despite having a favorable prognosis, the incidence of incurable metastatic disease and mortality in the US is about 28,000 per year. Although hormone-based androgen deprivation therapies typically result in rapid responses, nearly all patients eventually develop progressive castration-resistant disease state. With readily available prostate-specific antigen (PSA) testing, most of these patients are asymptomatic and manifest progression simply as a rising PSA. In patients with castration-resistant prostate cancer (CRPC), the median survival is about 1-2 years, with improvements in survival seen mostly with docetaxel-based regimens. The purpose of this article is to review the recent developments in the treatment of advanced CRPC. Since the two landmark trials (TAX-327 and Southwest Oncology Group 99-16) in CRPC, several newer cytotoxic drugs (epothilones, satraplatin), targeted agents (abiraterone, MDV3100) and vaccines have been tested in phase II and III setting with promising results. The role of newer agents in the treatment of CRPC still needs to be validated by phase III trials, which are currently ongoing. Whilst the novel biomarkers, 'circulating tumor cells', have been shown to provide important prognostic information and are anticipated to be incorporated in future clinical decision-making, their exact utility and relevance calls for a larger prospective validation.

  11. Cabazitaxel in patients with metastatic castration-resistant prostate cancer: results of a compassionate use program in the Netherlands

    NARCIS (Netherlands)

    Wissing, M.D.; Oort, I.M. van; Gerritsen, W.R.; Eertwegh, A.J. van den; Coenen, J.L.; Bergman, A.M.; Gelderblom, H.

    2013-01-01

    BACKGROUND: Cabazitaxel has been reimbursed as a second-line therapy for patients with metastatic castrate-resistant prostate cancer (mCRPC) in the Netherlands since 2011. Before reimbursement was available, cabazitaxel was provided through a Compassionate Use Program (CUP). We report the results of

  12. Sipuleucel-T: Autologous Cellular Immunotherapy for Men with Asymptomatic or Minimally Symptomatic Metastatic Castrate Resistant Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Robert B. Sims

    2011-01-01

    Full Text Available Sipuleucel T is an autologous cellular immunotherapy designed to stimulate an immune response in men diagnosed with asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory prostate cancer. Sipuleucel T improves overall survival and provides an additional treatment option for this patient population.

  13. Dendritic cell vaccination in combination with docetaxel for patients with metastatic castration-resistant prostate cancer

    DEFF Research Database (Denmark)

    Kongsted, Per; Borch, Troels Holz; Ellebaek, Eva

    2017-01-01

    Background aims  We investigated whether the addition of an autologous dendritic cell–based cancer vaccine (DCvac) induces an immune response in patients with metastatic castration-resistant prostate cancer treated with docetaxel.  Methods  Forty-three patients were randomized 1:1 to receive up...... twice through treatment cycles 1–4 and once through treatment cycles 5–10. Immune cell composition and antigen-specific responses were analyzed using flow cytometry, ELISpot and delayed type hypersensitivity (DTH) tests. Toxicity was graded according to Common Terminology Criteria for Adverse Events...... to local reactions. Decline in myeloid-derived suppressor cells at the third treatment cycle was found to be an independent predictor of DSS.  Conclusions  The addition of DCvac was safe. Immune responses were detected in approximately half of the patients investigated....

  14. Challenges to improved therapeutics for metastatic castrate resistant prostate cancer: from recent successes and failures

    Directory of Open Access Journals (Sweden)

    Huang Xuan

    2012-07-01

    Full Text Available Abstract Men with metastatic castration-resistant prostate cancer (mCRPC carry poor prognosis despite the use of docetaxel-based regimens which has modest survival benefit shown by randomized clinical trials. Significant progress in the discovery of novel therapeutic agents has been made in the past few years. While sipuleucel-T, cabazitaxel, and abiraterone gained regulatory approval in 2010 and 2011, several highly promising candidates/regimens have failed in large scale clinical trials. Challenges remain to optimize the design and interpretation of clinical trial results and develop more effective strategies for mCRPC. In this review, we examined the positive and negative clinical trials in mCRPC in the past and discussed the various aspects of clinical trial design including selection of targets and appropriate outcome measures, biomarker development and implementation, and strategies for combination therapy.

  15. Cabazitaxel as second-line or third-line therapy in patients with metastatic castration-resistant prostate cancer

    DEFF Research Database (Denmark)

    Kongsted, Per; Svane, Inge M; Lindberg, Henriette

    2016-01-01

    To compare treatment outcomes in patients with metastatic castration-resistant prostate cancer treated with cabazitaxel (CA) as second-line or third-line therapy in the everyday clinical setting. Charts from 94 patients treated with CA as second-line (n=28) or third-line therapy (n=66) were...... evaluated. Common Terminology Criteria for Adverse Events were used to register grade 3-4 nonhematological toxicity during treatment with CA. Baseline metastatic castration-resistant prostate cancer-related prognostic factors, duration of therapy, and maximum prostate-specific antigen (PSA) percentage...... change were registered during treatment with CA and previous/subsequent novel androgen receptor targeting therapies. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. A median of 6 versus 5 treatment cycles was administered in patients treated...

  16. Impact of cabazitaxel on 2-year survival and palliation of tumour-related pain in men with metastatic castration-resistant prostate cancer treated in the TROPIC trial

    DEFF Research Database (Denmark)

    Bahl, A; Oudard, S; Tombal, B

    2013-01-01

    Cabazitaxel significantly improves overall survival (OS) versus mitoxantrone in patients with metastatic castration-resistant prostate cancer after docetaxel failure. We examined patient survival at 2 years and tumour-related pain with cabazitaxel versus mitoxantrone....

  17. Abiraterone in the treatment of metastatic castration-resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Mostaghel EA

    2014-01-01

    Full Text Available Elahe A Mostaghel Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA Abstract: Androgen deprivation therapy remains the single most effective treatment for the initial therapy of advanced prostate cancer, but is uniformly marked by progression to castration-resistant prostate cancer (CRPC. Residual tumor androgens and androgen axis activation are now recognized to play a prominent role in mediating CRPC progression. Despite suppression of circulating testosterone to castrate levels, castration does not eliminate androgens from the prostate tumor microenvironment and residual androgen levels are well within the range capable of activating the androgen receptor (AR and AR-mediated gene expression. Accordingly, therapeutic strategies that more effectively target production of intratumoral androgens are necessary. The introduction of abiraterone, a potent suppressor of cytochrome P450 17 α-hydroxysteroid dehydrogenase-mediated androgen production, has heralded a new era in the hormonal treatment of men with metastatic CRPC. Herein, the androgen and AR-mediated mechanisms that contribute to CRPC progression and establish cytochrome P450 17 α-hydroxysteroid dehydrogenase as a critical therapeutic target are briefly reviewed. The mechanism of action and pharmacokinetics of abiraterone are reviewed and its recently described activity against AR and 3-β-hydroxysteroid dehydrogenase is discussed. The Phase I and II data initially demonstrating the efficacy of abiraterone and Phase III data supporting its approval for patients with metastatic CRPC are reviewed. The safety and tolerability of abiraterone, including the incidence and management of side effects and potential drug interactions, are discussed. The current place of abiraterone in CRPC therapy is reviewed and early evidence regarding cross-resistance of abiraterone with taxane therapy, mechanisms of resistance to abiraterone, and observations of an

  18. Profile of apalutamide in the treatment of metastatic castration-resistant prostate cancer: evidence to date.

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    Chong, Julio T; Oh, William K; Liaw, Bobby C

    2018-01-01

    Advances in therapies have led to the approval of six therapeutic agents since 2004, each demonstrating overall survival benefit in randomized studies, and these have significantly improved the outlook for men facing metastatic castration-resistant prostate cancer (CRPC). More recently, efforts have been directed at trying to effect change at earlier phases of the disease. Apalutamide (ARN-509), a second-generation androgen receptor antagonist, recently received approval in the nonmetastatic (M0) CRPC space. Similar to enzalutamide, apalutamide inhibits the binding of androgen to androgen receptor (AR), nuclear translocation of the androgen-AR complex, and binding of AR transcription complex to DNA-binding sites and transcription elements. Phase I and II trial experience demonstrates the safety and tolerability of apalutamide, as well as its efficacy in effecting prostate-specific antigen response and radiographic-free survival in CRPC. US Food and Drug Administration approval in M0 CRPC was granted following positive results from the phase III SPARTAN study, where apalutamide demonstrated significant improvements in metastasis-free survival and time to symptomatic progression as compared to placebo.

  19. Abiraterone in the treatment of metastatic castration-resistant prostate cancer

    International Nuclear Information System (INIS)

    Mostaghel, Elahe A

    2014-01-01

    Androgen deprivation therapy remains the single most effective treatment for the initial therapy of advanced prostate cancer, but is uniformly marked by progression to castration-resistant prostate cancer (CRPC). Residual tumor androgens and androgen axis activation are now recognized to play a prominent role in mediating CRPC progression. Despite suppression of circulating testosterone to castrate levels, castration does not eliminate androgens from the prostate tumor microenvironment and residual androgen levels are well within the range capable of activating the androgen receptor (AR) and AR-mediated gene expression. Accordingly, therapeutic strategies that more effectively target production of intratumoral androgens are necessary. The introduction of abiraterone, a potent suppressor of cytochrome P450 17 α-hydroxysteroid dehydrogenase-mediated androgen production, has heralded a new era in the hormonal treatment of men with metastatic CRPC. Herein, the androgen and AR-mediated mechanisms that contribute to CRPC progression and establish cytochrome P450 17 α-hydroxysteroid dehydrogenase as a critical therapeutic target are briefly reviewed. The mechanism of action and pharmacokinetics of abiraterone are reviewed and its recently described activity against AR and 3-β-hydroxysteroid dehydrogenase is discussed. The Phase I and II data initially demonstrating the efficacy of abiraterone and Phase III data supporting its approval for patients with metastatic CRPC are reviewed. The safety and tolerability of abiraterone, including the incidence and management of side effects and potential drug interactions, are discussed. The current place of abiraterone in CRPC therapy is reviewed and early evidence regarding cross-resistance of abiraterone with taxane therapy, mechanisms of resistance to abiraterone, and observations of an abiraterone withdrawal response are presented. Future directions in the use of abiraterone, including optimal dosing strategies, the role of

  20. Challenges in the sequencing of therapies for the management of metastatic castration-resistant prostate cancer.

    Science.gov (United States)

    Parente, Phillip; Parnis, Francis; Gurney, Howard

    2014-09-01

    Prior to 2010, docetaxel was the standard option for chemotherapy in men with metastatic castration-resistant prostate cancer (mCRPC). Today, the picture is vastly different: several additional therapies have each demonstrated a survival benefit such that we now have chemotherapy (cabazitaxel), androgen suppressive agents (abiraterone acetate and enzalutamide), a cellular vaccine (sipuleucel-T) and radium-233 (for symptomatic bone metastases). With several other agents in the pipeline for late-stage disease, the future looks promising for mCRPC. As the available data are not able to inform as to the optimum sequencing of therapy, this remains a challenge. This paper draws on insights from published and ongoing clinical studies to provide a practical patient-focused approach to maximize the benefits of the current therapeutic armamentarium. Preliminary sequencing suggestions are made based on clinical trial criteria. But until more data become available, clinical gestalt, experience, cost and individual patient preferences will continue to drive choices. © 2014 Wiley Publishing Asia Pty Ltd.

  1. Prostate-specific Antigen Decline After 4 Weeks of Treatment with Abiraterone Acetate and Overall Survival in Patients with Metastatic Castration-resistant Prostate Cancer

    NARCIS (Netherlands)

    Rescigno, P.; Lorente, D.; Bianchini, D.; Ferraldeschi, R.; Kolinsky, M.P.; Sideris, S.; Zafeiriou, Z.; Sumanasuriya, S.; Smith, A.D.; Mehra, N.; Jayaram, A.; Perez-Lopez, R.; Mateo, J.; Parker, C.; Dearnaley, D.P.; Tunariu, N.; Reid, A.; Attard, G.; Bono, J.S. de

    2016-01-01

    BACKGROUND: The availability of multiple new treatments for metastatic castration-resistant prostate cancer (mCRPC) mandates earlier treatment switches in the absence of a response. A decline in prostate-specific antigen (PSA) is widely used to monitor treatment response, but is not validated as an

  2. Symptoms and Impacts in Non-Metastatic Castration-Resistant Prostate Cancer: Qualitative Study Findings.

    Science.gov (United States)

    Tomaszewski, Erin L; Moise, Pierre; Krupnick, Robert N; Downing, Jared; Meyer, Margaret; Naidoo, Shevani; Holmstrom, Stefan

    2017-10-01

    We developed a conceptual model to define key concepts associated with patients' experiences with the signs, symptoms, and impacts of non-metastatic castration-resistant prostate cancer (M0-CRPC). A targeted review of peer-reviewed literature, and other publicly available information, identified and categorized symptoms and impacts related to early-stage prostate cancer. Semi-structured interviews with five clinical experts helped determine the most relevant and important concepts for patients with M0-CRPC. Qualitative interviews with 17 patients with M0-CRPC identified the most frequently experienced symptoms and impacts, and their degree of interference with patients' lives. The findings from these three lines of evidence were summarized in a conceptual model. Literature searches identified mainly urinary, intestinal, and sexual symptoms. Experts noted the symptoms most frequently mentioned by patients include erectile dysfunction, loss of sexual desire or interest, incontinence/leaking, urgency, and hot flashes. Patient interviews confirmed the high frequency of erectile dysfunction, loss of libido, urinary urgency, and incontinence. The most frequently mentioned impacts expressed by patients were the need to monitor/plan for urinary frequency, interference with/restriction of daily activities, and frustration or anxiety over diagnosis, symptoms, or treatment. Symptoms and impacts most frequently experienced by patients were typically not those with the greatest effects on their lives; rather, those with the greatest consequences were related to treatment. The leading concerns associated with M0-CRPC were related to voiding and sexual dysfunction. The most relevant symptoms and impacts expressed by patients may be a consequence of therapy rather than of the disease.

  3. Metastatic castration-resistant prostate cancer: a current view on drug therapy and alternative tumor cell regulation

    Directory of Open Access Journals (Sweden)

    R. A. Gafanov

    2018-01-01

    Full Text Available Prostate cancer (PC is one of the most common causes of death from malignant neoplasms in men in many countries around the world. Transmission of the signal in the androgenic axis of regulation is crucial for the development and progression of PC. Despite the constant dependence on androgen receptor signals in castration resistance, the use of new anti-androgenic drugs invariably leads to the stability  of the ongoing treatment. The interaction of androgen receptor and alternative (phosphoinositide-3-kinases, PI3K pathways in the regulation of cells can be one of the mechanisms of resistance to treatment. In this article, we describe current treatments for metastatic castration-resistant PC and the possible role of the PI3K pathway in the pathogenesis and progression of PC.

  4. A single-center experience with abiraterone as treatment for metastatic castration-resistant prostate cancer

    DEFF Research Database (Denmark)

    Thortzen, Anita; Thim, Stine; Røder, Martin Andreas

    2016-01-01

    BACKGROUND: Continuous stimulation of the androgen receptor (AR) axis is a prerequisite for growth in castration-resistant prostate cancer (CRPC). Abiraterone acetate (AA) is a potent inhibitor of extracellular and intracellular androgen synthesis by inhibition of the CYP-17 enzyme system, which...... at Rigshospitalet, Denmark, and compare the results with phase III trial outcomes. MATERIAL AND METHODS: Single-centre, retrospective study including consecutive patients managed on AA for more than 2-year period. Treatment consisted of 1,000mg AA and 5mg prednisone twice daily. Outcomes of interest were prostate...

  5. Budget Impact of Enzalutamide for Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer.

    Science.gov (United States)

    Bui, Cat N; O'Day, Ken; Flanders, Scott; Oestreicher, Nina; Francis, Peter; Posta, Linda; Popelar, Breanna; Tang, Hong; Balk, Mark

    2016-02-01

    Prostate cancer is expected to account for approximately one quarter of all new diagnoses of cancer in American men in 2015. The cost of prostate cancer care is expected to reach $15.1 billion by the year 2020, up from $11.9 billion in 2010. Given the high burden of prostate cancer, health care payers are interested in quantifying the potential budget impact of new therapies. To estimate the budget impact of enzalutamide for the treatment of chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) from a U.S. payer perspective. A model was developed to assess the budget impact of enzalutamide for treatment of chemotherapy-naïve mCRPC patients in a hypothetical 1-million-member U.S. health plan over a 1-year time horizon. Comparators included abiraterone acetate, sipuleucel-T, radium Ra 223 dichloride, and docetaxel. Epidemiologic data, including National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) incidence rates, were used to estimate the number of chemotherapy-naïve mCRPC patients. Dosing, administration, duration of therapy, and adverse event rates were based on package inserts and pivotal studies. Drug costs were obtained from RED BOOK and Centers for Medicare & Medicaid Services (CMS) average sales price pricing files, costs of administration and monitoring from the CMS physician fee schedule, and adverse events from the Agency for Healthcare Research and Quality Healthcare Cost and Utilization Project and published literature. Market shares were estimated for each comparator before and after adoption of enzalutamide. The incremental aggregate budget impact, per patient per year (PPPY), per patient per month (PPPM), and per member per month (PMPM), was calculated. One-way sensitivity analyses were performed. In a population of 115 chemotherapy-naïve mCRPC patients, adopting enzalutamide had an annual incremental budget impact of $510,641 ($4,426 PPPY, $369 PPPM, and $0.04 PMPM). Results were most sensitive to

  6. Enzalutamide treatment in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy and abiraterone acetate

    DEFF Research Database (Denmark)

    Thomsen, Frederik Birkebaek; Røder, Martin Andreas; Rathenborg, Per

    2014-01-01

    OBJECTIVE: The aim of this study was to record prostate-specific antigen (PSA) response and overall survival (OS) for a group of metastatic castration-resistant prostate cancer (mCRPC) patients treated with enzalutamide following progression after abiraterone treatment in the post-chemotherapy se......OBJECTIVE: The aim of this study was to record prostate-specific antigen (PSA) response and overall survival (OS) for a group of metastatic castration-resistant prostate cancer (mCRPC) patients treated with enzalutamide following progression after abiraterone treatment in the post......-chemotherapy setting. MATERIAL AND METHODS: Twenty-four mCRPC patients with progression after abiraterone treatment following primary docetaxel therapy received enzalutamide 160 mg/day. The percentage PSA response was recorded following first line docetaxel, abiraterone and enzalutamide treatment. Fischer's exact test......, Mann-Whitney U test and linear regression model were used to test for differences in PSA response. RESULTS: All patients had a follow-up of at least 3 months. The median PSA response following 1 month of enzalutamide was -12% (range -56% to 76%), while the median best PSA response was -22% (-76% to 76...

  7. Phase III Study of Cabozantinib in Previously Treated Metastatic Castration-Resistant Prostate Cancer: COMET-1.

    Science.gov (United States)

    Smith, Matthew; De Bono, Johann; Sternberg, Cora; Le Moulec, Sylvestre; Oudard, Stéphane; De Giorgi, Ugo; Krainer, Michael; Bergman, Andries; Hoelzer, Wolfgang; De Wit, Ronald; Bögemann, Martin; Saad, Fred; Cruciani, Giorgio; Thiery-Vuillemin, Antoine; Feyerabend, Susan; Miller, Kurt; Houédé, Nadine; Hussain, Syed; Lam, Elaine; Polikoff, Jonathan; Stenzl, Arnulf; Mainwaring, Paul; Ramies, David; Hessel, Colin; Weitzman, Aaron; Fizazi, Karim

    2016-09-01

    Cabozantinib is an inhibitor of kinases, including MET and vascular endothelial growth factor receptors, and has shown activity in men with previously treated metastatic castration-resistant prostate cancer (mCRPC). This blinded phase III trial compared cabozantinib with prednisone in patients with mCRPC. Men with progressive mCRPC after docetaxel and abiraterone and/or enzalutamide were randomly assigned at a two-to-one ratio to cabozantinib 60 mg once per day or prednisone 5 mg twice per day. The primary end point was overall survival (OS). Bone scan response (BSR) at week 12 as assessed by independent review committee was the secondary end point; radiographic progression-free survival (rPFS) and effects on circulating tumor cells (CTCs), bone biomarkers, serum prostate-specific antigen (PSA), and symptomatic skeletal events (SSEs) were exploratory assessments. A total of 1,028 patients were randomly assigned to cabozantinib (n = 682) or prednisone (n = 346). Median OS was 11.0 months with cabozantinib and 9.8 months with prednisone (hazard ratio, 0.90; 95% CI, 0.76 to 1.06; stratified log-rank P = .213). BSR at week 12 favored cabozantinib (42% v 3%; stratified Cochran-Mantel-Haenszel P < .001). rPFS was improved in the cabozantinib group (median, 5.6 v 2.8 months; hazard ratio, 0.48; 95% CI, 0.40 to 0.57; stratified log-rank P < .001). Cabozantinib was associated with improvements in CTC conversion, bone biomarkers, and post-random assignment incidence of SSEs but not PSA outcomes. Grade 3 to 4 adverse events and discontinuations because of adverse events were higher with cabozantinib than with prednisone (71% v 56% and 33% v 12%, respectively). Cabozantinib did not significantly improve OS compared with prednisone in heavily treated patients with mCRPC and progressive disease after docetaxel and abiraterone and/or enzalutamide. Cabozantinib had some activity in improving BSR, rPFS, SSEs, CTC conversions, and bone biomarkers but not PSA outcomes. © 2016 by

  8. PSMA-Based Radioligand Therapy for Metastatic Castration-Resistant Prostate Cancer: The Bad Berka Experience Since 2013.

    Science.gov (United States)

    Kulkarni, Harshad R; Singh, Aviral; Schuchardt, Christiane; Niepsch, Karin; Sayeg, Manal; Leshch, Yevgeniy; Wester, Hans-Juergen; Baum, Richard P

    2016-10-01

    A potential milestone in personalized nuclear medicine is theranostics of metastatic castration-resistant prostate cancer (mCRPC) based on molecular imaging using PET/CT with 68 Ga-labeled prostate-specific membrane antigen (PSMA) ligands and molecular radiotherapy using PSMA-targeted radioligand therapy (PRLT) with 177 Lu-PSMA ligands. 68 Ga-PSMA PET/CT enables accurate detection of mCRPC lesions with high diagnostic sensitivity and specificity and provides quantitative and reproducible data that can be used to select patients for PRLT and therapeutic monitoring. Our comprehensive experience over the last 3 years using different radioligands indicates that PRLT is highly effective for the treatment of mCRPC, even in advanced cases, and potentially lends a significant benefit to overall and progression-free survival. Additionally, significant improvement in clinical symptoms and excellent palliation of pain can be achieved. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

  9. Further analysis of PREVAIL: enzalutamide use in chemotherapy-naïve men with metastatic castration-resistant prostate cancer.

    Science.gov (United States)

    Aragon-Ching, Jeanny B

    2014-01-01

    PREVAIL was a phase III multinational, double-blind, placebo-controlled trial that enrolled chemotherapy-naïve men with metastatic castration-resistant prostate cancer (mCRPC), which showed remarkable improvement in co-primary endpoints with an overall 81% reduction in the risk of radiographic progression, as well as 29% reduction in the risk of death in favor of the enzalutamide arm over placebo. All secondary endpoints including time to subsequent chemotherapy initiation and prostate specific antigen (PSA) progression were in favor of the enzalutamide arm. The results of PREVAIL shows the utility of enzalutamide that would likely soon expand the indication to asymptomatic or minimally symptomatic men with mCRPC not previously treated with chemotherapy.

  10. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial

    DEFF Research Database (Denmark)

    de Bono, Johann Sebastian; Oudard, Stephane; Ozguroglu, Mustafa

    2010-01-01

    Cabazitaxel is a novel tubulin-binding taxane drug with antitumour activity in docetaxel-resistant cancers. We aimed to compare the efficacy and safety of cabazitaxel plus prednisone with those of mitoxantrone plus prednisone in men with metastatic castration-resistant prostate cancer with progre...

  11. Randomized, Double-Blind, Phase III Trial of Ipilimumab Versus Placebo in Asymptomatic or Minimally Symptomatic Patients With Metastatic Chemotherapy-Naive Castration-Resistant Prostate Cancer

    DEFF Research Database (Denmark)

    Beer, Tomasz M; Kwon, Eugene D; Drake, Charles G

    2017-01-01

    Purpose Ipilimumab increases antitumor T-cell responses by binding to cytotoxic T-lymphocyte antigen 4. We evaluated treatment with ipilimumab in asymptomatic or minimally symptomatic patients with chemotherapy-naive metastatic castration-resistant prostate cancer without visceral metastases. Pat...

  12. Enzalutamide in Men with Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer: Extended Analysis of the Phase 3 PREVAIL Study

    NARCIS (Netherlands)

    Beer, T.M.; Armstrong, A.J.; Rathkopf, D.; Loriot, Y.; Sternberg, C.N.; Higano, C.S.; Iversen, P.; Evans, C.P.; Kim, C.S.; Kimura, G.; Miller, K.; Saad, F.; Bjartell, A.S.; Borre, M.; Mulders, P.; Tammela, T.L.; Parli, T.; Sari, S.; Os, S. van; Theeuwes, A.; Tombal, B.

    2017-01-01

    Enzalutamide significantly improved radiographic progression-free survival (rPFS) and overall survival (OS) among men with chemotherapy-naive metastatic castration-resistant prostate cancer at the prespecified interim analysis of PREVAIL, a phase 3, double-blind, randomized study. We evaluated the

  13. Clinical activity and tolerability of enzalutamide (MDV3100) in patients with metastatic, castration-resistant prostate cancer who progress after docetaxel and abiraterone treatment

    NARCIS (Netherlands)

    Badrising, S.; Noort, V van; Oort, I.M. van; Berg, H.P. van den; Los, M.; Hamberg, P.; Coenen, J.L.; Eertwegh, A.J. van den; Jong, I.J. de; Kerver, E.D.; Tinteren, H. van; Bergman, A.M.

    2014-01-01

    BACKGROUND: Enzalutamide (Enz) and abiraterone acetate (AA) are hormone treatments that have a proven survival advantage in patients with metastatic, castration-resistant prostate cancer who previously received docetaxel (Doc). Recently, limited activity of AA after Enz and of Enz after AA was

  14. Randomized, Placebo-Controlled, Phase III Trial of Sunitinib Plus Prednisone Versus Prednisone Alone in Progressive, Metastatic, Castration-Resistant Prostate Cancer

    DEFF Research Database (Denmark)

    Michaelson, M Dror; Oudard, Stephane; Ou, Yen-Chuan

    2014-01-01

    PURPOSE: We evaluated angiogenesis-targeted sunitinib therapy in a randomized, double-blind trial of metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: Men with progressive mCRPC after docetaxel-based chemotherapy were randomly assigned 2:1 to receive sunitinib 37.5 mg...

  15. Budgetary Impact of Cabazitaxel Use After Docetaxel Treatment for Metastatic Castration-Resistant Prostate Cancer.

    Science.gov (United States)

    Flannery, Kyle; Drea, Ed; Hudspeth, Louis; Corman, Shelby; Gao, Xin; Xue, Mei; Miao, Raymond

    2017-04-01

    With the approval of several new treatments for metastatic castration-resistant prostate cancer (mCRPC), budgetary impact is a concern for health plan decision makers. Budget impact models (BIMs) are becoming a requirement in many countries as part of formulary approval or reimbursement decisions. Cabazitaxel is a second-generation taxane developed to overcome resistance to docetaxel and is approved for the treatment of patients with mCRPC previously treated with a docetaxel-containing regimen. To estimate a 1-year projected budget impact of varying utilization rates of cabazitaxel as a second-line treatment for mCRPC following docetaxel, using a hypothetical U.S. private managed care plan with 1 million members. A BIM was developed to evaluate costs for currently available treatment options for patients with mCRPC previously treated with docetaxel. Treatments included in the model were cabazitaxel, abiraterone acetate, enzalutamide, and radium-223, with utilization rates derived from market research data. Medication costs were calculated according to published pricing benchmarks factored by dosing and duration of therapy as stated in the prescribing information for each agent. Published rates and costs of grade 3-4 adverse events were also factored into the model. In addition, the model reports budget impact under 2 scenarios. In the first base-case scenario, patient out-of-pocket costs were subtracted from the total cost of treatment. In the second scenario, all treatment costs were assumed to be paid by the plan. In a hypothetical 1 million-member health plan population, 100 patients were estimated to receive second-line treatment for mCRPC after treatment with docetaxel. Using current utilization rates for the 4 agents of interest, the base-case scenario estimated the cost of second-line treatment after docetaxel to be $6,331,704, or $0.528 per member per month (PMPM). In a scenario where cabazitaxel use increases from the base-rate case of 24% to a

  16. Noninvasive Detection of AR-FL/AR-V7 as a Predictive Biomarker for Therapeutic Resistance in Men with Metastatic Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2017-10-01

    acknowledged federal support) 5. Antonarakis ES, Armstrong AJ, Dehm SM, Luo J. Androgen receptor variant-driven prostate cancer : clinical implications...Resistant Prostate Cancer abstract Purpose A splice variant of the androgen receptor , AR-V7, confers resistance to AR-targeted therapies (ATTs) but not...androgen receptor ; AR-V7, androgen receptor splice variant 7; mCRPC, metastatic castration-resistant prostate cancer ; n/N, number of patients in that

  17. Pharmacodynamic study of the oral hedgehog pathway inhibitor, vismodegib, in patients with metastatic castration-resistant prostate cancer.

    Science.gov (United States)

    Maughan, Benjamin L; Suzman, Daniel L; Luber, Brandon; Wang, Hao; Glavaris, Stephanie; Hughes, Robert; Sullivan, Rana; Harb, Rana; Boudadi, Karim; Paller, Channing; Eisenberger, Mario; Demarzo, Angelo; Ross, Ashely; Antonarakis, Emmanuel S

    2016-12-01

    Hedgehog (Hh) pathway signaling has been implicated in prostate cancer tumorigenesis and metastatic development and may be upregulated even further in the castration-resistant state. We hypothesized that antagonism of the Hh pathway with vismodegib in men with metastatic castration-resistant prostate cancer (mCRPC) would result in pathway engagement, inhibition and perhaps induce measurable clinical responses in patients. This is a single-arm study of oral daily vismodegib in men with mCRPC. All patients were required to have biopsies of the tumor and skin (a surrogate tissue) at baseline and after 4 weeks of therapy. Ten patients were planned for enrollment. The primary outcome was the pharmacodynamic assessment of Gli1 mRNA suppression with vismodegib in tumor tissue. Secondary outcomes included PSA response rates, progression-free survival (PFS), overall survival (OS) and safety. Nine patients were enrolled. Gli1 mRNA was significantly suppressed by vismodegib in both tumor tissue (4/7 evaluable biopsies, 57%) and benign skin biopsies (6/8 evaluable biopsies, 75%). The median number of treatment cycles completed was three, with a median PFS of 1.9 months (95% CI 1.3, NA), and a median OS of 7.04 months (95% CI 3.4, NA). No patient achieved a PSA reduction or a measurable tumor response. Safety data were consistent with the known toxicities of vismodegib. Hh signaling, as measured by Gli1 mRNA expression in mCRPC tissues, was suppressed with vismodegib in the majority of patients. Despite this pharmacodynamic response that indicated target inhibition in some patients, there was no apparent signal of clinical activity. Vismodegib will not be developed further as monotherapy in mCRPC.

  18. Practical recommendations for radium-223 treatment of metastatic castration-resistant prostate cancer

    International Nuclear Information System (INIS)

    Du, Yong; Carrio, Ignasi; De Vincentis, Giuseppe; Fanti, Stefano; Ilhan, Harun; Mommsen, Caroline; Nitzsche, Egbert; Sundram, Francis; Vogel, Wouter; Oyen, Wim; Lewington, Val

    2017-01-01

    Radium Ra 223 dichloride (radium-223, Xofigo registered) is the first targeted alpha therapy for patients with castration-resistant prostate cancer and symptomatic bone metastases. Radium-223 provides a new treatment option for this setting, but also necessitates a new treatment management approach. We provide straightforward and practical recommendations for European nuclear medicine centres to optimize radium-223 service provision. An independent research consultancy agency observed radium-223 procedures and conducted interviews with all key staff members involved in radium-223 treatment delivery in 11 nuclear medicine centres across six countries (Germany, Italy, the Netherlands, Spain, Switzerland and the UK) experienced in administering radium-223. The findings were collated and discussed at a meeting of experts from these centres, during which key consensus recommendations were defined. The recommendations cover centre organization and preparation; patient referral; radium-223 ordering, preparation and disposal; radium-223 treatment delivery/administration; and patient experience. Guidance includes structured coordination and communication within centres and multidisciplinary teams, focusing on sharing best practice to provide high-quality, patient-centred care throughout the treatment pathway. These expert recommendations are intended to complement existing management guidelines. Sharing best practice and experience will help nuclear medicine centres to optimize radium-223 service provision and improve patient care. (orig.)

  19. Practical recommendations for radium-223 treatment of metastatic castration-resistant prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Du, Yong [The Royal Marsden NHS Foundation Trust, Department of Nuclear Medicine and PET/CT, London (United Kingdom); Carrio, Ignasi [Hospital Sant Pau, Barcelona (Spain); De Vincentis, Giuseppe [Policlinico Umberto I University Hospital Rome, Rome (Italy); Fanti, Stefano [University Hospital Bologna, Bologna (Italy); Ilhan, Harun [Ludwig-Maximilians-University Hospital, Munich (Germany); Mommsen, Caroline [Praxis fuer diagnostische und therapeutische Nuklearmedizin Berlin, Berlin (Germany); Nitzsche, Egbert [Canton Hospital Aarau, Aarau (Switzerland); Sundram, Francis [University Hospital Southampton NHS Foundation Trust, Southampton (United Kingdom); Vogel, Wouter [The Netherlands Cancer Institute, Amsterdam (Netherlands); Oyen, Wim [The Royal Marsden NHS Foundation Trust, Department of Nuclear Medicine and PET/CT, London (United Kingdom); The Institute of Cancer Research, London (United Kingdom); Lewington, Val [Guy' s and St Thomas' NHS Foundation Trust, London (United Kingdom)

    2017-09-15

    Radium Ra 223 dichloride (radium-223, Xofigo registered) is the first targeted alpha therapy for patients with castration-resistant prostate cancer and symptomatic bone metastases. Radium-223 provides a new treatment option for this setting, but also necessitates a new treatment management approach. We provide straightforward and practical recommendations for European nuclear medicine centres to optimize radium-223 service provision. An independent research consultancy agency observed radium-223 procedures and conducted interviews with all key staff members involved in radium-223 treatment delivery in 11 nuclear medicine centres across six countries (Germany, Italy, the Netherlands, Spain, Switzerland and the UK) experienced in administering radium-223. The findings were collated and discussed at a meeting of experts from these centres, during which key consensus recommendations were defined. The recommendations cover centre organization and preparation; patient referral; radium-223 ordering, preparation and disposal; radium-223 treatment delivery/administration; and patient experience. Guidance includes structured coordination and communication within centres and multidisciplinary teams, focusing on sharing best practice to provide high-quality, patient-centred care throughout the treatment pathway. These expert recommendations are intended to complement existing management guidelines. Sharing best practice and experience will help nuclear medicine centres to optimize radium-223 service provision and improve patient care. (orig.)

  20. SU-D-303-01: Spatial Distribution of Bone Metastases In Metastatic Castrate-Resistant Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Perk, T; Bradshaw, T; Harmon, S; Perlman, S; Liu, G; Jeraj, R [University of Wisconsin, Madison, WI (United States)

    2015-06-15

    Purpose: Identification of metastatic bone lesions is critical in prostate cancer, where treatments may be more effective in patients with fewer lesions. This study aims characterize the distribution and spread of bone lesions and create a probability map of metastatic spread in bone. Methods: Fifty-five metastatic castrate-resistant prostate cancer patients received up to 3 whole-body [F-18]NaF PET/CT scans. Lesions were identified by physician on PET/CT and contoured using a threshold of SUV>15. An atlas-based segmentation method was used to create CT regions, which determined skeletal location of lesions. Patients were divided into 3 groups with low (N<40), medium (40100) numbers of lesions. A combination of articulated and deformable registrations was used to register the skeletal segments and lesions of each patient to a single skeleton. All the lesion data was then combined to make a probability map. Results: A total of 4038 metastatic lesions (mean 74, range 2–304) were identified. Skeletal regions with highest occurrence of lesions included ribs, thoracic spine, and pelvis with 21%, 19%, and 15% of the total number lesions and 8%, 18%, and 31 % of the total lesion volume, respectively. Interestingly, patients with fewer lesions were found to have a lower proportion of lesions in the ribs (9% in low vs. 27% in high number of lesions). Additionally, the probability map showed specific areas in the spine and pelvis where over 75% of patients had metastases, and other areas in the skeleton with a less than 2% of metastases. Conclusion: We identified skeletal regions with higher incidence of metastases and specific sub-regions in the skeleton that had high or low probability of occurrence of metastases. Additionally, we found that metastatic lesions in the ribs and skull occur more commonly in advanced disease. These results may have future applications in computer-aided diagnosis. Funding from the Prostate Cancer Foundation.

  1. Docetaxel chemotherapy in metastatic castration-resistant prostate cancer: cost of care in Medicare and commercial populations.

    Science.gov (United States)

    Armstrong, A; Bui, C; Fitch, K; Sawhney, T Goss; Brown, B; Flanders, S; Balk, M; Deangelis, J; Chambers, J

    2017-06-01

    To estimate the healthcare costs and characteristics of docetaxel chemotherapy episodes of care for men with metastatic castration-resistant prostate cancer (mCRPC). This study used the Medicare 5% sample and MarketScan Commercial (2010-2013) claims data sets to identify men with mCRPC and initial episodes of docetaxel treatment. Docetaxel episodes included docetaxel claim costs from the first claim until 30 days after the last claim, with earlier termination for death, insurance disenrollment, or the end of a 24-month look-forward period from initial docetaxel index date. Docetaxel drug claim costs were adjusted for 2011 generic docetaxel introduction, while other costs were adjusted to 2015 values using the national average annual unit cost increase. This study identified 281 Medicare-insured and 155 commercially insured men, with 325 and 172 docetaxel episodes, respectively. The average number of cycles (unique docetaxel infusion days) per episode was 6.9 for Medicare and 6.3 for commercial cohorts. The average cost per episode was $28,792 for Medicare and $67,958 for commercial cohorts, with docetaxel drug costs contributing $2,588 and $13,169 per episode, respectively. The average cost per episode on docetaxel infusion days was $8,577 (30%) for Medicare and $28,412 (42%) for commercial. Non-docetaxel infusion day costs included $7,074 (25%) for infused or injected drugs for Medicare, $10,838 (16%) for commercial cohorts, and $6,875 (24%) and $9,324 (14%) for inpatient admissions, respectively. The applicability is only to the metastatic castration-resistance clinical setting, rather than the metastatic hormone-sensitive setting, and the lack of data on the cost effectiveness of different sequencing strategies of a range of systemic therapies including enzalutamide, abiraterone, radium-223, and taxane chemotherapy. The majority of docetaxel episode costs in Medicare and commercial mCRPC populations were non-docetaxel drug costs. Future research should evaluate

  2. Delayed response after repeated {sup 177}Lu-PSMA-617 radioligand therapy in patients with metastatic castration resistant prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Rahbar, Kambiz; Schaefers, Michael [University Hospital Muenster, Department of Nuclear Medicine, Muenster (Germany); Boegeman, Martin [University Hospital Muenster, Department of Urology, Muenster (Germany); Yordanova, Anna; Essler, Markus; Ahmadzadehfar, Hojjat [University Hospital Bonn, Department of Nuclear Medicine, Bonn (Germany); Eveslage, Maria [University Hospital Muenster, Institute for Biostatistics, Muenster (Germany)

    2018-02-15

    Radioligand therapy (RLT) using Lutetium-177 labeled PSMA-617 (Lu-PSMA) ligand is a new therapeutic option for salvage therapy in heavily pretreated patients with metastatic castration resistant prostate cancer. The aim of this retrospective study was to analyze response in patients receiving 3 cycles of Lu-PSMA. Seventy-one patients (median age: 72 years; range 44-87) received 3 cycles of RLT with Lu-PSMA (mean administered activity: 6.016 ± 0.543 GBq) every 8 weeks. Response was evaluated using serum PSA levels and a PSA decline ≥50% was considered as biochemical response. Additionally, any PSA decline after the first cycle was evaluated for further therapy effects after the second and third cycle. A total of 213 cycles were performed in 71 patients. Data for response and adverse events were available for all patients. A PSA decline ≥50% and some PSA decline occurred in 56% and 66% of the patients. Of 30 patients with a PSA response after the first cycle, 28 remained responders and 12/41 of non-responders responded to further therapy cycles. RLT with Lu-177-PSMA-617 shows respectable response rates. In this retrospective analysis, a relevant number of patients showed a delayed response, even if they did not respond to the first cycle of the therapy. (orig.)

  3. Radiographic progression with nonrising PSA in metastatic castration-resistant prostate cancer: post hoc analysis of PREVAIL.

    Science.gov (United States)

    Bryce, A H; Alumkal, J J; Armstrong, A; Higano, C S; Iversen, P; Sternberg, C N; Rathkopf, D; Loriot, Y; de Bono, J; Tombal, B; Abhyankar, S; Lin, P; Krivoshik, A; Phung, D; Beer, T M

    2017-06-01

    Advanced prostate cancer is a phenotypically diverse disease that evolves through multiple clinical courses. PSA level is the most widely used parameter for disease monitoring, but it has well-recognized limitations. Unlike in clinical trials, in practice, clinicians may rely on PSA monitoring alone to determine disease status on therapy. This approach has not been adequately tested. Chemotherapy-naive asymptomatic or mildly symptomatic men (n=872) with metastatic castration-resistant prostate cancer (mCRPC) who were treated with the androgen receptor inhibitor enzalutamide in the PREVAIL study were analyzed post hoc for rising versus nonrising PSA (empirically defined as >1.05 vs ⩽1.05 times the PSA level from 3 months earlier) at the time of radiographic progression. Clinical characteristics and disease outcomes were compared between the rising and nonrising PSA groups. Of 265 PREVAIL patients with radiographic progression and evaluable PSA levels on the enzalutamide arm, nearly one-quarter had a nonrising PSA. Median progression-free survival in this cohort was 8.3 months versus 11.1 months in the rising PSA cohort (hazard ratio 1.68; 95% confidence interval 1.26-2.23); overall survival was similar between the two groups, although less than half of patients in either group were still at risk at 24 months. Baseline clinical characteristics of the two groups were similar. Non-rising PSA at radiographic progression is a common phenomenon in mCRPC patients treated with enzalutamide. As restaging in advanced prostate cancer patients is often guided by increases in PSA levels, our results demonstrate that disease progression on enzalutamide can occur without rising PSA levels. Therefore, a disease monitoring strategy that includes imaging not entirely reliant on serial serum PSA measurement may more accurately identify disease progression.

  4. Progression of metastatic castrate-resistant prostate cancer: impact of therapeutic intervention in the post-docetaxel space

    Directory of Open Access Journals (Sweden)

    Sartor A Oliver

    2011-04-01

    Full Text Available Abstract Despite the proven success of hormonal therapy for prostate cancer using chemical or surgical castration, most patients eventually will progress to a phase of the disease that is metastatic and shows resistance to further hormonal manipulation. This has been termed metastatic castrate-resistant prostate cancer (mCRPC. Despite this designation, however, there is evidence that androgen receptor (AR-mediated signaling and gene expression can persist in mCRPC, even in the face of castrate levels of androgen. This may be due in part to the upregulation of enzymes involved in androgen synthesis, the overexpression of AR, or the emergence of mutant ARs with promiscuous recognition of various steroidal ligands. The therapeutic options were limited and palliative in nature until trials in 2004 demonstrated that docetaxel chemotherapy could significantly improve survival. These results established first-line docetaxel as the standard of care for mCRPC. After resistance to further docetaxel therapy develops, treatment options were once again limited. Recently reported results from phase 3 trials have shown that additional therapy with the novel taxane cabazitaxel (with prednisone, or treatment with the antiandrogen abiraterone (with prednisone could improve survival for patients with mCRPC following docetaxel therapy. Compared with mitoxantrone/prednisone, cabazitaxel/prednisone significantly improved overall survival, with a 30% reduction in rate of death, in patients with progression of mCRPC after docetaxel therapy in the TROPIC trial. Similarly, abiraterone acetate (an inhibitor of androgen biosynthesis plus prednisone significantly decreased the rate of death by 35% compared with placebo plus prednisone in mCRPC patients progressing after prior docetaxel therapy in the COU-AA-301 trial. Results of these trials have thus established two additional treatment options for mCRPC patients in the "post-docetaxel space." In view of the continued AR

  5. Castration-resistant prostate cancer: AUA Guideline.

    Science.gov (United States)

    Cookson, Michael S; Roth, Bruce J; Dahm, Philipp; Engstrom, Christine; Freedland, Stephen J; Hussain, Maha; Lin, Daniel W; Lowrance, William T; Murad, Mohammad Hassan; Oh, William K; Penson, David F; Kibel, Adam S

    2013-08-01

    This Guideline is intended to provide a rational basis for the management of patients with castration-resistant prostate cancer based on currently available published data. A systematic review and meta-analysis of the published literature was conducted using controlled vocabulary supplemented with keywords relating to the relevant concepts of prostate cancer and castration resistance. The search strategy was developed and executed by reference librarians and methodologists to create an evidence report limited to English-language, published peer-reviewed literature. This review yielded 303 articles published from 1996 through 2013 that were used to form a majority of the guideline statements. Clinical Principles and Expert Opinions were used for guideline statements lacking sufficient evidence-based data. Guideline statements were created to inform clinicians on the appropriate use of observation, androgen-deprivation and antiandrogen therapy, androgen synthesis inhibitors, immunotherapy, radionuclide therapy, systemic chemotherapy, palliative care and bone health. These were based on six index patients developed to represent the most common scenarios encountered in clinical practice. As a direct result of the significant increase in FDA-approved therapeutic agents for use in patients with metastatic CRPC, clinicians are challenged with a multitude of treatment options and potential sequencing of these agents that, consequently, make clinical decision-making more complex. Given the rapidly evolving nature of this field, this guideline should be used in conjunction with recent systematic literature reviews and an understanding of the individual patient's treatment goals. In all cases, patients' preferences and personal goals should be considered when choosing management strategies. Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  6. Enzalutamide Antitumour Activity Against Metastatic Castration-resistant Prostate Cancer Previously Treated with Docetaxel and Abiraterone

    DEFF Research Database (Denmark)

    Brasso, Klaus; Thomsen, Frederik B; Schrader, Andres J

    2015-01-01

    prostate-specific antigen (PSA) kinetics, patient characteristics, and progression-free survival, respectively. Kaplan-Meier survival analysis and Cox proportional hazard analysis were performed. RESULTS AND LIMITATIONS: We identified 137 patients who prior to enzalutamide had progressed following a median...... of eight cycles of docetaxel and seven courses of abiraterone. The median time on enzalutamide was 3.2 mo; median OS from the time patients started enzalutamide was 8.3 mo (95% confidence interval, 6.8-9.8). Only 45 (38%) and 22 (18%) patients had PSA declines (unconfirmed) >30% and 50%, respectively....... Patients who had more than 30% or 50% falls in PSA had improved survival compared with patients who had no such PSA fall (11.4 mo vs 7.1 mo; p=0.001 and 12.6 vs 7.4 mo; p=0.007, respectively). Poor performance status and low haemoglobin was negatively associated with OS. CONCLUSIONS: Median OS...

  7. 177Lu-DKFZ-PSMA-617 therapy in metastatic castration resistant prostate cancer: safety, efficacy, and quality of life assessment

    International Nuclear Information System (INIS)

    Yadav, Madhav Prasad; Ballal, Sanjana; Tripathi, Madhavi; Damle, Nishikant Avinash; Bal, Chandrasekhar; Sahoo, Ranjit Kumar; Seth, Amlesh

    2017-01-01

    The purpose of this study was to evaluate the efficacy and safety of a novel theranostic agent, 177 Lu-DKFZ-PSMA-617 therapy in metastatic castration resistant prostate cancer (mCRPC). Thirty-one mCRPC patients with progressive disease despite second-line hormonal therapy and/or docetaxel chemotherapy were recruited for the study. All patients underwent diagnostic 68 Ga-PSMA-HBED-CCPET/CT, prior to inclusion for therapy. Included patients then underwent quarterly 177 Lu-DKFZ-PSMA-617 therapy. Hematological, kidney function, liver function tests, and serum PSA levels were recorded before and after therapy at 2 weeks, 4 weeks, and 3 month intervals. Biochemical response was assessed with trend in serum PSA levels. Metabolic response was assessed by PERCIST 1 criteria. Clinical response was assessed by visual analogue score (VASmax) analgesic score (AS), Karanofsky performance status (KPS), and toxicity and response criteria of the Eastern Cooperative Oncology Group (ECOG) criteria. The mean age of patients was 65.93 ± 9.77 years (range: 38-81 years). The mean activity administered in the 31 patients was 5069 ± 1845 MBq ranging from one to four cycles. There was a decline in the mean serum PSA levels from the baseline (baseline: 275 ng/mL, post 1st cycle therapy: 141.75 ng/mL). Based on biochemical response criteria 2/31, 20/31, 3/31, and 6/31 had complete response (CR), partial response(PR), stable disease (SD), and progressive disease (PD), respectively. Metabolic response revealed 2/6 patients with CR, and the remaining 3/6 patients with PR and 1/6 patients with SD. The mean VASmax score decreased from 7.5 to 3. The mean analgesic score decreased from 2.5 to 1.8 after therapy. The mean KPS score improved from 50.32 to 65.42 after therapies. The mean ECOG performance status improved from 2.54 to 1.78 after therapy. Two patients experienced grade I and grade II hemoglobin toxicity each. None of the patients experienced nephrotoxicity or hepatotoxicity. 177 Lu

  8. Impact of body composition parameters on clinical outcomes in patients with metastatic castrate-resistant prostate cancer treated with docetaxel.

    Science.gov (United States)

    Cushen, Samantha J; Power, Derek G; Murphy, Kevin P; McDermott, Ray; Griffin, Brendan T; Lim, Marvin; Daly, Louise; MacEneaney, Peter; O' Sullivan, Kathleen; Prado, Carla M; Ryan, Aoife M

    2016-06-01

    Body composition may influence clinical outcomes of certain chemotherapeutic agents. We examined the prognostic significance of skeletal muscle mass and adipose tissue on docetaxel toxicity and overall survival in patients with metastatic castrate resistant prostate cancer (mCRPC). A retrospective review of patients medical records with mCRPC, treated with docetaxel was conducted. Body composition parameters (skeletal muscle mass, muscle attenuation [MA], visceral and subcutaneous adipose tissue) were measured at L3 by computed tomography (CT) and defined using previously established cut points. Toxicity profile was assessed after 3 cycles of the drug and graded according to the National Cancer Institute Common Toxicity Criteria (version 4). Overall survival was analysed. Overall 63 patients, mean age 69 years (SD 8.3), were included. Sarcopenia was present in 47% (n = 30) and of these 26.7% (8/30) were sarcopenic obese. Common toxicities (all grades) observed included fatigue (80.9%), pain (46%), and constipation (34.9%). DLT occurred in 22 (34.9%) patients; of these 10 patients (15.8%) experienced dose reductions and 12 patients (19%) experienced dose terminations. Measurements of adiposity were not predictive of DLT, however 59.1% patients who had a combination of both sarcopenia and low MA experienced DLT compared to 29.3% of patients without sarcopenia and low MA (p = 0.021). Skeletal muscle index and MA were significantly lower in patients who experienced neutropenia (grade I-II) (46.5 cm 2 /m 2 vs. 51.2 cm 2 /m 2 , p = 0.005) compared to their counterparts (24.6 HU vs. 32.2 HU, p = 0.044). Neither sarcopenia nor sarcopenic obesity was associated with overall survival. In multivariate analysis, BMI ≥25 kg/m 2 (HR: 0.349, CI: 0.156-0.782, p = 0.010) was a significant predictor of longer overall survival and both visceral fat index ≥ median 58.7 cm 2 /m 2 (HR: 2.266 CI: 1.066-4.814, p = 0.033) and anaemia (HR: 2.81, CI: 1.297-6.091, p

  9. Enzalutamide in Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer: Extended Analysis of the Phase 3 PREVAIL Study.

    Science.gov (United States)

    Beer, Tomasz M; Armstrong, Andrew J; Rathkopf, Dana; Loriot, Yohann; Sternberg, Cora N; Higano, Celestia S; Iversen, Peter; Evans, Christopher P; Kim, Choung-Soo; Kimura, Go; Miller, Kurt; Saad, Fred; Bjartell, Anders S; Borre, Michael; Mulders, Peter; Tammela, Teuvo L; Parli, Teresa; Sari, Suha; van Os, Steve; Theeuwes, Ad; Tombal, Bertrand

    2017-02-01

    Enzalutamide significantly improved radiographic progression-free survival (rPFS) and overall survival (OS) among men with chemotherapy-naïve metastatic castration-resistant prostate cancer at the prespecified interim analysis of PREVAIL, a phase 3, double-blind, randomized study. We evaluated the longer-term efficacy and safety of enzalutamide up to the prespecified number of deaths in the final analysis, which included an additional 20 mo of follow-up for investigator-assessed rPFS, 9 mo of follow-up for OS, and 4 mo of follow-up for safety. Enzalutamide reduced the risk of radiographic progression or death by 68% (hazard ratio [HR] 0.32, 95% confidence interval [CI] 0.28-0.37; pPREVAIL provides more complete assessment of the clinical benefit of enzalutamide. PREVAIL is registered on ClinicalTrials.gov as NCT01212991. According to data from longer follow-up, enzalutamide continued to provide benefit over placebo in patients with metastatic castration-resistant prostate cancer. Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

  10. Castration-resistant prostate cancer: systemic therapy in 2012

    Directory of Open Access Journals (Sweden)

    Fernando C. Maluf

    2012-01-01

    Full Text Available Prostate cancer is the most common non-cutaneous neoplasm in the male population worldwide. It is typically diagnosed in its early stages, and the disease exhibits a relatively indolent course in most patients. Despite the curability of localized disease with prostatectomy and radiation therapy, some patients develop metastatic disease and die. Although androgen deprivation is present in the majority of patients with metastatic prostate cancer, a state of androgen resistance eventually develops. Castration-resistant prostate cancer, defined when there is progression of disease despite low levels of testosterone, requires specialized care, and improved communication between medical and urologic oncologists has been identified as a key component in delivering effective therapy. Despite being considered a chemoresistant tumor in the past, the use of a prostate-specific antigen has paved the way for a new generation of trials for castration-resistant prostate cancer. Docetaxel is a life-prolonging chemotherapy that has been established as the standard first-line agent in two phase III clinical trials. Cabazitaxel, a novel taxane with activity in cancer models resistant to paclitaxel and docetaxel, is the only agent that has been compared to a chemotherapy control in a phase III clinical trial as a second-line therapy; it was found to prolong the overall survival of patients with castration-resistant prostate cancer previously treated with docetaxel when compared to mitoxantrone. Other agents used in this setting include abiraterone and sipuleucel-T, and novel therapies are continually being investigated in an attempt to improve the outcome for patients with castration-resistant prostate cancer.

  11. Evaluation of Tumor Viability for Primary and Bone Metastases in Metastatic Castration-Resistant Prostate Cancer Using Whole-Body Magnetic Resonance Imaging

    Directory of Open Access Journals (Sweden)

    Hiromichi Iwamura

    2018-01-01

    Full Text Available In contrast to bone scan and computed tomography (CT, which depend on osteoblastic response to detect bone metastasis, whole-body magnetic resonance imaging (WB-MRI may be able to directly detect viable tumors. A 75-year-old male who had progressive metastatic prostate cancer during primary androgen deprivation therapy was referred to our hospital. Although bone scan and CT showed multiple bone metastases, WB-MRI suggested nonviable bone metastasis and viable tumor of the primary lesion. Prostate needle biopsy demonstrated viable prostate cancer cells from 10 of 12 cores. In contrast, CT-guided needle biopsy from bone metastasis of the lumbar vertebra revealed no malignant cells. Based on these findings, we reasoned that viable tumor cells inducing disease progression may primarily exist in the primary lesions and not in the metastatic lesions, and combined prostate radiotherapy and systemic hormonal therapy resulted in successful clinical response and disease control. The use of WB-MRI to detect viable disease lesions may enable us to design optimal treatment strategies for patients with metastatic castration-resistant prostate cancer.

  12. Prediction of overall survival for patients with metastatic castration-resistant prostate cancer: development of a prognostic model through a crowdsourced challenge with open clinical trial data.

    Science.gov (United States)

    Guinney, Justin; Wang, Tao; Laajala, Teemu D; Winner, Kimberly Kanigel; Bare, J Christopher; Neto, Elias Chaibub; Khan, Suleiman A; Peddinti, Gopal; Airola, Antti; Pahikkala, Tapio; Mirtti, Tuomas; Yu, Thomas; Bot, Brian M; Shen, Liji; Abdallah, Kald; Norman, Thea; Friend, Stephen; Stolovitzky, Gustavo; Soule, Howard; Sweeney, Christopher J; Ryan, Charles J; Scher, Howard I; Sartor, Oliver; Xie, Yang; Aittokallio, Tero; Zhou, Fang Liz; Costello, James C

    2017-01-01

    Improvements to prognostic models in metastatic castration-resistant prostate cancer have the potential to augment clinical trial design and guide treatment strategies. In partnership with Project Data Sphere, a not-for-profit initiative allowing data from cancer clinical trials to be shared broadly with researchers, we designed an open-data, crowdsourced, DREAM (Dialogue for Reverse Engineering Assessments and Methods) challenge to not only identify a better prognostic model for prediction of survival in patients with metastatic castration-resistant prostate cancer but also engage a community of international data scientists to study this disease. Data from the comparator arms of four phase 3 clinical trials in first-line metastatic castration-resistant prostate cancer were obtained from Project Data Sphere, comprising 476 patients treated with docetaxel and prednisone from the ASCENT2 trial, 526 patients treated with docetaxel, prednisone, and placebo in the MAINSAIL trial, 598 patients treated with docetaxel, prednisone or prednisolone, and placebo in the VENICE trial, and 470 patients treated with docetaxel and placebo in the ENTHUSE 33 trial. Datasets consisting of more than 150 clinical variables were curated centrally, including demographics, laboratory values, medical history, lesion sites, and previous treatments. Data from ASCENT2, MAINSAIL, and VENICE were released publicly to be used as training data to predict the outcome of interest-namely, overall survival. Clinical data were also released for ENTHUSE 33, but data for outcome variables (overall survival and event status) were hidden from the challenge participants so that ENTHUSE 33 could be used for independent validation. Methods were evaluated using the integrated time-dependent area under the curve (iAUC). The reference model, based on eight clinical variables and a penalised Cox proportional-hazards model, was used to compare method performance. Further validation was done using data from a

  13. A genetic variant in SLC28A3, rs56350726, is associated with progression to castration-resistant prostate cancer in a Korean population with metastatic prostate cancer.

    Science.gov (United States)

    Jo, Jung Ku; Oh, Jong Jin; Kim, Yong Tae; Moon, Hong Sang; Choi, Hong Yong; Park, Seunghyun; Ho, Jin-Nyoung; Yoon, Sungroh; Park, Hae Young; Byun, Seok-Soo

    2017-11-14

    Genetic variation which related with progression to castration-resistant prostate cancer (CRPC) during androgen-deprivation therapy (ADT) has not been elucidated in patients with metastatic prostate cancer (mPCa). Therefore, we assessed the association between genetic variats in mPCa and progession to CRPC. Analysis of exome genotypes revealed that 42 SNPs were significantly associated with mPCa. The top five polymorphisms were statistically significantly associated with metastatic disease. In addition, one of these SNPs, rs56350726, was significantly associated with time to CRPC in Kaplan-Meier analysis (Log-rank test, p = 0.011). In multivariable Cox regression, rs56350726 was strongly associated with progression to CRPC (HR = 4.172 95% CI = 1.223-14.239, p = 0.023). We assessed genetic variation among 1000 patients with PCa with or without metastasis, using 242,221 single nucleotide polymorphisms (SNPs) on the custom HumanExome BeadChip v1.0 (Illuminam Inc.). We analyzed the time to CRPC in 110 of the 1000 patients who were treated with ADT. Genetic data were analyzed using unconditional logistic regression and odds ratios calculated as estimates of relative risk of metastasis. We identified SNPs associated with metastasis and analyzed the relationship between these SNPs and time to CRPC in mPCa. Based on a genetic variation, the five top SNPs were observed to associate with mPCa. And one (SLC28A3, rs56350726) of five SNP was found the association with the progression to CRPC in patients with mPCa.

  14. Clinical outcomes and survival surrogacy studies of prostate-specific antigen declines following enzalutamide in men with metastatic castration-resistant prostate cancer previously treated with docetaxel.

    Science.gov (United States)

    Armstrong, Andrew J; Saad, Fred; Phung, De; Dmuchowski, Carl; Shore, Neal D; Fizazi, Karim; Hirmand, Mohammad; Forer, David; Scher, Howard I; Bono, Johann De

    2017-06-15

    In the AFFIRM trial, enzalutamide significantly increased overall survival (OS) for men with metastatic castration-resistant prostate cancer (mCRPC) after chemotherapy versus placebo and significantly decreased prostate-specific antigen (PSA) levels. The goal of this post hoc analysis was to associate levels of PSA decline from baseline after enzalutamide with clinical outcomes in the postchemotherapy mCRPC setting. Men in the AFFIRM trial (n = 1199) were grouped by maximal PSA decline in the first 90 days of treatment. Kaplan-Meier estimates evaluated the association of defined PSA changes from baseline with OS, progression-free survival (PFS), radiographic PFS (rPFS), and pain response. Each PSA decline category was assessed for OS surrogacy using Prentice criteria, proportion of treatment effect explained (PTE), and proportion of variation explained. Men treated with enzalutamide had improved OS (hazard ratio, 0.63; P 19.0; P .20). PSA declines of any, ≥30%, and ≥50% following enzalutamide were associated with greater clinical and pain response and improvements in PFS and OS. Surrogacy of PSA decline for OS was not fully established, possibly due to lack of PSA declines with placebo, and discordant results between PSA and imaging responses over time, and because some declines were not durable due to rapid resistance development. However, a lack of PSA decline by 90 days following enzalutamide treatment was a poor prognosis indicator in this setting. Conclusions from sensitivity analyses of maximal PSA decline from baseline over the entire treatment period are consistent with PSA declines restricted to the first 90 days. Cancer 2017;123:2303-2311. © 2017 American Cancer Society. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

  15. Radiographic Progression-Free Survival as a Clinically Meaningful End Point in Metastatic Castration-Resistant Prostate Cancer: The PREVAIL Randomized Clinical Trial.

    Science.gov (United States)

    Rathkopf, Dana E; Beer, Tomasz M; Loriot, Yohann; Higano, Celestia S; Armstrong, Andrew J; Sternberg, Cora N; de Bono, Johann S; Tombal, Bertrand; Parli, Teresa; Bhattacharya, Suman; Phung, De; Krivoshik, Andrew; Scher, Howard I; Morris, Michael J

    2018-05-01

    Drug development for metastatic castration-resistant prostate cancer has been limited by a lack of clinically relevant trial end points short of overall survival (OS). Radiographic progression-free survival (rPFS) as defined by the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) is a candidate end point that represents a clinically meaningful benefit to patients. To demonstrate the robustness of the PCWG2 definition and to examine the relationship between rPFS and OS. PREVAIL was a phase 3, randomized, double-blind, placebo-controlled multinational study that enrolled 1717 chemotherapy-naive men with metastatic castration-resistant prostate cancer from September 2010 through September 2012. The data were analyzed in November 2016. Patients were randomized 1:1 to enzalutamide 160 mg or placebo until confirmed radiographic disease progression or a skeletal-related event and initiation of either cytotoxic chemotherapy or an investigational agent for prostate cancer treatment. Sensitivity analyses (SAs) of investigator-assessed rPFS were performed using the final rPFS data cutoff (May 6, 2012; 439 events; SA1) and the interim OS data cutoff (September 16, 2013; 540 events; SA2). Additional SAs using investigator-assessed rPFS from the final rPFS data cutoff assessed the impact of skeletal-related events (SA3), clinical progression (SA4), a confirmatory scan for soft-tissue disease progression (SA5), and all deaths regardless of time after study drug discontinuation (SA6). Correlations between investigator-assessed rPFS (SA2) and OS were calculated using Spearman ρ and Kendall τ via Clayton copula. In the 1717 men (mean age, 72.0 [range, 43.0-93.0] years in enzalutamide arm and 71.0 [range, 42.0-93.0] years in placebo arm), enzalutamide significantly reduced risk of radiographic progression or death in all SAs, with hazard ratios of 0.22 (SA1; 95% CI, 0.18-0.27), 0.31 (SA2; 95% CI, 0.27-0.35), 0.21 (SA3; 95% CI, 0.18-0.26), 0.21 (SA4; 95% CI, 0.17-0.26), 0

  16. Phenotypic and genetic heterogeneity of tumor tissue and circulating tumor cells in patients with metastatic castration-resistant prostate cancer: A report from the PETRUS prospective study.

    Science.gov (United States)

    Massard, Christophe; Oulhen, Marianne; Le Moulec, Sylvestre; Auger, Nathalie; Foulon, Stéphanie; Abou-Lovergne, Aurélie; Billiot, Fanny; Valent, Alexander; Marty, Virginie; Loriot, Yohann; Fizazi, Karim; Vielh, Philippe; Farace, Francoise

    2016-08-23

    Molecular characterization of cancer samples is hampered by tumor tissue availability in metastatic castration-resistant prostate cancer (mCRPC) patients. We reported the results of prospective PETRUS study of biomarker assessment in paired primary prostatic tumors, metastatic biopsies and circulating tumor cells (CTCs). Among 54 mCRPC patients enrolled, 38 (70%) had biopsies containing more than 50% tumour cells. 28 (52%) patients were analyzed for both tissue samples and CTCs. FISH for AR-amplification and TMPRSS2-ERG translocation were successful in 54% and 32% in metastatic biopsies and primary tumors, respectively. By comparing CellSearch and filtration (ISET)-enrichment combined to four color immunofluorescent staining, we showed that CellSearch and ISET isolated distinct subpopulations of CTCs: CTCs undergoing epithelial-to-mesenchymal transition, CTC clusters and large CTCs with cytomorphological characteristics but no detectable markers were isolated using ISET. Epithelial CTCs detected by the CellSearch were mostly lost during the ISET-filtration. AR-amplification was detected in CellSearch-captured CTCs, but not in ISET-enriched CTCs which harbor exclusively AR gain of copies. Eighty-eight percent concordance for ERG-rearrangement was observed between metastatic biopsies and CTCs even if additional ERG-alteration patterns were detected in ISET-enriched CTCs indicating a higher heterogeneity in CTCs.Molecular screening of metastatic biopsies is achievable in a multicenter context. Our data indicate that CTCs detected by the CellSearch and the ISET-filtration systems are not only phenotypically but also genetically different. Close attention must be paid to CTC characterization since neither approach tested here fully reflects the tremendous phenotypic and genetic heterogeneity present in CTCs from mCRPC patients.

  17. Overview of treatment of castration-resistant prostate cancer

    International Nuclear Information System (INIS)

    Obertova, J.

    2012-01-01

    Prostatic cancer is a very heterogenic disease. Initial treatment of metastatic disease is androgen deprivation therapy, however upon the time eventually all cases develop castrate resistant disease (CRCP). In CRPC the combination of docetaxel with prednisone is considered to be the gold standard first line therapy with prolongation of overall survival. Until recently there was not standardly defined second line treatment. According to the international guidelines of today cabazitaxel and abirateron is recommended as second line therapy. The objective of this article is to present a review of the therapy of CRPC upon results from randomised phase III clinical trials. (author)

  18. Custirsen in combination with docetaxel and prednisone for patients with metastatic castration-resistant prostate cancer (SYNERGY trial): a phase 3, multicentre, open-label, randomised trial.

    Science.gov (United States)

    Chi, Kim N; Higano, Celestia S; Blumenstein, Brent; Ferrero, Jean-Marc; Reeves, James; Feyerabend, Susan; Gravis, Gwenaelle; Merseburger, Axel S; Stenzl, Arnulf; Bergman, Andries M; Mukherjee, Som D; Zalewski, Pawel; Saad, Fred; Jacobs, Cindy; Gleave, Martin; de Bono, Johann S

    2017-04-01

    Clusterin is a chaperone protein associated with treatment resistance and upregulated by apoptotic stressors such as chemotherapy. Custirsen is a second-generation antisense oligonucleotide that inhibits clusterin production. The aim of the SYNERGY trial was to investigate the effect of custirsen in combination with docetaxel and prednisone on overall survival in patients with metastatic castration-resistant prostate cancer. SYNERGY was a phase 3, multicentre, open-label, randomised trial set at 134 study centres in 12 countries. Patients were eligible for participation if they had: metastatic castration-resistant prostate cancer and had received no previous chemotherapy; prostate-specific antigen greater than 5 ng/mL; and a Karnofsky performance score of 70% or higher. Patients were randomly assigned 1:1 centrally to either the docetaxel, prednisone, and custirsen combination or docetaxel and prednisone alone. Patients were not masked to treatment allocation. Randomisation was stratified by opioid use for cancer-related pain and radiographic evidence of progression. All patients received docetaxel 75 mg/m 2 intravenously with 5 mg of prednisone orally twice daily. Patients assigned docetaxel, prednisone, and custirsen received weekly doses of custirsen 640 mg intravenously after three loading doses of 640 mg. The primary endpoint was overall survival analysed in the intention-to-treat population. Patients who received at least one study dose were included in the safety analysis set. This trial is registered with ClinicalTrials.gov, number NCT01188187. The trial is completed and final analyses are reported here. Between Dec 10, 2010, and Nov 7, 2012, 1022 patients were enrolled to the trial, of whom 510 were assigned docetaxel, prednisone, and custirsen and 512 were allocated docetaxel and prednisone. No difference in overall survival was recorded between the two groups (median survival 23·4 months [95% CI 20·9-24·8] with docetaxel, prednisone, and custirsen vs

  19. Nuclear-specific AR-V7 Protein Localization is Necessary to Guide Treatment Selection in Metastatic Castration-resistant Prostate Cancer.

    Science.gov (United States)

    Scher, Howard I; Graf, Ryon P; Schreiber, Nicole A; McLaughlin, Brigit; Lu, David; Louw, Jessica; Danila, Daniel C; Dugan, Lyndsey; Johnson, Ann; Heller, Glenn; Fleisher, Martin; Dittamore, Ryan

    2017-06-01

    Circulating tumor cells (CTCs) expressing AR-V7 protein localized to the nucleus (nuclear-specific) identify metastatic castration-resistant prostate cancer (mCRPC) patients with improved overall survival (OS) on taxane therapy relative to the androgen receptor signaling inhibitors (ARSi) abiraterone acetate, enzalutamide, and apalutamide. To evaluate if expanding the positivity criteria to include both nuclear and cytoplasmic AR-V7 localization ("nuclear-agnostic") identifies more patients who would benefit from a taxane over an ARSi. The study used a cross-sectional cohort. Between December 2012 and March 2015, 193 pretherapy blood samples, 191 of which were evaluable, were collected and processed from 161 unique mCRPC patients before starting a new line of systemic therapy for disease progression at the Memorial Sloan Kettering Cancer Center. The association between two AR-V7 scoring criteria, post-therapy prostate-specific antigen (PSA) change (PTPC) and OS following ARSi or taxane treatment, was explored. One criterion required nuclear-specific AR-V7 localization, and the other required an AR-V7 signal but was agnostic to protein localization in CTCs. Correlation of AR-V7 status to PTPC and OS was investigated. Relationships with survival were analyzed using multivariable Cox regression and log-rank analyses. A total of 34 (18%) samples were AR-V7-positive using nuclear-specific criteria, and 56 (29%) were AR-V7-positive using nuclear-agnostic criteria. Following ARSi treatment, none of the 16 nuclear-specific AR-V7-positive samples and six of the 32 (19%) nuclear-agnostic AR-V7-positive samples had ≥50% PTPC at 12 weeks. The strongest baseline factor influencing OS was the interaction between the presence of nuclear-specific AR-V7-positive CTCs and treatment with a taxane (hazard ratio 0.24, 95% confidence interval 0.078-0.79; p=0.019). This interaction was not significant when nuclear-agnostic criteria were used. To reliably inform treatment selection

  20. Skeletal-related events significantly impact health-related quality of life in metastatic castration-resistant prostate cancer: data from PREVAIL and AFFIRM trials.

    Science.gov (United States)

    Saad, F; Ivanescu, C; Phung, D; Loriot, Y; Abhyankar, S; Beer, T M; Tombal, B; Holmstrom, S

    2017-03-01

    We investigated the impact of skeletal-related events (SREs) on health-related quality of life (HRQoL) in patients with metastatic castration-resistant prostate cancer (mCRPC) in phase III trials of enzalutamide versus placebo. Patients with mCRPC experiencing at least one SRE during AFFIRM and PREVAIL were assessed for trajectory-adjusted mean change in HRQoL by first SRE using Functional Assessment of Cancer Therapy-Prostate (FACT-P; AFFIRM, three domains, and PREVAIL, nine domains) and EQ-5D (PREVAIL) instruments. First SREs caused HRQoL deterioration in both trials. Spinal cord compression had the largest impact, with clinically meaningful reductions in seven of nine FACT-P domains in PREVAIL and all three in AFFIRM (mean (95% confidence interval (CI)) change in FACT-P total score -16.95 (-26.47, -7.44) and -9.69 (-16.10, -3.27), respectively). In PREVAIL, first SREs caused clinically meaningful declines in EQ-5D utility index, irrespective of category; spinal cord compression had the largest impact (mean (95% CI) change -0.24 (-0.39, -0.08)). In AFFIRM, FACT-P and FACT-General total scores showed clinically meaningful declines after radiation/surgery to bone. SREs were associated with clinically meaningful functional declines in the daily lives of patients with mCRPC. Spinal cord compression had the largest impact on HRQoL.

  1. The PREVAIL Study: Primary Outcomes by Site and Extent of Baseline Disease for Enzalutamide-treated Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer.

    Science.gov (United States)

    Evans, Christopher P; Higano, Celestia S; Keane, Thomas; Andriole, Gerald; Saad, Fred; Iversen, Peter; Miller, Kurt; Kim, Choung-Soo; Kimura, Go; Armstrong, Andrew J; Sternberg, Cora N; Loriot, Yohann; de Bono, Johann; Noonberg, Sarah B; Mansbach, Hank; Bhattacharya, Suman; Perabo, Frank; Beer, Tomasz M; Tombal, Bertrand

    2016-10-01

    Enzalutamide, an oral androgen receptor inhibitor, significantly improved overall survival (OS) and radiographic progression-free survival (rPFS) versus placebo in the PREVAIL trial of men with chemotherapy-naïve metastatic castration-resistant prostate cancer. To assess the effects of enzalutamide versus placebo in patients from PREVAIL based on site and extent of baseline disease. One thousand seven hundred and seventeen asymptomatic or minimally symptomatic patients were randomized to enzalutamide (n=872) or placebo (n=845). Subgroup analyses included nonvisceral (only bone and/or nodal; n=1513), visceral (lung and/or liver; n=204), low-volume bone disease (1 in patients with visceral disease (HR, 0.82; 95% CI, 0.55-1.23). Enzalutamide was well tolerated in patients with or without visceral disease. Enzalutamide provided clinically significant benefits in men with chemotherapy-naïve metastatic castration-resistant prostate cancer, with or without visceral disease, low- or high-volume bone disease, or lymph node only disease. Patients with metastatic castration-resistant prostate cancer-including those with or without visceral disease or widespread bone disease-benefitted from enzalutamide, an active well-tolerated therapy. Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

  2. TRAF4 and Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2017-10-01

    AWARD NUMBER: W81XWH-15-1-0536 TITLE: TRAF4 and Castration-Resistant Prostate Cancer PRINCIPAL INVESTIGATOR: Ping Yi CONTRACTING...Castration Resistant prostate cancer 5b. GRANT NUMBER W81XWH-15-1-0536 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Ping Yi 5d. PROJECT NUMBER 5e. TASK...to be a critical player in castration-resistant prostate cancers . It was suggested that the function of AR in CRPC is not to turn on the same

  3. Effect of Visceral Disease Site on Outcomes in Patients With Metastatic Castration-resistant Prostate Cancer Treated With Enzalutamide in the PREVAIL Trial.

    Science.gov (United States)

    Alumkal, Joshi J; Chowdhury, Simon; Loriot, Yohann; Sternberg, Cora N; de Bono, Johann S; Tombal, Bertrand; Carles, Joan; Flaig, Thomas W; Dorff, Tanya B; Phung, De; Forer, David; Noonberg, Sarah B; Mansbach, Hank; Beer, Tomasz M; Higano, Celestia S

    2017-10-01

    The Multinational Phase 3, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of Oral MDV3100 in Chemotherapy-Naive Patients With Progressive Metastatic Prostate Cancer Who Have Failed Androgen Deprivation Therapy (PREVAIL) trial was unique as it included patients with visceral disease. This analysis was designed to describe outcomes for the subgroup of men from PREVAIL with specific sites of visceral disease to help clinicians understand how these patients responded to enzalutamide prior to chemotherapy. Prespecified analyses examined the coprimary endpoints of radiographic progression-free survival (rPFS) and overall survival (OS) only. All other efficacy analyses were post hoc. The visceral subgroup was divided into liver or lung subsets. Patients with both liver and lung metastases were included in the liver subset. Of the 1717 patients in PREVAIL, 204 (12%) had visceral metastases at screening (liver only or liver/lung metastases, n = 74; lung only metastases, n = 130). In patients with liver metastases, enzalutamide was associated with an improvement in rPFS (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.22-0.90) but not OS (HR, 1.04; 95% CI, 0.57-1.87). In patients with lung metastases only, the HR for rPFS (0.14; 95% CI, 0.06-0.36) and the HR for OS (0.59; 95% CI, 0.33-1.06) favored enzalutamide over placebo. Patients with liver metastases had worse outcomes than those with lung metastases, regardless of treatment. Enzalutamide was well tolerated in patients with visceral disease. Enzalutamide is an active first-line treatment option for men with asymptomatic or mildly symptomatic chemotherapy-naive metastatic castration-resistant prostate cancer and visceral disease. Patients with lung-only disease fared better than patients with liver disease, regardless of treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial

    DEFF Research Database (Denmark)

    Kwon, Eugene D; Drake, Charles G; Scher, Howard I

    2014-01-01

    BACKGROUND: Ipilimumab is a fully human monoclonal antibody that binds cytotoxic T-lymphocyte antigen 4 to enhance antitumour immunity. Our aim was to assess the use of ipilimumab after radiotherapy in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel...... chemotherapy. METHODS: We did a multicentre, randomised, double-blind, phase 3 trial in which men with at least one bone metastasis from castration-resistant prostate cancer that had progressed after docetaxel treatment were randomly assigned in a 1:1 ratio to receive bone-directed radiotherapy (8 Gy in one...... fraction) followed by either ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Non-progressing patients could continue to receive ipilimumab at 10 mg/kg or placebo as maintenance therapy every 3 months until disease progression, unacceptable toxic effect, or death. Patients were randomly...

  5. New possibilities and view for treatment of castration resistant prostate cancer

    International Nuclear Information System (INIS)

    Barilla, R.; Andrasina, I.

    2012-01-01

    Prostate cancer is currently known as the most common cancer and the second leading cause of death from cancer in men in Western population. Advanced prostate cancer is initially sensitive to androgen-deprivation therapy (ADT) but later on progresses to castration resistant state. Understanding the mechanisms that transform prostate cancer (PCA) into a castration-resistant state enables investigators to explore suppression of extraresticular andronegs and other critical pathways to suggest appropriate and rational therapeutic design. Docetaxel based chemotherapy is established as the standard first line chemotherapy in patients with metastatic castration-resistant advanced prostate cancer with improved survival. However, prognosis remains poor and median survival is usually not longer than 2 years. Several Phase III studies have been completed recently, e.g. with new antiandrogens, new taxanes, immunotherapy and therapeutic antibodies. Multidisciplinary management and optimization of their role and and the most appropriate timing is the most important task in the treatment of advanced prostate cancer. (author)

  6. Effect of abiraterone acetate plus prednisone on the pharmacokinetics of dextromethorphan and theophylline in patients with metastatic castration-resistant prostate cancer.

    Science.gov (United States)

    Chi, K N; Tolcher, A; Lee, P; Rosen, P J; Kollmannsberger, C K; Papadopoulos, K P; Patnaik, A; Molina, A; Jiao, J; Pankras, C; Kaiser, B; Bernard, A; Tran, N; Acharya, M

    2013-01-01

    To assess the effect of abiraterone acetate plus prednisone on the pharmacokinetics of dextromethorphan HBr (CYP2D6 substrate) and theophylline (CYP1A2 substrate) in patients with metastatic castration-resistant prostate cancer (mCRPC). Men with progressive metastatic mCRPC who failed gonadotropin-releasing hormone therapy and ≥1 lines of chemotherapy were enrolled. Patients received two doses of dextromethorphan HBr-30 mg (n = 18; group A) or theophylline-100 mg (n = 16; group B) under fasting conditions; one dose on cycle 1, day -8, and the other dose on cycle 1, day 8. Only patients with extensive CYP2D6 metabolizing status were assigned to group A. All patients received continuous daily oral abiraterone acetate (1,000 mg) plus prednisone (10 mg) starting on cycle 1, day 1. Coadministration of abiraterone acetate plus prednisone increased the systemic exposure of dextromethorphan by approximately 100%. Ratios of geometric means for maximum plasma concentration (C(max)) (275.36%) and area under plasma concentration-time curves from time 0 to 24 h (AUC(24h)) (268.14%) of dextromethorphan were outside the bioequivalence limit. The pharmacokinetics of theophylline was unaltered following coadministration of abiraterone acetate plus prednisone. Ratios of geometric means [C(max); 102.36% and AUC(24h); 108.03%] of theophylline exposure parameters were within the bioequivalence limit. The safety profile of abiraterone acetate was consistent with reported toxicities. Abiraterone acetate plus prednisone increased the exposure of dextromethorphan, suggesting a need for caution when coadministrating with known CYP2D6 substrates. The pharmacokinetics of theophylline was unaffected when coadministered with abiraterone acetate plus prednisone.

  7. Large Oncosomes: A Novel Liquid Biopsy for Genetic Profiling in Patients with Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2017-09-01

    Resistant Prostate Cancer PRINCIPAL INVESTIGATOR: Dolores Di Vizio, MD, PhD CONTRACTING ORGANIZATION: Cedars-Sinai Medical Center Los Angeles...Castration-Resistant Prostate Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-16-1-0397 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Dolores Di...biopsy” changing the landscape of precision medicine. 15. SUBJECT TERMS Metastatic Castration Resistant Prostate Cancer , Extracellular Vesicles

  8. The PREVAIL trial of enzalutamide in men with chemotherapy-naïve, metastatic castration-resistant prostate cancer: Post hoc analysis of Korean patients.

    Science.gov (United States)

    Kim, Choung-Soo; Theeuwes, Ad; Kwon, Dong Deuk; Choi, Young Deuk; Chung, Byung Ha; Lee, Hyun Moo; Lee, Kang Hyun; Lee, Sang Eun

    2016-05-01

    This post hoc analysis evaluated treatment effects, safety, and pharmacokinetics of enzalutamide in Korean patients in the phase 3, double-blind, placebo-controlled PREVAIL trial. Asymptomatic or mildly symptomatic chemotherapy-naive men with metastatic castration-resistant prostate cancer that progressed on androgen deprivation therapy received 160 mg/d oral enzalutamide or placebo (1:1) until death or discontinuation due to radiographic progression or skeletal-related event and initiation of subsequent therapy. Coprimary end points were centrally assessed radiographic progression-free survival (rPFS) and overall survival (OS). Secondary end points included investigator-assessed rPFS, time to initiation of chemotherapy, time to prostate-specific antigen (PSA) progression, PSA response (≥50% decline), and time to skeletal-related event. Of 1,717 total patients, 78 patients were enrolled in Korea (enzalutamide, n=40; placebo, n=38). Hazard ratios (95% confidence interval) for enzalutamide versus placebo were 0.23 (0.02-2.24) for centrally assessed rPFS, 0.77 (0.28-2.15) for OS, 0.21 (0.08-0.51) for time to chemotherapy, and 0.31 (0.17-0.56) for time to PSA progression. A PSA response was observed in 70.0% of enzalutamide-treated and 10.5% of placebo-treated Korean patients. Adverse events of grade ≥3 occurred in 33% of enzalutamide-treated and 11% of placebo-treated Korean patients, with median treatment durations of 13.0 and 5.1 months, respectively. At 13 weeks, the plasma concentration of enzalutamide plus N-desmethyl enzalutamide was similar in Korean and non-Korean patients (geometric mean ratio, 1.04; 90% confidence interval, 0.97-1.10). In Korean patients, treatment effects and safety of enzalutamide were consistent with those observed in the overall PREVAIL study population (ClinicalTrials.gov Identifier: NCT01212991).

  9. An analysis of leukapheresis and central venous catheter use in the randomized, placebo controlled, phase 3 IMPACT trial of Sipuleucel-T for metastatic castrate resistant prostate cancer.

    Science.gov (United States)

    Flanigan, Robert C; Polcari, Anthony J; Shore, Neil D; Price, Thomas H; Sims, Robert B; Maher, Johnathan C; Whitmore, James B; Corman, John M

    2013-02-01

    Sipuleucel-T is an autologous cellular immunotherapy. We review the safety of the leukapheresis procedure required for sipuleucel-T preparation and complications related to venous catheter use in the randomized, placebo controlled phase 3 IMPACT (IMmunotherapy for ProstAte Cancer Trial) study (NCT 00065442). A total of 512 patients with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer were enrolled in the study. All patients were scheduled to undergo 3 standard 1.5 to 2.0 blood volume leukapheresis procedures at 2-week intervals. Leukapheresis related adverse events and those related to venous catheter use were reviewed. Immune cell counts were examined throughout the treatment course. Of 512 enrolled patients 506 underwent 1 or more leukapheresis procedures and were included in this analysis. Adverse events were comparable between the sipuleucel-T and control arms. Leukapheresis related adverse events were primarily associated with transient hypocalcemia (39.3%). Most leukapheresis related adverse events (97%) were of mild/moderate intensity. Median white blood cell count and absolute monocyte and lymphocyte counts were stable and within normal ranges throughout the treatment course. Of all patients 23.3% had a central venous catheter placed primarily for leukapheresis. Patients with vs without a central venous catheter had a higher risk of infection potentially related to catheter use (11.9% vs 1.3%, p nervous system (5.9% vs 2.1%, p = 0.06). Adverse events related to leukapheresis are manageable and quickly reversible. The majority of patients can undergo leukapheresis without a central venous catheter. Central venous catheters are associated with an increased risk of infections and venous vascular events. Peripheral intravenous access should be used when feasible. Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  10. PSA response to cabazitaxel is associated with improved progression-free survival in metastatic castration-resistant prostate cancer: the non-interventional QoLiTime study.

    Science.gov (United States)

    Hammerer, Peter; Al-Batran, Salah-Eddin; Windemuth-Kieselbach, Christine; Keller, Martin; Hofheinz, Ralf-Dieter

    2018-03-01

    To evaluate the association between prostate-specific antigen (PSA) response and progression-free and overall survival in men with metastatic castration-resistant prostate cancer (mCRPC) treated with cabazitaxel. Men with mCRPC receiving cabazitaxel (25 mg/m 2 , every 3 weeks) plus oral prednis(ol)one (10 mg/day) were enrolled in the non-interventional, prospective QoLiTime study. Main outcome measures were progression-free survival and overall survival, in all patients and in those who showed a ≥ 50 or a ≥ 30% decrease in PSA relative to baseline after four cycles of cabazitaxel, as well as quality-of-life parameters. Of the 527 men (median age 72 years), 266 received ≥ 4 cycles of cabazitaxel and had PSA response data. After four cycles, 34.6% of men achieved a PSA decrease ≥ 50% and 49.6% a decrease ≥ 30%. Median progression-free survival was 7.7 (95% CI 6.2, 9.5) months, and overall survival was 19.5 (95% CI 16.0, 30.9) months, corresponding to 1-year event rates of 39.4 and 78.8%, respectively. Median progression-free survival was longer in PSA responders versus non-responders (15.7 vs 5.5 months at 50% cut-off; 15.7 vs 5.3 months for 30% cut-off; both P PSA response after four cycles of cabazitaxel is associated with improved progression-free survival in men with mCRPC treated with cabazitaxel plus prednis(ol)one.

  11. Comparison of Timed Automata with Discrete Event Simulation for Modeling of Biomarker-Based Treatment Decisions: An Illustration for Metastatic Castration-Resistant Prostate Cancer.

    Science.gov (United States)

    Degeling, Koen; Schivo, Stefano; Mehra, Niven; Koffijberg, Hendrik; Langerak, Rom; de Bono, Johann S; IJzerman, Maarten J

    2017-12-01

    With the advent of personalized medicine, the field of health economic modeling is being challenged and the use of patient-level dynamic modeling techniques might be required. To illustrate the usability of two such techniques, timed automata (TA) and discrete event simulation (DES), for modeling personalized treatment decisions. An early health technology assessment on the use of circulating tumor cells, compared with prostate-specific antigen and bone scintigraphy, to inform treatment decisions in metastatic castration-resistant prostate cancer was performed. Both modeling techniques were assessed quantitatively, in terms of intermediate outcomes (e.g., overtreatment) and health economic outcomes (e.g., net monetary benefit). Qualitatively, among others, model structure, agent interactions, data management (i.e., importing and exporting data), and model transparency were assessed. Both models yielded realistic and similar intermediate and health economic outcomes. Overtreatment was reduced by 6.99 and 7.02 weeks by applying circulating tumor cell as a response marker at a net monetary benefit of -€1033 and -€1104 for the TA model and the DES model, respectively. Software-specific differences were observed regarding data management features and the support for statistical distributions, which were considered better for the DES software. Regarding method-specific differences, interactions were modeled more straightforward using TA, benefiting from its compositional model structure. Both techniques prove suitable for modeling personalized treatment decisions, although DES would be preferred given the current software-specific limitations of TA. When these limitations are resolved, TA would be an interesting modeling alternative if interactions are key or its compositional structure is useful to manage multi-agent complex problems. Copyright © 2017 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights

  12. Enzalutamide in Japanese patients with chemotherapy-naïve, metastatic castration-resistant prostate cancer: A post-hoc analysis of the placebo-controlled PREVAIL trial.

    Science.gov (United States)

    Kimura, Go; Yonese, Junji; Fukagai, Takashi; Kamba, Tomomi; Nishimura, Kazuo; Nozawa, Masahiro; Mansbach, Hank; Theeuwes, Ad; Beer, Tomasz M; Tombal, Bertrand; Ueda, Takeshi

    2016-05-01

    To evaluate the treatment effects, safety and pharmacokinetics of enzalutamide in Japanese patients. This was a post-hoc analysis of the phase 3, double-blind, placebo-controlled PREVAIL trial. Asymptomatic or mildly symptomatic chemotherapy-naïve patients with metastatic castration-resistant prostate cancer progressing on androgen deprivation therapy were randomized one-to-one to 160 mg/day oral enzalutamide or placebo until discontinuation on radiographic progression or skeletal-related event and initiation of subsequent antineoplastic therapy. Coprimary end-points were centrally assessed radiographic progression-free survival and overall survival. Secondary end-points were investigator-assessed radiographic progression-free survival, time to initiation of chemotherapy, time to prostate-specific antigen progression, prostate-specific antigen response (≥50% decline) and time to skeletal-related event. Of 1717 patients, 61 were enrolled in Japan (enzalutamide, n = 28; placebo, n = 33); hazard ratios (95% confidence interval) of 0.30 for centrally assessed radiographic progression-free survival (0.03-2.95), 0.59 for overall survival (0.20-1.8), 0.46 for time to chemotherapy (0.22-0.96) and 0.36 for time to prostate-specific antigen progression (0.17-0.75) showed the treatment benefit of enzalutamide over the placebo. Prostate-specific antigen responses were observed in 60.7% of enzalutamide-treated men versus 21.2% of placebo-treated men. Plasma concentrations of enzalutamide were higher in Japanese patients: the geometric mean ratio of Japanese/non-Japanese patients was 1.126 (90% confidence interval 1.018-1.245) at 13 weeks. Treatment-related adverse events grade ≥3 occurred in 3.6% of enzalutamide- and 6.1% of placebo-treated Japanese patients. Treatment effects and safety in Japanese patients were generally consistent with the overall results from PREVAIL. © 2016 The Authors. International Journal of Urology published by John Wiley & Sons Australia, Ltd on

  13. Super-Penetrant Androgen Receptor: Overcoming Enzalutamide Sensitivity in Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2016-07-01

    Prostate Cancer Research Symposium- Prostate Cancer Epigenetic Reprogramming of the Androgen Receptor in Castration Resistant Prostate Cancer , May19... cancer cells rely critically on the androgen receptor (AR) for initiation, growth and progression to castration resistant prostate cancer (CRPC...Androgen receptor, castration resistant prostate cancer , Enzalutamide , kinases. 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER

  14. The Role of the Neutrophil to Lymphocyte Ratio for Survival Outcomes in Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Abiraterone

    Directory of Open Access Journals (Sweden)

    Martin Boegemann

    2017-02-01

    Full Text Available The purpose of this study was to examine the prognostic capability of baseline neutrophil-to-lymphocyte-ratio (NLR and NLR-change under Abiraterone in metastatic castration-resistant prostate cancer patients. The impact of baseline NLR and change after eight weeks of treatment on progression-free survival (PFS and overall survival (OS was analyzed using Kaplan-Meier-estimates and Cox-regression. 79 men with baseline NLR <5 and 17 with NLR >5 were analyzed. In baseline analysis of PFS NLR >5 was associated with non-significantly shorter median PFS (five versus 10 months (HR: 1.6 (95%CI:0.9–2.8; p = 0.11. After multivariate adjustment (MVA, ECOG > 0–1, baseline LDH>upper limit of normal (UNL and presence of visceral metastases were independent prognosticators. For OS, NLR >5 was associated with shorter survival (seven versus 19 months (HR: 2.3 (95%CI:1.3–4.0; p < 0.01. In MVA, ECOG > 0–1 and baseline LDH > UNL remained independent prognosticators. After 8 weeks of Abiraterone NLR-change to <5 prognosticated worse PFS (five versus 12 months (HR: 4.1 (95%CI:1.1–15.8; p = 0.04. MVA showed a trend towards worse PFS for NLR-change to <5 (p = 0.11. NLR-change to <5 led to non-significant shorter median OS (seven versus 16 months (HR: 2.3 (95%CI:0.7–7.1; p = 0.15. MVA showed non-significant difference for OS. We concluded baseline NLR <5 is associated with improved survival. In contrast, in patients with baseline NLR >5, NLR-change to <5 after eight weeks of Abiraterone was associated with worse survival and should be interpreted carefully.

  15. Systemic therapy in men with metastatic castration-resistant prostate cancer:American Society of Clinical Oncology and Cancer Care Ontario clinical practice guideline.

    Science.gov (United States)

    Basch, Ethan; Loblaw, D Andrew; Oliver, Thomas K; Carducci, Michael; Chen, Ronald C; Frame, James N; Garrels, Kristina; Hotte, Sebastien; Kattan, Michael W; Raghavan, Derek; Saad, Fred; Taplin, Mary-Ellen; Walker-Dilks, Cindy; Williams, James; Winquist, Eric; Bennett, Charles L; Wootton, Ted; Rumble, R Bryan; Dusetzina, Stacie B; Virgo, Katherine S

    2014-10-20

    To provide treatment recommendations for men with metastatic castration-resistant prostate cancer (CRPC). The American Society of Clinical Oncology and Cancer Care Ontario convened an expert panel to develop evidence-based recommendations informed by a systematic review of the literature. When added to androgen deprivation, therapies demonstrating improved survival, improved quality of life (QOL), and favorable benefit-harm balance include abiraterone acetate/prednisone, enzalutamide, and radium-223 ((223)Ra; for men with predominantly bone metastases). Improved survival and QOL with moderate toxicity risk are associated with docetaxel/prednisone. For asymptomatic/minimally symptomatic men, improved survival with unclear QOL impact and low toxicity are associated with sipuleucel-T. For men who previously received docetaxel, improved survival, unclear QOL impact, and moderate to high toxicity risk are associated with cabazitaxel/prednisone. Modest QOL benefit (without survival benefit) and high toxicity risk are associated with mitoxantrone/prednisone after docetaxel. No benefit and excess toxicity are observed with bevacizumab, estramustine, and sunitinib. Continue androgen deprivation (pharmaceutical or surgical) indefinitely. Abiraterone acetate/prednisone, enzalutamide, or (223)Ra should be offered; docetaxel/prednisone should also be offered, accompanied by discussion of toxicity risk. Sipuleucel-T may be offered to asymptomatic/minimally symptomatic men. For men who have experienced progression with docetaxel, cabazitaxel may be offered, accompanied by discussion of toxicity risk. Mitoxantrone may be offered, accompanied by discussion of limited clinical benefit and toxicity risk. Ketoconazole or antiandrogens (eg, bicalutamide, flutamide, nilutamide) may be offered, accompanied by discussion of limited known clinical benefit. Bevacizumab, estramustine, and sunitinib should not be offered. There is insufficient evidence to evaluate optimal sequences or

  16. Prognostic value of 18F-choline PET/CT metabolic parameters in patients with metastatic castration-resistant prostate cancer treated with abiraterone or enzalutamide

    Energy Technology Data Exchange (ETDEWEB)

    Caroli, Paola; Fantini, Lorenzo; Celli, Monica; Paganelli, Giovanni; Matteucci, Federica [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Nuclear Medicine Unit, Meldola (Italy); De Giorgi, Ugo; Conteduca, Vincenza; Rossi, Lorena [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Department of Medical Oncology, Meldola (Italy); Scarpi, Emanuela [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Unit of Biostatistics and Clinical Trials Unit, Meldola (Italy); Moretti, Andrea; Galassi, Riccardo [Morgagni Pierantoni Hospital, Nuclear Medicine Unit, Forli (Italy); Bianchi, Emanuela [Infermi Hospital, Department of Medical Oncology, Rimini (Italy)

    2018-03-15

    The role of 18F-choline positron emission tomography/computed tomography (FCH-PET/CT) in patients with metastatic castration-resistant prostate cancer (mCRPC) has been firmly established in recent years. We analyzed the prognostic value of functional parameters such as mean standardized uptake volume (SUVmean), maximum standardized uptake volume (SUVmax), metabolic total volume (MTV; the volume of interest consisting of all spatially connected voxels within a fixed threshold of 40% of the SUVmax), and total lesion activity (TLA: the product of MTV and mean standardized uptake value) estimated with FCH-PET/CT in mCRPC patients in progression after docetaxel and treated with new antiandrogen receptor therapies, abiraterone or enzalutamide. We retrospectively studied 94 mCRPC patients, mean age 74 years (range 42-90), previously treated with docetaxel who were treated with either abiraterone (n = 52) or enzalutamide (n = 42). An FCH-PET/CT was performed at baseline, and patients were evaluated on a monthly basis for serological PSA response and every 3 months for radiological response. We measured MTV, SUVmean, SUVmax and TLA for each lesion and analyzed the sum of MTV (SMTV), SUVmean (SSUVmean), SUVmax (SSUVmax) and TLA (STLA) values for a maximum of 20 lesions. Univariate analysis was used to correlate these data with PFS and OS. We observed a median SMTV of 130 cm{sup 3}, median SSUVmax of 106.5 and a median STLA of 495,070. All of these parameters were significant for PFS and OS in univariate analysis, while only STLA was significant for PFS and OS in multivariate analysis after adjusting for lesion and age (p < 0.0001 and p = 0.001, respectively). Baseline PSA values maintained a certain reliability for OS (p = 0.034). Semiquantitative parameters of FCH-PET/CT play a prognostic role in mCRCP patients treated with abiraterone or enzalutamide. (orig.)

  17. Randomized, placebo-controlled, phase III trial of sunitinib plus prednisone versus prednisone alone in progressive, metastatic, castration-resistant prostate cancer.

    Science.gov (United States)

    Michaelson, M Dror; Oudard, Stephane; Ou, Yen-Chuan; Sengeløv, Lisa; Saad, Fred; Houede, Nadine; Ostler, Peter; Stenzl, Arnulf; Daugaard, Gedske; Jones, Robert; Laestadius, Fredrik; Ullèn, Anders; Bahl, Amit; Castellano, Daniel; Gschwend, Juergen; Maurina, Tristan; Chow Maneval, Edna; Wang, Shaw-Ling; Lechuga, Maria Jose; Paolini, Jolanda; Chen, Isan

    2014-01-10

    We evaluated angiogenesis-targeted sunitinib therapy in a randomized, double-blind trial of metastatic castration-resistant prostate cancer (mCRPC). Men with progressive mCRPC after docetaxel-based chemotherapy were randomly assigned 2:1 to receive sunitinib 37.5 mg/d continuously or placebo. Patients also received oral prednisone 5 mg twice daily. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS). Two interim analyses were planned. Overall, 873 patients were randomly assigned to receive sunitinib (n = 584) or placebo (n = 289). The independent data monitoring committee stopped the study for futility after the second interim analysis. After a median overall follow-up of 8.7 months, median OS was 13.1 months and 11.8 months for sunitinib and placebo, respectively (hazard ratio [HR], 0.914; 95% CI, 0.762 to 1.097; stratified log-rank test, P = .168). PFS was significantly improved in the sunitinib arm (median 5.6 v 4.1 months; HR, 0.725; 95% CI, 0.591 to 0.890; stratified log-rank test, P < .001). Toxicity and rates of discontinuations because of adverse events (AEs; 27% v 7%) were greater with sunitinib than placebo. The most common treatment-related grade 3/4 AEs were fatigue (9% v 1%), asthenia (8% v 2%), and hand-foot syndrome (7% v 0%). Frequent treatment-emergent grade 3/4 hematologic abnormalities were lymphopenia (20% v 11%), anemia (9% v 8%), and neutropenia (6% v < 1%). The addition of sunitinib to prednisone did not improve OS compared with placebo in docetaxel-refractory mCRPC. The role of antiangiogenic therapy in mCRPC remains investigational.

  18. Preliminary study of the specific endothelin a receptor antagonist zibotentan in combination with docetaxel in patients with metastatic castration-resistant prostate cancer.

    Science.gov (United States)

    Trump, Donald L; Payne, Heather; Miller, Kurt; de Bono, Johann S; Stephenson, Joe; Burris, Howard A; Nathan, Faith; Taboada, Maria; Morris, Thomas; Hubner, Andreas

    2011-09-01

    This two-part study assessed the safety and tolerability of combined treatment with zibotentan (ZD4054), a specific endothelin A receptor antagonist, plus docetaxel in patients with metastatic castration-resistant prostate cancer. Part A was an open-label, dose-finding phase to determine the safety and toxicity profile of zibotentan in combination with docetaxel. Patients received once-daily oral zibotentan 10 mg (initial cohort) or 15 mg in combination with docetaxel 75 mg/m(2) (administered on day 1 of each 21-day cycle) for up to 10 cycles. Part B was a double-blind phase which evaluated the safety and preliminary activity of zibotentan plus docetaxel. Patients were randomized 2:1 to receive zibotentan (at the highest tolerated dose identified in part A) plus docetaxel or placebo plus docetaxel. Six patients were enrolled in part A (n  = 3, zibotentan 10 mg; n = 3, zibotentan 15 mg). No dose-limiting toxicity was observed, thus zibotentan 15 mg in combination with docetaxel was evaluated in part B (n = 20, zibotentan plus docetaxel; n = 11, placebo plus docetaxel). CTCAE grade ≥3, most commonly neutropenia or leucopenia, were reported in 10 (50%) and nine (82%) patients in the zibotentan and placebo groups, respectively. One (17%) patient receiving placebo achieved complete response, two (22%) patients receiving zibotentan achieved partial response and stable disease occurred in six (67%) and three (50%) patients receiving zibotentan and placebo, respectively. The tolerability of zibotentan plus docetaxel was consistent with the known profiles of each drug. Sufficient preliminary activity was seen with this combination to merit continued development. Copyright © 2011 Wiley-Liss, Inc.

  19. Final quality of life and safety data for patients with metastatic castration-resistant prostate cancer treated with cabazitaxel in the UK Early Access Programme (EAP) (NCT01254279).

    Science.gov (United States)

    Bahl, Amit; Masson, Susan; Malik, Zafar; Birtle, Alison J; Sundar, Santhanam; Jones, Rob J; James, Nicholas D; Mason, Malcolm D; Kumar, Satish; Bottomley, David; Lydon, Anna; Chowdhury, Simon; Wylie, James; de Bono, Johann S

    2015-12-01

    To compile the safety profile and quality of life (QoL) data for patients with metastatic castration-resistant prostate cancer (mCRPC) treated with cabazitaxel in the UK Early Access Programme (UK EAP). A total of 112 patients participated at 12 UK cancer centres. All had mCRPC with disease progression during or after docetaxel. Patients received cabazitaxel 25 mg/m(2) every 3 weeks with prednisolone 10 mg daily for up to 10 cycles. Safety assessments were performed before each cycle and QoL was recorded at alternate cycles using the EQ-5D-3L questionnaire and visual analogue scale (VAS). The safety profile was compiled after completion of the UK EAP and QoL measures were analysed to record trends. No formal statistical analysis was carried out. The incidences of neutropenic sepsis (6.3%), grade 3 and 4 diarrhoea (4.5%) and grade 3 and 4 cardiac toxicity (0%) were low. Neutropenic sepsis episodes, though low, occurred only in patients who did not receive prophylactic granulocyte-colony stimulating factor. There were trends towards improved VAS and EQ-5D-3L pain scores during treatment. The UK EAP experience indicates that cabazitaxel might improve QoL in mCRPC and represents an advance and a useful addition to the armamentarium of treatment for patients whose disease has progressed during or after docetaxel. In view of the potential toxicity, careful patient selection is important. © 2015 The Authors BJU International © 2015 BJU International Published by John Wiley & Sons Ltd.

  20. Targeting the androgen receptor pathway in castration-resistant prostate cancer: progresses and prospects

    Science.gov (United States)

    Ferraldeschi, R; Welti, J; Luo, J; Attard, G; de Bono, JS

    2015-01-01

    Androgen receptor (AR) signaling is a critical pathway for prostate cancer cells, and androgen-deprivation therapy (ADT) remains the principal treatment for patients with locally advanced and metastatic disease. However, over time, most tumors become resistant to ADT. The view of castration-resistant prostate cancer (CRPC) has changed dramatically in the last several years. Progress in understanding the disease biology and mechanisms of castration resistance led to significant advancements and to paradigm shift in the treatment. Accumulating evidence showed that prostate cancers develop adaptive mechanisms for maintaining AR signaling to allow for survival and further evolution. The aim of this review is to summarize molecular mechanisms of castration resistance and provide an update in the development of novel agents and strategies to more effectively target the AR signaling pathway. PMID:24837363

  1. Novel Junction-specific and Quantifiable In Situ Detection of AR-V7 and its Clinical Correlates in Metastatic Castration-resistant Prostate Cancer.

    Science.gov (United States)

    Zhu, Yezi; Sharp, Adam; Anderson, Courtney M; Silberstein, John L; Taylor, Maritza; Lu, Changxue; Zhao, Pei; De Marzo, Angelo M; Antonarakis, Emmanuel S; Wang, Mindy; Wu, Xingyong; Luo, Yuling; Su, Nan; Nava Rodrigues, Daniel; Figueiredo, Ines; Welti, Jonathan; Park, Emily; Ma, Xiao-Jun; Coleman, Ilsa; Morrissey, Colm; Plymate, Stephen R; Nelson, Peter S; de Bono, Johann S; Luo, Jun

    2018-05-01

    Androgen receptor splice variant 7 (AR-V7) has been implicated in resistance to abiraterone and enzalutamide treatment in men with metastatic castration-resistant prostate cancer (mCRPC). Tissue- or cell-based in situ detection of AR-V7, however, has been limited by lack of specificity. To address current limitations in precision measurement of AR-V7 by developing a novel junction-specific AR-V7 RNA in situ hybridization (RISH) assay compatible with automated quantification. We designed a RISH method to visualize single splice junctions in cells and tissue. Using the validated assay for junction-specific detection of the full-length AR (AR-FL) and AR-V7, we generated quantitative data, blinded to clinical data, for 63 prostate tumor biopsies. We evaluated clinical correlates of AR-FL/AR-V7 measurements, including association with prostate-specific antigen progression-free survival (PSA-PFS) and clinical and radiographic progression-free survival (PFS), in a subset of patients starting treatment with abiraterone or enzalutamide following biopsy. Quantitative AR-FL/AR-V7 data were generated from 56 of the 63 (88.9%) biopsy specimens examined, of which 44 were mCRPC biopsies. Positive AR-V7 signals were detected in 34.1% (15/44) mCRPC specimens, all of which also co-expressed AR-FL. The median AR-V7/AR-FL ratio was 11.9% (range 2.7-30.3%). Positive detection of AR-V7 was correlated with indicators of high disease burden at baseline. Among the 25 CRPC biopsies collected before treatment with abiraterone or enzalutamide, positive AR-V7 detection, but not higher AR-FL, was significantly associated with shorter PSA-PFS (hazard ratio 2.789, 95% confidence interval 1.12-6.95; p=0.0081). We report for the first time a RISH method for highly specific and quantifiable detection of splice junctions, allowing further characterization of AR-V7 and its clinical significance. Higher AR-V7 levels detected and quantified using a novel method were associated with poorer response to

  2. Subsequent Chemotherapy and Treatment Patterns After Abiraterone Acetate in Patients with Metastatic Castration-resistant Prostate Cancer: Post Hoc Analysis of COU-AA-302.

    Science.gov (United States)

    de Bono, Johann S; Smith, Matthew R; Saad, Fred; Rathkopf, Dana E; Mulders, Peter F A; Small, Eric J; Shore, Neal D; Fizazi, Karim; De Porre, Peter; Kheoh, Thian; Li, Jinhui; Todd, Mary B; Ryan, Charles J; Flaig, Thomas W

    2017-04-01

    Treatment patterns for metastatic castration-resistant prostate cancer (mCRPC) have changed substantially in the last few years. In trial COU-AA-302 (chemotherapy-naïve men with mCRPC), abiraterone acetate plus prednisone (AA) significantly improved radiographic progression-free survival and overall survival (OS) when compared to placebo plus prednisone (P). This post hoc analysis investigated clinical responses to docetaxel as first subsequent therapy (FST) among patients who progressed following protocol-specified treatment with AA, and characterized subsequent treatment patterns among older (≥75 yr) and younger (AA arm received subsequent treatment with one or more agents approved for mCRPC. Efficacy analysis was performed for patients for whom baseline and at least one post-baseline prostate-specific antigen (PSA) values were available. Baseline and at least one post-baseline PSA values were available for 100 AA patients who received docetaxel as FST. While acknowledging the limitations of post hoc analyses, 40% (40/100) of these patients had an unconfirmed ≥50% PSA decline with first subsequent docetaxel therapy, and 27% (27/100) had a confirmed ≥50% PSA decline. The median docetaxel treatment duration among these 100 patients was 4.2 mo. Docetaxel was the most common FST among older and younger patients from each treatment arm. However, 43% (79/185) of older patients who progressed on AA received no subsequent therapy for mCRPC, compared with 17% (60/361) of younger patients. Patients with mCRPC who progress with AA treatment may still derive benefit from subsequent docetaxel therapy. These data support further assessment of treatment patterns following AA treatment for mCRPC, particularly among older patients. ClinicalTrials.gov NCT00887198. Treatment patterns for advanced prostate cancer have changed substantially in the last few years. This additional analysis provides evidence of clinical benefit for subsequent chemotherapy in men with advanced

  3. Budgetary impact on a U.S. health plan adopting abiraterone acetate plus prednisone for the treatment of patients with metastatic castration-resistant prostate cancer.

    Science.gov (United States)

    Sorensen, Sonja; Ellis, Lorie; Wu, Ying; Hutchins, Valerie; Linnehan, John E; Senbetta, Mekré

    2013-01-01

    Abiraterone acetate, an androgen biosynthesis inhibitor, received FDA approval in 2011 for metastatic castration-resistant prostate cancer (mCRPC) patients who have received prior chemotherapy containing docetaxel. To estimate the projected budgetary impact of adopting abiraterone for mCRPC patients from a U.S. health plan perspective. A decision analytic model compared mCRPC treatment cost before and after abiraterone acetate adoption based on a hypothetical 1,000,000-member plan. Plan mCRPC prevalence was derived from prostate cancer incidence reported in U.S. epidemiology statistics and disease progression data from published trials. Market shares for comparator mCRPC treatments (prednisone alone; cabazitaxel + prednisone; mitoxantrone + prednisone; docetaxel retreatment + prednisone) were derived from market research simulation. Abiraterone + prednisone uptake (8% - scenario 1 to 55% - scenario 3) was based on assumptions for illustrative purposes. Treatment costs were computed using prescribing information, treatment duration from phase III trials, and drug costs considering common U.S. cost listing and reimbursement schemes. Prevalence and costs of managing treatment-related toxicities were estimated from literature, treatment guidelines, and expert clinical opinion. The model evaluated the perspectives of a commercial payer with no Medicare beneficiaries and a commercial payer with a subset of Medicare beneficiaries. Sensitivity analyses were conducted to assess changing input values. In each modeled scenario, 57 patients with prior docetaxel therapy received treatment for mCRPC. For the commercial perspective, the incremental per-member-per-month (PMPM) cost attributable to abiraterone ranged from $0.0019 in scenario 1 to $0.0133 in scenario 3. For the commercial/Medicare perspective, the incremental PMPM ranged from $0.0026 in scenario 1 to $0.0176 in scenario 3. The average incremental PMPM cost over 3 scenarios is $0.0112. When testing key sensitivity

  4. Antitumour Activity and Safety of Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer Previously Treated with Abiraterone Acetate Plus Prednisone for ≥24 weeks in Europe.

    Science.gov (United States)

    de Bono, Johann S; Chowdhury, Simon; Feyerabend, Susan; Elliott, Tony; Grande, Enrique; Melhem-Bertrandt, Amal; Baron, Benoit; Hirmand, Mohammad; Werbrouck, Patrick; Fizazi, Karim

    2018-07-01

    Enzalutamide and abiraterone acetate plus prednisone, which target the androgen receptor axis, have expanded the treatment of advanced prostate cancer. Retrospective analyses suggest some cross-resistance between these two drugs when used sequentially, but robust, prospective studies have not yet been reported. To fulfil a regulatory postregistration commitment by evaluating the efficacy and safety of enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) who progressed following abiraterone acetate plus prednisone treatment. Multicentre, single-arm, open-label study, enrolled patients with progressing mCRPC after ≥24 wk of abiraterone acetate plus prednisone treatment. All patients maintained castration therapy during the trial. Prior chemotherapy was allowed but not required. Patients received enzalutamide 160mg/d orally. The primary endpoint was radiographic progression-free survival. Secondary endpoints were overall survival, prostate-specific antigen (PSA) response, and time-to-PSA progression. Safety data were also assessed. Kaplan-Meier methods were used to descriptively analyse time-to-event endpoints. Overall, 214 patients received enzalutamide treatment, 145 of whom were chemotherapy-naïve. Median radiographic progression-free survival was 8.1 mo (95% confidence interval: 6.1-8.3); median overall survival had not been reached. Unconfirmed PSA response rate was 27% (48 of 181). Median time-to-PSA progression was 5.7 mo (95% confidence interval: 5.6-5.8). The most common treatment-emergent adverse events were fatigue (32%), decreased appetite (25%), asthenia (18%), back pain (17%), and arthralgia (16%). No seizures were reported. Enzalutamide showed antitumour activity in some patients with mCRPC who had previously progressed following ≥24 wk of abiraterone acetate plus prednisone treatment. Patients with mCRPC who progressed on previous abiraterone acetate plus prednisone treatment, with or without prior chemotherapy

  5. Efficacy and safety of enzalutamide in patients 75 years or older with chemotherapy-naive metastatic castration-resistant prostate cancer: results from PREVAIL.

    Science.gov (United States)

    Graff, J N; Baciarello, G; Armstrong, A J; Higano, C S; Iversen, P; Flaig, T W; Forer, D; Parli, T; Phung, D; Tombal, B; Beer, T M; Sternberg, C N

    2016-02-01

    Prostate cancer disproportionately affects older men. Because age affects treatment decisions, it is important to understand the efficacy and tolerability of therapies for advanced prostate cancer in elderly men. This analysis describes efficacy and safety outcomes in men aged ≥75 years who received enzalutamide, an androgen receptor inhibitor, in the phase III PREVAIL trial. PREVAIL was a randomised, double-blind, multinational study of oral enzalutamide 160 mg/day (N = 872) versus placebo (N = 845) in chemotherapy-naive men with metastatic castration-resistant prostate cancer. Overall survival (OS) and radiographic progression-free survival (rPFS) were coprimary end points. Subgroup analysis of men aged ≥75 years (elderly) and men aged PREVAIL, median treatment duration was 16.6 and 5.0 months in the enzalutamide and placebo arms, respectively. In the elderly subgroup, OS was greater with enzalutamide than with placebo [32.4 months (95% confidence interval (CI) 27.7-not yet reached] versus 25.1 months (95% CI 22.6-28.0); hazard ratio (HR) = 0.61 (95% CI 0.47-0.79); P = 0.0001], as was rPFS [not yet reached (95% CI 12.3-not yet reached) versus 3.7 months (95% CI 3.6-5.3); HR = 0.17 (95% CI 0.12-0.24); P < 0.0001]. Irrespective of treatment assignment, incidence of AEs was similar between the two age groups, except for an overall higher incidence of falls among elderly patients than younger patients [84/609 (13.8%) versus 62/1106 (5.6%)] and among elderly patients receiving enzalutamide than those receiving placebo [61/317 (19.2%) versus 23/292 (7.9%)]. Elderly men benefited from treatment with enzalutamide in terms of OS and rPFS. Enzalutamide was well tolerated in the elderly subgroup and those aged <75 years. Age and enzalutamide treatment were associated with a higher incidence of falls. NCT01212991, ClinicalTrials.gov. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For

  6. Targeted α-Therapy of Metastatic Castration-Resistant Prostate Cancer with 225Ac-PSMA-617: Swimmer-Plot Analysis Suggests Efficacy Regarding Duration of Tumor Control.

    Science.gov (United States)

    Kratochwil, Clemens; Bruchertseifer, Frank; Rathke, Hendrik; Hohenfellner, Markus; Giesel, Frederik L; Haberkorn, Uwe; Morgenstern, Alfred

    2018-05-01

    The aim of this evaluation was to identify the first indicators of efficacy for 225 Ac-labeled prostate-specific membrane antigen (PSMA)-617 therapy in a retrospectively analyzed group of patients. Methods: Forty patients with metastatic castration-resistant prostate cancer were selected for treatment with three 100 kBq/kg cycles of 225 Ac-PSMA-617 at 2-mo intervals. Prostate-specific antigen (PSA) and blood cell count were measured every 4 wk. PSMA PET/CT or PSMA SPECT/CT were used for baseline staging and imaging follow-up at month 6. Follow-up included the duration of PSA response and radiologic progression-free survival at month 6. Patient histories were reviewed for the duration of previous treatment lines, and a swimmer plot was used to intraindividually compare the duration of tumor control by PSMA therapy versus prior treatment modalities. Results: Thirty-one of 40 patients were treated per protocol. Five patients discontinued treatment because of nonresponse, and 4 because of xerostomia. Of the 38 patients surviving at least 8 wk, 24 (63%) had a PSA decline of more than 50%, and 33 (87%) had a PSA response of any degree. The median duration of tumor control under 225 Ac-PSMA-617 last-line therapy was 9.0 mo; 5 patients had an enduring response of more than 2 y. Because all patients had advanced disease, this result compares favorably with the tumor control rates associated with earlier-phase disease; the most common preceding first-, second-, third-, and fourth-line therapies were abiraterone (median duration 10.0 mo), docetaxel (6.5 mo), enzalutamide (6.5 mo), and cabazitaxel (6.0 mo), respectively. Conclusion: A positive response for surrogate parameters demonstrates remarkable antitumor activity for 225 Ac-PSMA-617. Swimmer-plot analysis indicates a promising duration of tumor control, especially considering the unfavorable prognostic profile of the selected advanced-stage patients. Xerostomia was the main reason patients discontinued therapy or refused

  7. Epigenetic Machinery Regulates Alternative Splicing of Androgen Receptor (AR) Gene in Castration Resistant Prostate Cancer

    Science.gov (United States)

    2017-09-01

    resistant prostate cancer PRINCIPAL INVESTIGATOR: Zhi-Ping Liu CONTRACTING ORGANIZATION: UT Southwestern Medical Center Dallas, TX 75390 REPORT DATE...NUMBER gene in castration-resistant prostate cancer 5b. GRANT NUMBER W81XWH-16-1-0531 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Zhi-Ping Liu 5d...NOTES 14. ABSTRACT Androgen deprivation therapy (ADT) is the primary treatment for metastatic prostate cancer (PCa) since PCa depends on androgen for

  8. [Molecular biology of castration-resistant prostate cancer].

    Science.gov (United States)

    Doucet, Ludovic; Terrisse, Safae; Gauthier, Hélène; Pouessel, Damien; Le Maignan, Christine; Teixeira, Luis; Culine, Stéphane

    2015-06-01

    Castration-resistant prostate cancer was subjected to a paradigm switch from hormone resistance to androgen deprivation therapy resistance during the last decade. Indeed, new therapeutics targeting the androgen receptor showed clinical efficacy in patients with progressive disease under castration. Thus, it is a proof that the AR remains a dominant driver of oncogenesis in earlier-called hormone resistant prostate cancer. This review summarizes the molecular mechanisms involved in castration-resistant prostate cancer. Copyright © 2015 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

  9. Transcription-Based Molecular Imaging and Gene Therapy for Castration-resistant and Metastatic Prostate Cancer in Translational Models

    OpenAIRE

    Jiang, Ziyue

    2013-01-01

    The advanced stage of prostate cancer is the second leading cause of cancer-related death for American men. Novel, effective treatment options and more cancer-specific diagnostic tools are urgently needed to facilitate patient management. Here, we explored the construction and application of an array of gene-based molecular imaging and therapeutic vectors in a variety of clinically relevant settings. These vectors exploit prostate cancer-specific promoters to control the transcription of imag...

  10. Quality of Life in Second-Line Treatment of Metastatic Castration-Resistant Prostate Cancer Using Cabazitaxel or Other Therapies After Previous Docetaxel Chemotherapy: Swiss Observational Treatment Registry.

    Science.gov (United States)

    Stenner, Frank; Rothschild, Sacha I; Betticher, Daniel; Caspar, Clemens; Morant, Rudolf; Popescu, Razvan; Rauch, Daniel; Huber, Urs; Zenhäusern, Reinhard; Rentsch, Cyrill; Cathomas, Richard

    2017-08-24

    The aim was to evaluate quality of life (QoL), pain, and fatigue in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with different regimens after first-line docetaxel, as well as disease progression. Patients with mCRPC having received first-line chemotherapy with docetaxel were eligible. Second-line treatment choice was at the discretion of the local investigator. All patients had regular assessments of QoL with the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire, of fatigue with the Brief Fatigue Inventory, and of pain with the McGill Pain Questionnaire-Short Form. The primary end point was QoL maintenance defined as having a maximum decrease in 2 functional domains of the FACT-P. One hundred thirty-eight patients were included in 36 oncology centers across Switzerland. QoL analysis was available for all patients (59 who received cabazitaxel; 79 who received other therapy [OT] including 75 who received abiraterone). No significant differences for any of the end points were found between groups. A numerically higher number of patients had QoL maintenance with OT (25 of 79 patients, 32%) compared with cabazitaxel (8 of 59 patients, 14%). QoL improvement was found in 20% of patients (12 of 59) who received cabazitaxel and 24% (19 of 79) who received OT. Mean FACT-P score did not change in a clinically relevant manner over time in either group. Pain was present in 70% of patients (96 of 138), and a pain response to treatment was noted in 22% (13 of 59) who received cabazitaxel and 29% (23 of 79) who received OT. A similar but minor improvement of fatigue was noted in both groups. Some degree of QoL decrease was seen in most patients regardless of second-line treatment. No significant differences in QoL parameters between cabazitaxel or other second line treatments were found. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Third-line treatment and 177Lu-PSMA radioligand therapy of metastatic castration-resistant prostate cancer: a systematic review

    International Nuclear Information System (INIS)

    Edler von Eyben, Finn; Roviello, Giandomenico; Kiljunen, Timo; Kairemo, Kalevi; Joensuu, Timo; Uprimny, Christian; Virgolini, Irene

    2018-01-01

    There is a controversy as to the relative efficacy of 177 Lu prostate specific membrane antigen (PSMA) radioligand therapy (RLT) and third-line treatment for patients with metastatic castration-resistant prostate cancer (mCRPC). The aim of our systematic review was to elucidate whether 177 Lu-PSMA RLT and third-line treatment have similar effects and adverse effects (PROSPERO ID CRD42017067743). The review followed Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Searches in Pubmed and Embase selected articles up to September 2017. A search in ClinicalTrials.gov indicated ongoing studies. The meta-analysis used the random-effects model. Twelve studies including 669 patients reported 177 Lu-PSMA RLT. Overall, 43% of the patients had a maximum decline of PSA of ≥50% following treatment with 177 Lu-PSMA RLT. The treatment with 177 Lu-PSMA-617 and 177 Lu-PSMA for imaging and therapy (I and T) had mainly transient adverse effects. Sixteen studies including 1338 patients reported third-line treatment. Overall, 21% of the patients had a best decline of PSA of ≥50% following third-line treatment. After third-line treatment with enzalutamide and cabazitaxel, adverse effects caused discontinuation of treatment for 10% to 23% of the patients. 177 Lu-PSMA RLT gave a best PSA decline ≥50% more often than third-line treatment (mean 44% versus 22%, p = 0.0002, t test). 177 Lu-PSMA RLT gave objective remission more often than third-line treatment (overall 31 of 109 patients versus 43 of 275 patients, p = 0.004, χ 2 test). Median survival was longer after 177 Lu-PSMA RLT than after third-line treatment, but the difference was not statistically significant (mean 14 months versus 12 months, p = 0.32, t test). Adverse effects caused discontinuation of treatment more often for third-line treatment than for 177 Lu-PSMA RLT (22 of 66 patients versus 0 of 469 patients, p < 0.001, χ 2 test). As for patients with mCRPC, treatment with 177 Lu

  12. Third-line treatment and {sup 177}Lu-PSMA radioligand therapy of metastatic castration-resistant prostate cancer: a systematic review

    Energy Technology Data Exchange (ETDEWEB)

    Edler von Eyben, Finn [Center of Tobacco Control Research, Odense (Denmark); Roviello, Giandomenico [San Donato Hospital, Department of Oncology, Medical Oncology Unit, Arezzo (Italy); University of Trieste, Department Medical, Surgery, and Health Sciences, Trieste (Italy); Kiljunen, Timo; Kairemo, Kalevi; Joensuu, Timo [Docrates Cancer Center, Helsinki (Finland); Uprimny, Christian; Virgolini, Irene [University Hospital Innsbruck, Department of Nuclear Medicine, Innsbruck (Austria)

    2018-03-15

    There is a controversy as to the relative efficacy of {sup 177}Lu prostate specific membrane antigen (PSMA) radioligand therapy (RLT) and third-line treatment for patients with metastatic castration-resistant prostate cancer (mCRPC). The aim of our systematic review was to elucidate whether {sup 177}Lu-PSMA RLT and third-line treatment have similar effects and adverse effects (PROSPERO ID CRD42017067743). The review followed Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Searches in Pubmed and Embase selected articles up to September 2017. A search in ClinicalTrials.gov indicated ongoing studies. The meta-analysis used the random-effects model. Twelve studies including 669 patients reported {sup 177}Lu-PSMA RLT. Overall, 43% of the patients had a maximum decline of PSA of ≥50% following treatment with {sup 177}Lu-PSMA RLT. The treatment with {sup 177}Lu-PSMA-617 and {sup 177}Lu-PSMA for imaging and therapy (I and T) had mainly transient adverse effects. Sixteen studies including 1338 patients reported third-line treatment. Overall, 21% of the patients had a best decline of PSA of ≥50% following third-line treatment. After third-line treatment with enzalutamide and cabazitaxel, adverse effects caused discontinuation of treatment for 10% to 23% of the patients. {sup 177}Lu-PSMA RLT gave a best PSA decline ≥50% more often than third-line treatment (mean 44% versus 22%, p = 0.0002, t test). {sup 177}Lu-PSMA RLT gave objective remission more often than third-line treatment (overall 31 of 109 patients versus 43 of 275 patients, p = 0.004, χ{sup 2} test). Median survival was longer after {sup 177}Lu-PSMA RLT than after third-line treatment, but the difference was not statistically significant (mean 14 months versus 12 months, p = 0.32, t test). Adverse effects caused discontinuation of treatment more often for third-line treatment than for {sup 177}Lu-PSMA RLT (22 of 66 patients versus 0 of 469 patients, p < 0.001, χ{sup 2

  13. PSMA targeted radioligandtherapy in metastatic castration resistant prostate cancer after chemotherapy, abiraterone and/or enzalutamide. A retrospective analysis of overall survival

    Energy Technology Data Exchange (ETDEWEB)

    Rahbar, K.; Schaefers, M. [University Hospital Muenster, Department of Nuclear Medicine, Muenster (Germany); Boegemann, M. [University Hospital Muenster, Department of Urology, Muenster (Germany); Yordanova, A.; Essler, M.; Ahmadzadehfar, H. [University Hospital Bonn, Department of Nuclear Medicine, Bonn (Germany); Eveslage, M. [University Hospital Muenster, Institute of Biostatistics and Clinical Research, Muenster (Germany)

    2018-01-15

    Our aim was to evaluate overall survival and parameters prognosticating longer survival in a large and homogeneous group of patients treated with {sup 177}Lu-PSMA-617 radioligand therapy with heavily pretreated advanced metastatic castration resistant prostate cancer. A total of 104 patients were treated with 351 cycles of {sup 177}Lu-PSMA-617. Prostate specific antigen (PSA) changes after the first cycle of therapy were documented prior to a second cycle. Patients were followed-up for overall survival (OS). Any PSA decline, PSA decline ≥50%, initial PSA, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), visceral metastases and cumulative injected activity were analyzed and evaluated according to OS. Multivariable analysis with parameters with a p-value ≤0.05 in univariate analysis was performed, additionally adjusting for age and presence of visceral metastases. A total of 51 patients (49%) died during the observation period. The majority of patients (97%) presented with bone metastases, 77% with lymph node metastases and 32% with visceral metastases. All patients were treated with at least one line of chemotherapy. Either abiraterone or enzalutamide had been given in 100% of the patients. Any PSA decline occurred in 70 (67%) and a PSA decline ≥50% in 34 (33%) of patients after the first cycle. The median OS was 56.0 weeks (95%CI: 50.5-61.5). Initial PSA decline ≥50%, initial LDH, visceral metastases, second line chemotherapy or prior radium-223 did not have an effect on survival, whereas any initial PSA decline, initial ALP <220 U/L and cumulative injected activity ≥18.8 GBq were associated with a longer survival. A step-by-step analysis revealed a PSA decline ≥20.87% as the most noticeable cut-off prognosticating longer survival, which remained an independent prognosticator of improved OS in the multivariate analysis. {sup 177}Lu-PSMA-617 RLT is a new effective therapeutic and seems to prolong survival in patients with advanced m

  14. Toward Maximizing Immunotherapy in Metastatic Castration-Resistant Prostate Cancer – Rationale for Combinatorial Approaches Using Chemotherapy

    International Nuclear Information System (INIS)

    Slovin, Susan R.

    2012-01-01

    Prostate cancer is particularly suited for active immunotherapy because of the expression of a distinctive number of antigens which are overexpressed on prostate cancer cells and cell lines. There is evidence in this disease that tumors promote immune tolerance starting early in the disease course. As such, chemotherapy, by suppressing tumors and activating immune system homeostatic mechanisms, may help overcome this tumor-induced immune tolerance. Sipuleucel-T which has recently been approved in the US, is an autologous cellular product immunotherapy that induces immune activity likely through activation of dendritic cells. This was associated with a survival benefit in the absence of significant toxicity. However, a post hoc analysis of phase III trial participants found a substantial survival benefit to receiving docetaxel some months after sipuleucel-T. However, another phase III immunotherapy trial combining a prostate cancer therapeutic vaccine GVAX plus docetaxel versus standard docetaxel therapy in advanced prostate cancer, observed a lower overall survival with the vaccine regimen. These trials highlight major unresolved questions concerning the optimum choice, dosing, and timing of chemotherapy relative to active immunotherapy and the overall merits of considering this approach. The ideal treatment approach remains unclear; advances in biomarker validation and trial design may likely improve our ability to assess biologic benefit irrespective of the development of true antitumor immunity.

  15. Toward Maximizing Immunotherapy in Metastatic Castration-Resistant Prostate Cancer – Rationale for Combinatorial Approaches Using Chemotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Slovin, Susan R., E-mail: slovins@mskcc.org [Genitourinary Oncology Service, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan–Kettering Cancer Center, New York, NY (United States)

    2012-05-30

    Prostate cancer is particularly suited for active immunotherapy because of the expression of a distinctive number of antigens which are overexpressed on prostate cancer cells and cell lines. There is evidence in this disease that tumors promote immune tolerance starting early in the disease course. As such, chemotherapy, by suppressing tumors and activating immune system homeostatic mechanisms, may help overcome this tumor-induced immune tolerance. Sipuleucel-T which has recently been approved in the US, is an autologous cellular product immunotherapy that induces immune activity likely through activation of dendritic cells. This was associated with a survival benefit in the absence of significant toxicity. However, a post hoc analysis of phase III trial participants found a substantial survival benefit to receiving docetaxel some months after sipuleucel-T. However, another phase III immunotherapy trial combining a prostate cancer therapeutic vaccine GVAX plus docetaxel versus standard docetaxel therapy in advanced prostate cancer, observed a lower overall survival with the vaccine regimen. These trials highlight major unresolved questions concerning the optimum choice, dosing, and timing of chemotherapy relative to active immunotherapy and the overall merits of considering this approach. The ideal treatment approach remains unclear; advances in biomarker validation and trial design may likely improve our ability to assess biologic benefit irrespective of the development of true antitumor immunity.

  16. Radium-223-Dichloride in Castration Resistant Metastatic Prostate Cancer—Preliminary Results of the Response Evaluation Using F-18-Fluoride PET/CT

    Directory of Open Access Journals (Sweden)

    Kalevi Kairemo

    2015-10-01

    Full Text Available The purpose of this study was to evaluate the outcome after Radium-223-dichloride (223RaCl2 treatment of patients with skeletal metastases of castration resistant prostate cancer using whole-body 18F-Fluoride PET/CT. Sodium 18F-fluoride [18F]-NaF PET/CT was performed prior the treatment of 223RaCl2, after the first cycle and after the sixth cycle. The skeletal metastases were analyzed quantitatively using modified PET response evaluation PERCIST criteria. The patients were also analyzed for S-PSA. All ten patients responded in [18F]-NaF scans after 6 cycles, but interim analysis after the 1st cycle did not give additional information about the outcome. The S-PSA decrease correlated with [18F]-NaF response, only 1 patient demonstrated progressive disease, i.e., >25% increase in S-PSA values during 223RaCl2. Our results (although preliminary suggest that 18F-Fluoride PET/CT is useful in the follow-up of castration resistant prostate cancer with skeletal metastases.

  17. Cost per median overall survival month associated with abiraterone acetate and enzalutamide for treatment of patients with metastatic castration-resistant prostate cancer.

    Science.gov (United States)

    Pilon, Dominic; Queener, Marykay; Lefebvre, Patrick; Ellis, Lorie A

    2016-08-01

    To calculate costs per median overall survival (OS) month in chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate plus prednisone (AA + P) or enzalutamide. Median treatment duration and median OS data from published Phase 3 clinical trials and prescribing information were used to calculate costs per median OS month based on wholesale acquisition costs (WACs) for patients with mCRPC treated with AA + P or enzalutamide. Sensitivity analyses were performed to understand how variations in treatment duration and treatment-related monitoring recommendations influenced cost per median OS month. Cost-effectiveness estimates of other Phase 3 trial outcomes were also explored: cost per month of chemotherapy avoided and per median radiographic progression-free survival (rPFS) month. The results demonstrated that AA + P has a lower cost per median OS month than enzalutamide ($3231 vs 4512; 28% reduction), based on the following assumptions: median treatment duration of 14 months for AA + P and 18 months for enzalutamide, median OS of 34.7 months for AA + P and 35.3 months for enzalutamide, and WAC per 30-day supply of $8007.17 for AA + P vs $8847.98 for enzalutamide. Sensitivity analyses showed that accounting for recommended treatment-related monitoring costs or assuming identical treatment durations for AA + P and enzalutamide (18 months) resulted in costs per median OS month 8-27% lower for AA + P than for enzalutamide. Costs per month of chemotherapy avoided were $4448 for AA + P and $5688 for enzalutamide, while costs per month to achieve median rPFS were $6794 for AA + P and $7963 for enzalutamide. This cost-effectiveness analysis demonstrated that costs per median OS month, along with costs of other Phase 3 trial outcomes, were lower for AA + P than for enzalutamide. The findings were robust to sensitivity analyses. These results have important implications

  18. {sup 177}Lu-DKFZ-PSMA-617 therapy in metastatic castration resistant prostate cancer: safety, efficacy, and quality of life assessment

    Energy Technology Data Exchange (ETDEWEB)

    Yadav, Madhav Prasad; Ballal, Sanjana; Tripathi, Madhavi; Damle, Nishikant Avinash; Bal, Chandrasekhar [All India Institute of Medical Sciences, Department of Nuclear Medicine, Ansari Nagar, New Delhi (India); Sahoo, Ranjit Kumar [All India Institute of Medical Sciences, Department of Medical Oncology, BR Ambedkar Rotary Cancer Hospital, New Delhi (India); Seth, Amlesh [All India Institute of Medical Sciences, Department of Urology, New Delhi (India)

    2017-01-15

    The purpose of this study was to evaluate the efficacy and safety of a novel theranostic agent, {sup 177}Lu-DKFZ-PSMA-617 therapy in metastatic castration resistant prostate cancer (mCRPC). Thirty-one mCRPC patients with progressive disease despite second-line hormonal therapy and/or docetaxel chemotherapy were recruited for the study. All patients underwent diagnostic{sup 68}Ga-PSMA-HBED-CCPET/CT, prior to inclusion for therapy. Included patients then underwent quarterly {sup 177}Lu-DKFZ-PSMA-617 therapy. Hematological, kidney function, liver function tests, and serum PSA levels were recorded before and after therapy at 2 weeks, 4 weeks, and 3 month intervals. Biochemical response was assessed with trend in serum PSA levels. Metabolic response was assessed by PERCIST 1 criteria. Clinical response was assessed by visual analogue score (VASmax) analgesic score (AS), Karanofsky performance status (KPS), and toxicity and response criteria of the Eastern Cooperative Oncology Group (ECOG) criteria. The mean age of patients was 65.93 ± 9.77 years (range: 38-81 years). The mean activity administered in the 31 patients was 5069 ± 1845 MBq ranging from one to four cycles. There was a decline in the mean serum PSA levels from the baseline (baseline: 275 ng/mL, post 1st cycle therapy: 141.75 ng/mL). Based on biochemical response criteria 2/31, 20/31, 3/31, and 6/31 had complete response (CR), partial response(PR), stable disease (SD), and progressive disease (PD), respectively. Metabolic response revealed 2/6 patients with CR, and the remaining 3/6 patients with PR and 1/6 patients with SD. The mean VASmax score decreased from 7.5 to 3. The mean analgesic score decreased from 2.5 to 1.8 after therapy. The mean KPS score improved from 50.32 to 65.42 after therapies. The mean ECOG performance status improved from 2.54 to 1.78 after therapy. Two patients experienced grade I and grade II hemoglobin toxicity each. None of the patients experienced nephrotoxicity or hepatotoxicity

  19. Analytical Validation and Clinical Qualification of a New Immunohistochemical Assay for Androgen Receptor Splice Variant-7 Protein Expression in Metastatic Castration-resistant Prostate Cancer.

    Science.gov (United States)

    Welti, Jonathan; Rodrigues, Daniel Nava; Sharp, Adam; Sun, Shihua; Lorente, David; Riisnaes, Ruth; Figueiredo, Ines; Zafeiriou, Zafeiris; Rescigno, Pasquale; de Bono, Johann S; Plymate, Stephen R

    2016-10-01

    The androgen receptor splice variant-7 (AR-V7) has been implicated in the development of castration-resistant prostate cancer (CRPC) and resistance to abiraterone and enzalutamide. To develop a validated assay for detection of AR-V7 protein in tumour tissue and determine its expression and clinical significance as patients progress from hormone-sensitive prostate cancer (HSPC) to CRPC. Following monoclonal antibody generation and validation, we retrospectively identified patients who had HSPC and CRPC tissue available for AR-V7 immunohistochemical (IHC) analysis. Nuclear AR-V7 expression was determined using IHC H score (HS) data. The change in nuclear AR-V7 expression from HSPC to CRPC and the association between nuclear AR-V7 expression and overall survival (OS) was determined. Nuclear AR-V7 expression was significantly lower in HSPC (median HS 50, interquartile range [IQR] 17.5-90) compared to CRPC (HS 135, IQR 80-157.5; pprostate cancer. A higher level of AR-V7 identifies a group of patients who respond less well to certain prostate cancer treatments and live for a shorter period of time. Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

  20. Abiraterone Acetate for the Treatment of Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer: An Evidence Review Group Perspective of an NICE Single Technology Appraisal.

    Science.gov (United States)

    Ramaekers, Bram L T; Riemsma, Rob; Tomini, Florian; van Asselt, Thea; Deshpande, Sohan; Duffy, Steven; Armstrong, Nigel; Severens, Johan L; Kleijnen, Jos; Joore, Manuela A

    2017-02-01

    The National Institute for Health and Care Excellence (NICE) invited Janssen, the company manufacturing abiraterone acetate (AA; tradename Zytiga ® ), to submit evidence for the clinical and cost effectiveness of AA in combination with prednisone/prednisolone (AAP) compared with watchful waiting (i.e. best supportive care [BSC]) for chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (mCRPC). Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Maastricht University Medical Center, was commissioned as the Evidence Review Group (ERG). This paper presents a summary of the company submission (CS), the ERG report, subsequent addenda, and the development of the NICE guidance for the use of this drug in England and Wales by the Appraisal Committee (AC). The ERG produced a critical review of the clinical and cost effectiveness of AAP based on the CS. An important question in this appraisal was, according to the ERG, whether AAP followed by docetaxel is more effective than BSC followed by docetaxel. In the COU-AA-302 trial, 239 of 546 (43.8 %) AAP patients and 304 of 542 (56.1 %) BSC patients received docetaxel as subsequent therapy, following AA or placebo. The results for this specific group of patients were not presented in the CS; therefore, the ERG asked the company to provide these data in the clarification letter; however, these data were presented as commercial-in-confidence and cannot therefore be reported here. The ERG's critical assessment of the company's economic evaluation highlighted a number of concerns, including (a) not using the intention-to-treat (ITT) population; (b) inconsistencies in estimating prediction equations; (c) not fully incorporating the impact of adverse events; (d) incorrectly incorporating the new patient access scheme (PAS); and (e) the assumption that AA non-compliance leads to recoverable drug costs. Although some of these issues were adjusted in the ERG base case, the ERG could not estimate

  1. Imaging response during therapy with radium-223 for castration-resistant prostate cancer with bone metastases

    DEFF Research Database (Denmark)

    Keizman, D; Fosboel, M O; Reichegger, H

    2017-01-01

    BACKGROUND: The imaging response to radium-223 therapy is at present poorly described. We aimed to describe the imaging response to radium-223 treatment. METHODS: We retrospectively evaluated the computed tomography (CT) and bone scintigraphy response of metastatic castration-resistant prostate c....../or radiological) may be noted during the first 3 months, and should not be confused with progression. Imaging by CT scan should be considered after three and six doses of radium-223 to rule out extraskeletal disease progression....

  2. Clinical Outcomes from Androgen Signaling-directed Therapy after Treatment with Abiraterone Acetate and Prednisone in Patients with Metastatic Castration-resistant Prostate Cancer: Post Hoc Analysis of COU-AA-302.

    Science.gov (United States)

    Smith, Matthew R; Saad, Fred; Rathkopf, Dana E; Mulders, Peter F A; de Bono, Johann S; Small, Eric J; Shore, Neal D; Fizazi, Karim; Kheoh, Thian; Li, Jinhui; De Porre, Peter; Todd, Mary B; Yu, Margaret K; Ryan, Charles J

    2017-07-01

    In the COU-AA-302 trial, abiraterone acetate plus prednisone significantly increased overall survival for patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC). Limited information exists regarding response to subsequent androgen signaling-directed therapies following abiraterone acetate plus prednisone in patients with mCRPC. We investigated clinical outcomes associated with subsequent abiraterone acetate plus prednisone (55 patients) and enzalutamide (33 patients) in a post hoc analysis of COU-AA-302. Prostate-specific antigen (PSA) response was assessed. Median time to PSA progression was estimated using the Kaplan-Meier method. The PSA response rate (≥50% PSA decline, unconfirmed) was 44% and 67%, respectively. The median time to PSA progression was 3.9 mo (range 2.6-not estimable) for subsequent abiraterone acetate plus prednisone and 2.8 mo (range 1.8-not estimable) for subsequent enzalutamide. The majority of patients (68%) received intervening chemotherapy before subsequent abiraterone acetate plus prednisone or enzalutamide. While acknowledging the limitations of post hoc analyses and high censoring (>75%) in both treatment groups, these results suggest that subsequent therapy with abiraterone acetate plus prednisone or enzalutamide for patients who progressed on abiraterone acetate is associated with limited clinical benefit. This analysis showed limited clinical benefit for subsequent abiraterone acetate plus prednisone or enzalutamide in patients with metastatic castration-resistant prostate cancer following initial treatment with abiraterone acetate plus prednisone. This analysis does not support prioritization of subsequent abiraterone acetate plus prednisone or enzalutamide following initial therapy with abiraterone acetate plus prednisone. Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

  3. Aflibercept versus placebo in combination with docetaxel and prednisone for treatment of men with metastatic castration-resistant prostate cancer (VENICE): a phase 3, double-blind randomised trial.

    Science.gov (United States)

    Tannock, Ian F; Fizazi, Karim; Ivanov, Sergey; Karlsson, Camilla Thellenberg; Fléchon, Aude; Skoneczna, Iwona; Orlandi, Francisco; Gravis, Gwenaelle; Matveev, Vsevolod; Bavbek, Sevil; Gil, Thierry; Viana, Luciano; Arén, Osvaldo; Karyakin, Oleg; Elliott, Tony; Birtle, Alison; Magherini, Emmanuelle; Hatteville, Laurence; Petrylak, Daniel; Tombal, Bertrand; Rosenthal, Mark

    2013-07-01

    Docetaxel plus prednisone is standard first-line chemotherapy for men with metastatic castrate-resistant prostate cancer. Aflibercept is a recombinant human fusion protein that binds A and B isoforms of VEGF and placental growth factor, thereby inhibiting angiogenesis. We assessed whether the addition of aflibercept to docetaxel and prednisone would improve overall survival in men with metastatic castrate-resistant prostate cancer compared with the addition of placebo to docetaxel and prednisone. VENICE was a phase 3, multicentre, randomised double-blind placebo-controlled parallel group study done in 31 countries (187 sites). Men with metastatic castrate-resistant prostate cancer, adequate organ function, and no prior chemotherapy were treated with docetaxel (75 mg/m(2) intravenously every 3 weeks) and oral prednisone (5 mg twice daily) and randomly allocated (1:1) to receive aflibercept (6 mg/kg) or placebo, intravenously, every 3 weeks. Treatment allocation was done centrally via an interactive voice response system, using a computer-generated sequence with a permuted-block size of four and stratified according Eastern Co-operative Group performance status (0-1 vs 2). Patients, investigators, and other individuals responsible for study conduct and data analysis were masked to treatment assignment. Aflibercept or placebo vials were supplied in identical boxes. The primary endpoint was overall survival using intention-to-treat analysis. This is the primary analysis of the completed trial. The study is registered with ClinicalTrials.gov, number NCT00519285 FINDINGS: Between Aug 17, 2007, and Feb 11, 2010, 1224 men were randomly allocated to treatment: 612 to each group. At final analysis, median follow-up was 35 months (IQR 29-41) and 873 men had died. Median overall survival was 22·1 months (95·6% CI 20·3-24·1) in the aflibercept group and 21·2 months (19·6-23·8) in the placebo group (stratified hazard ratio 0·94, 95·6% CI 0·82-1·08; p=0·38). We

  4. Overall survival and response pattern of castration-resistant metastatic prostate cancer to multiple cycles of radioligand therapy using [{sup 177}Lu]Lu-PSMA-617

    Energy Technology Data Exchange (ETDEWEB)

    Ahmadzadehfar, Hojjat; Wegen, Simone; Yordanova, Anna; Kuerpig, Stefan; Eppard, Elisabeth; Wei, Xiao; Schlenkhoff, Carl; Essler, Markus [University Hospital Bonn, Department of Nuclear Medicine, Bonn (Germany); Fimmers, Rolf [University of Bonn, Institute for Medical Biometry, Informatics and Epidemiology, Bonn (Germany); Hauser, Stefan [University Hospital Bonn, Department of Urology, Bonn (Germany)

    2017-08-15

    Up to 30% of patients with castration-resistant prostate cancer (CRPC) do not show any response to the first cycle of radioligand therapy (RLT) with [{sup 177}Lu]Lu-PSMA-617 (Lu-PSMA). We evaluated patient response to the second and third cycles of RLT in patients that underwent at least three cycles. The second aim of this study was to calculate the median overall survival (OS) of responders and non-responders after the first cycle and after all three cycles of RLT. CRPC patients were treated with Lu-PSMA, with a median interval of 8 weeks between each cycle. The tumour marker prostate-specific antigen (PSA) was used as the marker for response evaluation. Fifty-two patients underwent a total of 190 cycles of RLT (3-6 cycles per patient). Of these, 80.8% showed a decline in PSA 2 months after the first cycle, with 44.2% showing a PSA decline of ≥50%. When compared to baseline PSA, 73.1% showed a PSA decline after the third cycle. 50% of patients that did not show any response to the first cycle also did not respond to the second and third cycles. The median OS was 60 weeks in all patients. The median OS was significantly longer for patients that showed any PSA decline after the first cycle compared to patients without PSA decline (68 vs. 33 weeks). There was a significant difference in median OS between responders and non-responders for a change in PSA after the third cycle compared to baseline PSA. Patients with a positive response to RLT, regardless of the rate of decline, had a significantly longer median OS. Of the patients that did not show any response to the first cycle, 50% responded to the second or third cycles. (orig.)

  5. Overall survival and response pattern of castration-resistant metastatic prostate cancer to multiple cycles of radioligand therapy using [177Lu]Lu-PSMA-617.

    Science.gov (United States)

    Ahmadzadehfar, Hojjat; Wegen, Simone; Yordanova, Anna; Fimmers, Rolf; Kürpig, Stefan; Eppard, Elisabeth; Wei, Xiao; Schlenkhoff, Carl; Hauser, Stefan; Essler, Markus

    2017-08-01

    Up to 30% of patients with castration-resistant prostate cancer (CRPC) do not show any response to the first cycle of radioligand therapy (RLT) with [ 177 Lu]Lu-PSMA-617 (Lu-PSMA). We evaluated patient response to the second and third cycles of RLT in patients that underwent at least three cycles. The second aim of this study was to calculate the median overall survival (OS) of responders and non-responders after the first cycle and after all three cycles of RLT. CRPC patients were treated with Lu-PSMA, with a median interval of 8 weeks between each cycle. The tumour marker prostate-specific antigen (PSA) was used as the marker for response evaluation. Fifty-two patients underwent a total of 190 cycles of RLT (3-6 cycles per patient). Of these, 80.8% showed a decline in PSA 2 months after the first cycle, with 44.2% showing a PSA decline of ≥50%. When compared to baseline PSA, 73.1% showed a PSA decline after the third cycle. 50% of patients that did not show any response to the first cycle also did not respond to the second and third cycles. The median OS was 60 weeks in all patients. The median OS was significantly longer for patients that showed any PSA decline after the first cycle compared to patients without PSA decline (68 vs. 33 weeks). There was a significant difference in median OS between responders and non-responders for a change in PSA after the third cycle compared to baseline PSA. Patients with a positive response to RLT, regardless of the rate of decline, had a significantly longer median OS. Of the patients that did not show any response to the first cycle, 50% responded to the second or third cycles.

  6. External validation and newly development of a nomogram to predict overall survival of abiraterone-treated, castration-resistant patients with metastatic prostate cancer

    Directory of Open Access Journals (Sweden)

    Yun-Jie Yang

    2018-01-01

    Full Text Available Abiraterone acetate is approved for the treatment of castration-resistant prostate cancer (CRPC; however, its effects vary. An accurate prediction model to identify patient groups that will benefit from abiraterone treatment is therefore urgently required. The Chi model exhibits a good profile for risk classification, although its utility for the chemotherapy-naive group is unclear. This study aimed to externally validate the Chi model and develop a new nomogram to predict overall survival (OS. We retrospectively analyzed a cohort of 110 patients. Patients were distributed among good-, intermediate-, and poor-risk groups, according to the Chi model. The good-, intermediate-, and poor-risk groups had a sample size of 59 (53.6%, 34 (30.9%, and 17 (15.5% in our dataset, and a median OS of 48.4, 29.1, and 10.5 months, respectively. The C-index of external validation of Chi model was 0.726. Univariate and multivariate analyses identified low hemoglobin concentrations (<110 g l−1, liver metastasis, and a short time interval from androgen deprivation therapy to abiraterone initiation (<36 months as predictors of OS. Accordingly, a new nomogram was developed with a C-index equal to 0.757 (95% CI, 0.678–0.836. In conclusion, the Chi model predicted the prognosis of abiraterone-treated, chemotherapy-naive patients with mCRPC, and we developed a new nomogram to predict the overall survival of this group of patients with less parameters.

  7. Abiraterone Acetate: A Review in Metastatic Castration-Resistant Prostrate Cancer.

    Science.gov (United States)

    Scott, Lesley J

    2017-09-01

    Oral abiraterone acetate (Zytiga ® ) is a selective inhibitor of CYP17 and thereby inhibits androgen biosynthesis, with androgen signalling crucial in the progression from primary to metastatic prostate cancer (PC) and subsequently, in the development of metastatic castration-resistant PC (mCRPC). In large phase 3 trials and in the clinical practice setting, oral abiraterone acetate in combination with prednisone was an effective treatment and had an acceptable, manageable tolerability and safety profile in chemotherapy-naive and docetaxel-experienced men with mCRPC. In the pivotal global phase 3 trials, relative to placebo (+prednisone), abiraterone acetate (+prednisone) prolonged overall survival (OS) at data maturity (final analysis) and radiographic progression-free survival (rPFS) at all assessed timepoints. Given its efficacy in prolonging OS and its convenient once-daily oral regimen, in combination with prednisone, abiraterone acetate is an important first-line option for the treatment of mCRPC.

  8. Efficacy and safety of enzalutamide in patients 75 years or older with chemotherapy-naive metastatic castration-resistant prostate cancer

    DEFF Research Database (Denmark)

    Graff, J N; Baciarello, G; Armstrong, A J

    2016-01-01

    BACKGROUND: Prostate cancer disproportionately affects older men. Because age affects treatment decisions, it is important to understand the efficacy and tolerability of therapies for advanced prostate cancer in elderly men. This analysis describes efficacy and safety outcomes in men aged ≥75 years......-resistant prostate cancer. Overall survival (OS) and radiographic progression-free survival (rPFS) were coprimary end points. Subgroup analysis of men aged ≥75 years (elderly) and men aged ... who received enzalutamide, an androgen receptor inhibitor, in the phase III PREVAIL trial. PATIENTS AND METHODS: PREVAIL was a randomised, double-blind, multinational study of oral enzalutamide 160 mg/day (N = 872) versus placebo (N = 845) in chemotherapy-naive men with metastatic castration...

  9. Novel Imidazopyridine Derivatives Possess Anti-Tumor Effect on Human Castration-Resistant Prostate Cancer Cells.

    Directory of Open Access Journals (Sweden)

    Matthew A Ingersoll

    Full Text Available Prostate cancer (PCa is the second leading cause of cancer-related death afflicting United States males. Most treatments to-date for metastatic PCa include androgen-deprivation therapy and second-generation anti-androgens such as abiraterone acetate and enzalutamide. However, a majority of patients eventually develop resistance to these therapies and relapse into the lethal, castration-resistant form of PCa to which no adequate treatment option remains. Hence, there is an immediate need to develop effective therapeutic agents toward this patient population. Imidazopyridines have recently been shown to possess Akt kinase inhibitory activity; thus in this study, we investigated the inhibitory effect of novel imidazopyridine derivatives HIMP, M-MeI, OMP, and EtOP on different human castration-resistant PCa cells. Among these compounds, HIMP and M-MeI were found to possess selective dose- and time-dependent growth inhibition: they reduced castration-resistant PCa cell proliferation and spared benign prostate epithelial cells. Using LNCaP C-81 cells as the model system, these compounds also reduced colony formation as well as cell adhesion and migration, and M-MeI was the most potent in all studies. Further investigation revealed that while HIMP primarily inhibits PCa cell growth via suppression of PI3K/Akt signaling pathway, M-MeI can inhibit both PI3K/Akt and androgen receptor pathways and arrest cell growth in the G2 phase. Thus, our results indicate the novel compound M-MeI to be a promising candidate for castration-resistant PCa therapy, and future studies investigating the mechanism of imidazopyridine inhibition may aid to the development of effective anti-PCa agents.

  10. Novel Imidazopyridine Derivatives Possess Anti-Tumor Effect on Human Castration-Resistant Prostate Cancer Cells.

    Science.gov (United States)

    Ingersoll, Matthew A; Lyons, Anastesia S; Muniyan, Sakthivel; D'Cunha, Napoleon; Robinson, Tashika; Hoelting, Kyle; Dwyer, Jennifer G; Bu, Xiu R; Batra, Surinder K; Lin, Ming-Fong

    2015-01-01

    Prostate cancer (PCa) is the second leading cause of cancer-related death afflicting United States males. Most treatments to-date for metastatic PCa include androgen-deprivation therapy and second-generation anti-androgens such as abiraterone acetate and enzalutamide. However, a majority of patients eventually develop resistance to these therapies and relapse into the lethal, castration-resistant form of PCa to which no adequate treatment option remains. Hence, there is an immediate need to develop effective therapeutic agents toward this patient population. Imidazopyridines have recently been shown to possess Akt kinase inhibitory activity; thus in this study, we investigated the inhibitory effect of novel imidazopyridine derivatives HIMP, M-MeI, OMP, and EtOP on different human castration-resistant PCa cells. Among these compounds, HIMP and M-MeI were found to possess selective dose- and time-dependent growth inhibition: they reduced castration-resistant PCa cell proliferation and spared benign prostate epithelial cells. Using LNCaP C-81 cells as the model system, these compounds also reduced colony formation as well as cell adhesion and migration, and M-MeI was the most potent in all studies. Further investigation revealed that while HIMP primarily inhibits PCa cell growth via suppression of PI3K/Akt signaling pathway, M-MeI can inhibit both PI3K/Akt and androgen receptor pathways and arrest cell growth in the G2 phase. Thus, our results indicate the novel compound M-MeI to be a promising candidate for castration-resistant PCa therapy, and future studies investigating the mechanism of imidazopyridine inhibition may aid to the development of effective anti-PCa agents.

  11. Weekly ascorbic acid infusion in castration-resistant prostate cancer patients

    DEFF Research Database (Denmark)

    Nielsen, Torben K.; Højgaard, Martin; Andersen, Jon T.

    2017-01-01

    of this treatment. Methods: This non-comparative, single-center, phase II trial included patients with chemotherapy-naïve, metastatic castration-resistant prostate cancer (mCRPC) from an outpatient clinic to evaluate the efficacy and safety of IV AA therapy. Patients received weekly infusions of AA (week 1, 5 g....../L was recorded at week 12. Among the secondary endpoints, no signs of disease remission were observed. In total, 53 adverse events (AEs) were recorded. Eleven were graded as "serious". Three AEs were directly related to AA, and all of which were related to fluid load. Conclusions: Infusion with 60 g of AA did...

  12. Weekly ascorbic acid infusion in castration-resistant prostate cancer patients

    DEFF Research Database (Denmark)

    Nielsen, Torben K.; Højgaard, Martin; Andersen, Jon T.

    2017-01-01

    of this treatment.  Methods: This non-comparative, single-center, phase II trial included patients with chemotherapy-naïve, metastatic castration-resistant prostate cancer (mCRPC) from an outpatient clinic to evaluate the efficacy and safety of IV AA therapy. Patients received weekly infusions of AA (week 1, 5 g...... μg/L was recorded at week 12. Among the secondary endpoints, no signs of disease remission were observed. In total, 53 adverse events (AEs) were recorded. Eleven were graded as "serious". Three AEs were directly related to AA, and all of which were related to fluid load.  Conclusions: Infusion...

  13. Predictors of Chemotherapy-Induced Toxicity and Treatment Outcomes in Elderly Versus Younger Patients With Metastatic Castration-Resistant Prostate Cancer

    DEFF Research Database (Denmark)

    Kongsted, Per; Svane, Inge Marie; Lindberg, Henriette

    2016-01-01

    records from 421 consecutive patients treated with first-line docetaxel (75 mg/m(2) every 3 weeks) and low-dose prednisolone from 2007 to 2013 at Herlev University Hospital were reviewed. Common Terminology Criteria for Adverse Events, version 4.0, and the Prostate Cancer Working Group 2 guidelines were...... used to evaluate treatment-related toxicity and efficacy. Logistic and Cox regression models were used to predict toxicity and survival. RESULTS: Age ≥ 75 years (odds ratio [OR], 2.33), baseline levels of hemoglobin (OR, 0.89), and previous metastatic epidural spinal cord compression (MESCC; OR, 1...

  14. Post hoc analysis of Japanese patients from the placebo-controlled PREVAIL trial of enzalutamide in patients with chemotherapy-naive, metastatic castration-resistant prostate cancer-updated results.

    Science.gov (United States)

    Kimura, Go; Ueda, Takeshi

    2017-03-01

    A post hoc analysis of interim results from PREVAIL, a Phase III, double-blind, placebo-controlled trial of men with metastatic castration-resistant prostate cancer, demonstrated that the treatment effects, safety and pharmacokinetics of enzalutamide in Japanese patients were generally consistent with those of the overall population. A recent longer term analysis of PREVAIL demonstrated continued benefit of enzalutamide treatment over placebo. Here, we report results from a post hoc analysis of Japanese patients enrolled in PREVAIL at the prespecified number of deaths for the final analysis. In Japanese patients, enzalutamide reduced the risk of death by 35% (hazard ratio, 0.65; 95% confidence interval, 0.28-1.51) and the risk of investigator-assessed radiographic progression or death by 60% (hazard ratio, 0.40; 95% confidence interval, 0.18-0.90). These results show that treatment effects and safety in Japanese patients in the final analysis of PREVAIL continued to be generally consistent with those of the overall population. © The Author 2016. Published by Oxford University Press.

  15. Post hoc analysis of Japanese patients from the placebo-controlled PREVAIL trial of enzalutamide in patients with chemotherapy-naive, metastatic castration-resistant prostate cancer—updated results

    Science.gov (United States)

    Ueda, Takeshi

    2017-01-01

    Abstract A post hoc analysis of interim results from PREVAIL, a Phase III, double-blind, placebo-controlled trial of men with metastatic castration-resistant prostate cancer, demonstrated that the treatment effects, safety and pharmacokinetics of enzalutamide in Japanese patients were generally consistent with those of the overall population. A recent longer term analysis of PREVAIL demonstrated continued benefit of enzalutamide treatment over placebo. Here, we report results from a post hoc analysis of Japanese patients enrolled in PREVAIL at the prespecified number of deaths for the final analysis. In Japanese patients, enzalutamide reduced the risk of death by 35% (hazard ratio, 0.65; 95% confidence interval, 0.28–1.51) and the risk of investigator-assessed radiographic progression or death by 60% (hazard ratio, 0.40; 95% confidence interval, 0.18–0.90). These results show that treatment effects and safety in Japanese patients in the final analysis of PREVAIL continued to be generally consistent with those of the overall population. PMID:28003320

  16. Molecular biology of castration-resistant prostate cancer: basis for the novel therapeutic targets.

    Science.gov (United States)

    Mellado, Begoña; Marin Aguilera, Mercedes; Pereira, Maria Veronica

    2013-06-01

    Prostate cancer cells express the androgen receptor (AR) and need the presence of androgens to survive. Androgen suppression is the gold standard first-line therapy for metastatic disease. Almost all prostate cancer patients initially respond to hormonal therapy, but most of them gradually develop castration-resistant progression. Recent evidence has shown that progression at the castration resistant prostate cancer (CRPC) stage is often mediated by AR signalling. Importantly, subsequent AR androgen inhibition, by abiraterone acetate or enzalutamide, has shown to improve patients' survival. Several mechanisms that enhance AR signalling in an androgen-depleted environment have been elucidated:(1) AR mutations that allow activation by low androgen levels or by other endogenous steroids, (2) AR amplification and/or overexpression,(3)increased local intracrine synthesis of androgens, (4) changes in AR cofactors and (5) cross-talk with cytokines and growth factors. Today, there are under development a number of novel agents targeting the AR signaling pathway. This article reviews the postulated mechanisms of AR-driven resistance to androgen suppression that have contributed to the development of new hormonal therapeutic strategies in prostate cancer.

  17. Novel Therapeutic Targets to Inhibit Tumor Microenvironment Induced Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2017-12-01

    AWARD NUMBER: W81XWH-13-1-0163 TITLE: Novel Therapeutic Targets to Inhibit Tumor Microenvironment Induced Castration-resistant Prostate Cancer ...Prostate Cancer 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Feng Yang, Ph.D. 5d. PROJECT NUMBER 5e. TASK NUMBER E-Mail: fyang@bcm.edu...W81XWH-13-1-0163 " Novel Therapeutic Targets to Inhibit Tumor Microenvironment Induced Castration-resistant Prostate Cancer " Introduction AR signaling

  18. Castration resistant prostate cancer in the year 2013

    International Nuclear Information System (INIS)

    Marencak, J.

    2013-01-01

    Prostate cancer (PC) is the most frequent solid neoplasm in Europe and therefore is regarded as one of the major medical problems of the male population. PC is extremely complicated and interindividual different tumor. The method of treatment depends on several factors, but mainly on the stage of prostate cancer. The term Hormone resistant (refractory) prostate cancer (HRPC) was used in older terminology. HRPC is cancer that progresses despite castrate levels of testosterone achieved androgen deprivation therapy (ADT), which is resistant to any hormonal therapy. Currently is increasingly used (instead of name HRPC) name CRPC – so called PC resistant for castration (CRPC – castration resistant prostate cancer), which is still able to respond to certain hormonal manipulation, although it meets the the criteria for HRPC. Objectives of article: provide information to the general medical community (and especially urologists and oncologists) mainly about a treatment of complicated issues of CRPC. The basic data on the current and future. The article presented basic data on the current and future possibilities of such therapy and increasing basic knowledge about treating CRPC should improve the care of patients with advanced PC. (author)

  19. Circulating tumor cell counts are prognostic of overall survival in SWOG S0421: a phase III trial of docetaxel with or without atrasentan for metastatic castration-resistant prostate cancer.

    Science.gov (United States)

    Goldkorn, Amir; Ely, Benjamin; Quinn, David I; Tangen, Catherine M; Fink, Louis M; Xu, Tong; Twardowski, Przemyslaw; Van Veldhuizen, Peter J; Agarwal, Neeraj; Carducci, Michael A; Monk, J Paul; Datar, Ram H; Garzotto, Mark; Mack, Philip C; Lara, Primo; Higano, Celestia S; Hussain, Maha; Thompson, Ian Murchie; Cote, Richard J; Vogelzang, Nicholas J

    2014-04-10

    Circulating tumor cell (CTC) enumeration has not been prospectively validated in standard first-line docetaxel treatment for metastatic castration-resistant prostate cancer. We assessed the prognostic value of CTCs for overall survival (OS) and disease response in S0421, a phase III trial of docetaxel plus prednisone with or without atrasentan. CTCs were enumerated at baseline (day 0) and before cycle two (day 21) using CellSearch. Baseline counts and changes in counts from day 0 to 21 were evaluated for association with OS, prostate-specific antigen (PSA), and RECIST response using Cox regression as well as receiver operator characteristic (ROC) curves, integrated discrimination improvement (IDI) analysis, and regression trees. Median day-0 CTC count was five cells per 7.5 mL, and CTCs < versus ≥ five per 7.5 mL were significantly associated with baseline PSA, bone pain, liver disease, hemoglobin, alkaline phosphatase, and subsequent PSA and RECIST response. Median OS was 26 months for < five versus 13 months for ≥ five CTCs per 7.5 mL at day 0 (hazard ratio [HR], 2.74 [adjusting for covariates]). ROC curves had higher areas under the curve for day-0 CTCs than for PSA, and IDI analysis showed that adding day-0 CTCs to baseline PSA and other covariates increased predictive accuracy for survival by 8% to 10%. Regression trees yielded new prognostic subgroups, and rising CTC count from day 0 to 21 was associated with shorter OS (HR, 2.55). These data validate the prognostic utility of CTC enumeration in a large docetaxel-based prospective cohort. Baseline CTC counts were prognostic, and rising CTCs at 3 weeks heralded significantly worse OS, potentially serving as an early metric to help redirect and optimize therapy in this clinical setting.

  20. Castration resistant prostate cancer - something new in the year 2014?

    International Nuclear Information System (INIS)

    Marencak, J.

    2014-01-01

    Prostate cancer (PC) is the most frequent solid neoplasm in Europe and therefore is regarded as one of the major medical problem of the male population. PC is extremely complicated and interindividual different tumor. The method of treatment depends on several factors, but mainly on the stage of prostate cancer. The term Hormone resistant (refractory) prostate cancer (HRPC) was used in older terminology. HRPC is cancer that progresses despite castrate levels of testosterone achieved androgen deprivation therapy (ADT), which is resistant to any hormonal therapy. Currently is increasingly used (instead of name HRPC) name CRPC – so called PC resistant for castration (CRPC – castration resistant prostate cancer), which is still able to respond to certain hormonal manipulation, although it meets the the criteria for HRPC. This state probably arises from either clonal selection of androgen – independent cell lines or increased ligand – independent activation of androgen receptors. Men with CRPC are quite a heterogeneous group; they include men with increasing prostate specific antigen (PSA) only and no demonstrable metastases, and men who have many bone and/ or visceral metastases, pain and poor functional status. Survival can range from only a few months to 4 years or more. Historically, therapy had little effect beyond modest palliation. More recently, significantly more options have become available and there are now several treatments that not only improve quality of life and pain palliation, but also increase overall survival. Some of the trials with important results for the treatment of CRPC are summarized in this paper. Objectives of article: provide information to the general medical community (and especially urologists and oncologists) about the possible pathogenesis of CRPC, complicated issues of treatment and evaluation of its effectiveness in patients with CRPC. The article presented basic data on the current and future possibilities of such therapy

  1. Androgen receptor variant-7: an important predictive biomarker in castrate resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Oliver Sartor

    2015-06-01

    Full Text Available The recent manuscript in New England Journal of Medicine by Antonarakis et al. [1] has important clinical implications. This study evaluates mRNA expression of a particular androgen receptor splice variant-7 (AR-V7, in circulating tumor cells (CTCs from metastatic castrate-resistant prostate cancer (mCRPC patients receiving enzalutamide or abiraterone. The findings were striking, none of the 18 patients with detectable AR-V7 in CTCs had prostate-specific antigen (PSA responses. Further, the median time to PSA progression after enzalutamide or abiraterone treatment was only 1.3-1.4 months in AR-V7-positive patients as compared to 5.3-6.1 months in AR-V7 negative patients. AR-V7 in CTCs was also associated with shorter survival.

  2. Novel agents in the management of castration resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Shruti Chaturvedi

    2014-01-01

    Full Text Available Prostate cancer (PCa is a leading cause of cancer mortality in men and despite high cure rates with surgery and/or radiation, 30-40% of patients will eventually develop advanced disease. Androgen deprivation is the first line therapy for standard of care for men with advanced disease. Eventually however all men will progress to castration-resistant prostate cancer (CRPC. Insight into the molecular mechanisms of androgen resistance has led to the development of alternative novel hormonal agents. Newer hormonal agents such as abiraterone, enzalutamide and TOK-001; and the first cancer vaccine, Sipuleucel T have been approved for use in men with CRPC. The recognition of the importance of bone health and morbidity associated with skeletal related events has led to the introduction of the receptor activator of nuclear factor kappa-B-ligand inhibitor denosumab. Other molecularly targeted therapies have shown promise in pre-clinical studies, but this has not consistently translated into clinical efficacy. It is increasingly evident that CRPC is a heterogeneous disease and an individualized approach directed at identifying primary involvement of specific pathways could maximize the benefit from targeted therapies. This review focuses on targeted therapy for PCa with special emphasis on therapies that have been Food and Drug Administration approved for use in men with CRPC.

  3. Phase I/II clinical trial of dendritic-cell based immunotherapy (DCVAC/PCa) combined with chemotherapy in patients with metastatic, castration-resistant prostate cancer.

    Science.gov (United States)

    Podrazil, Michal; Horvath, Rudolf; Becht, Etienne; Rozkova, Daniela; Bilkova, Pavla; Sochorova, Klara; Hromadkova, Hana; Kayserova, Jana; Vavrova, Katerina; Lastovicka, Jan; Vrabcova, Petra; Kubackova, Katerina; Gasova, Zdenka; Jarolim, Ladislav; Babjuk, Marek; Spisek, Radek; Bartunkova, Jirina; Fucikova, Jitka

    2015-07-20

    We conducted an open-label, single-arm Phase I/II clinical trial in metastatic CRPC (mCRPC) patients eligible for docetaxel combined with treatment with autologous mature dendritic cells (DCs) pulsed with killed LNCaP prostate cancer cells (DCVAC/PCa). The primary and secondary endpoints were safety and immune responses, respectively. Overall survival (OS), followed as a part of the safety evaluation, was compared to the predicted OS according to the Halabi and MSKCC nomograms. Twenty-five patients with progressive mCRPC were enrolled. Treatment comprised of initial 7 days administration of metronomic cyclophosphamide 50 mg p.o. DCVAC/PCa treatment consisted of a median twelve doses of 1 × 107 dendritic cells per dose injected s.c. (Aldara creme was applied at the site of injection) during a one-year period. The initial 2 doses of DCVAC/PCa were administered at a 2-week interval, followed by the administration of docetaxel (75 mg/m2) and prednisone (5 mg twice daily) given every 3 weeks until toxicity or intolerance was observed. The DCVAC/PCa was then injected every 6 weeks up to the maximum number of doses manufactured from one leukapheresis. No serious DCVAC/PCa-related adverse events have been reported. The median OS was 19 months, whereas the predicted median OS was 11.8 months with the Halabi nomogram and 13 months with the MSKCC nomogram. Kaplan-Meier analyses showed that patients had a lower risk of death compared with both MSKCC (Hazard Ratio 0.26, 95% CI: 0.13-0.51) and Halabi (Hazard Ratio 0.33, 95% CI: 0.17-0.63) predictions. We observed a significant decrease in Tregs in the peripheral blood. The long-term administration of DCVAC/PCa led to the induction and maintenance of PSA specific T cells. We did not identify any immunological parameter that significantly correlated with better OS. In patients with mCRPC, the combined chemoimmunotherapy with DCVAC/PCa and docetaxel was safe and resulted in longer than expected survival. Concomitant chemotherapy

  4. Androgens as therapy for androgen receptor-positive castration-resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Lin Hui-Ping

    2011-08-01

    Full Text Available Abstract Prostate cancer is the most frequently diagnosed non-cutaneous tumor of men in Western countries. While surgery is often successful for organ-confined prostate cancer, androgen ablation therapy is the primary treatment for metastatic prostate cancer. However, this therapy is associated with several undesired side-effects, including increased risk of cardiovascular diseases. Shortening the period of androgen ablation therapy may benefit prostate cancer patients. Intermittent Androgen Deprivation therapy improves quality of life, reduces toxicity and medical costs, and delays disease progression in some patients. Cell culture and xenograft studies using androgen receptor (AR-positive castration-resistant human prostate cancers cells (LNCaP, ARCaP, and PC-3 cells over-expressing AR suggest that androgens may suppress the growth of AR-rich prostate cancer cells. Androgens cause growth inhibition and G1 cell cycle arrest in these cells by regulating c-Myc, Skp2, and p27Kip via AR. Higher dosages of testosterone cause greater growth inhibition of relapsed tumors. Manipulating androgen/AR signaling may therefore be a potential therapy for AR-positive advanced prostate cancer.

  5. Targeting Alternative Sites on the Androgen Receptor to Treat Castration-Resistant Prostate Cancer

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    Paul S. Rennie

    2013-06-01

    Full Text Available Recurrent, metastatic prostate cancer continues to be a leading cause of cancer-death in men. The androgen receptor (AR is a modular, ligand-inducible transcription factor that regulates the expression of genes that can drive the progression of this disease, and as a consequence, this receptor is a key therapeutic target for controlling prostate cancer. The current drugs designed to directly inhibit the AR are called anti-androgens, and all act by competing with androgens for binding to the androgen/ligand binding site. Unfortunately, with the inevitable progression of the cancer to castration resistance, many of these drugs become ineffective. However, there are numerous other regulatory sites on this protein that have not been exploited therapeutically. The regulation of AR activity involves a cascade of complex interactions with numerous chaperones, co-factors and co-regulatory proteins, leading ultimately to direct binding of AR dimers to specific DNA androgen response elements within the promoter and enhancers of androgen-regulated genes. As part of the family of nuclear receptors, the AR is organized into modular structural and functional domains with specialized roles in facilitating their inter-molecular interactions. These regions of the AR present attractive, yet largely unexploited, drug target sites for reducing or eliminating androgen signaling in prostate cancers. The design of small molecule inhibitors targeting these specific AR domains is only now being realized and is the culmination of decades of work, including crystallographic and biochemistry approaches to map the shape and accessibility of the AR surfaces and cavities. Here, we review the structure of the AR protein and describe recent advancements in inhibiting its activity with small molecules specifically designed to target areas distinct from the receptor’s androgen binding site. It is anticipated that these new classes of anti-AR drugs will provide an additional

  6. A Novel Role for Raloxifene Nanomicelles in Management of Castrate Resistant Prostate Cancer

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    Sebastien Taurin

    2014-01-01

    Full Text Available Of patients with castrate resistant prostate cancer (CRPC, less than 25–33% survive more than five years. Recent studies have implicated estrogen, acting either alone or synergistically with androgens in the development of castrate resistant prostate cancer. Several in vitro and in vivo studies, as well as a limited number of clinical trials, have highlighted the potential of selective estrogen receptor modulators, such as raloxifene (Ral for the treatment of castrate resistant prostate cancer. However, the poor oral bioavailability and metabolism of selective estrogen receptor modulators limit their efficiency in clinical application. To overcome these limitations, we have used styrene co-maleic acid (SMA micelle to encapsulate raloxifene. Compared to free drug, SMA-Ral micelles had 132 and 140% higher cytotoxicity against PC3 and DU 145 prostate cell lines, respectively. SMA-Ral effectively inhibits cell cycle progression, increases apoptosis, and alters the integrity of tumor spheroid models. In addition, the micellar system induced changes in expression and localization of estrogen receptors, epidermal growth factor receptor (EGFR, and downstream effectors associated with cell proliferation and survival. Finally, SMA-Ral treatment decreased migration and invasion of castrate resistant prostate cancer cell lines. In conclusion, SMA-Ral micelles can potentially benefit new strategies for clinical management of castrate resistant prostate cancer.

  7. The association between health-related quality-of-life scores and clinical outcomes in metastatic castration-resistant prostate cancer patients: Exploratory analyses of AFFIRM and PREVAIL studies.

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    Beer, Tomasz M; Miller, Kurt; Tombal, Bertrand; Cella, David; Phung, De; Holmstrom, Stefan; Ivanescu, Cristina; Skaltsa, Konstantina; Naidoo, Shevani

    2017-12-01

    Our exploratory analysis examined the association between health-related quality of life (HRQoL) (baseline and change over time) and clinical outcomes (overall survival [OS]/radiographic progression-free survival [rPFS]) in metastatic castration-resistant prostate cancer (mCRPC). HRQoL, OS and rPFS were assessed in phase III trials comparing enzalutamide with placebo in chemotherapy-naïve (PREVAIL; NCT01212991) or post-chemotherapy (AFFIRM; NCT00974311) mCRPC. HRQoL was assessed using the Functional Assessment of Cancer Therapy-Prostate (FACT-P). Multivariate analyses evaluated the prognostic significance of baseline and time-dependent scores after adjusting for treatment and clinical/demographic variables. Hazard ratios (HRs) and 95% confidence intervals (CIs) represented the hazard of rPFS or OS per minimally important difference (MID) score change in HRQoL variables. In baseline and time-dependent multivariate analyses, OS was independently associated with multiple HRQoL measures across both studies. In time-dependent analyses, a 10-point (upper bound of MID range) increase (improvement) in FACT-P total score was associated with reductions in mortality risk of 19% in AFFIRM (HR 0.81 [95% CI 0.78-0.84]) and 21% in PREVAIL (HR 0.79 [0.76-0.83]). For baseline analyses, a 10-point increase in FACT-P total score was associated with reductions in mortality risk of 12% (HR 0.88 [0.84-0.93]) and 10% (HR 0.90 [0.86-0.95]) in AFFIRM and PREVAIL, respectively. rPFS was associated with a subset of HRQoL domains in both studies. Several baseline HRQoL domains were prognostic for rPFS and OS in patients with mCRPC, and this association was maintained during treatment, indicating that changes in HRQoL are informative for patients' expected survival. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. Post hoc analyses of East Asian patients from the randomized placebo-controlled PREVAIL trial of enzalutamide in patients with chemotherapy-naïve, metastatic castration-resistant prostate cancer.

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    Kim, Choung Soo; Choi, Young Deuk; Lee, Sang Eun; Lee, Hyun Moo; Ueda, Takeshi; Yonese, Junji; Fukagai, Takashi; Chiong, Edmund; Lau, Weber; Abhyankar, Sarang; Theeuwes, Ad; Tombal, Bertrand; Beer, Tomasz M; Kimura, Go

    2017-07-01

    Enzalutamide is an androgen receptor (AR) inhibitor that acts on different steps in the AR signaling pathway. In PREVAIL, an international, phase III, double-blind, placebo-controlled trial, enzalutamide significantly reduced the risk of radiographic progression by 81% (hazard ratio [HR], 0.19; P PREVAIL trial, we performed a post hoc analysis of the Japanese, Korean, and Singaporean patients. PREVAIL enrolled patients with asymptomatic or mildly symptomatic chemotherapy-naïve metastatic castration-resistant prostate cancer who had progressed on androgen deprivation therapy. During the study, patients received enzalutamide (160 mg/d) or placebo (1:1) until death or discontinuation because of radiographic progression or skeletal-related event and initiation of subsequent therapy. Centrally assessed radiographic progression-free survival (rPFS) and overall survival (OS) were coprimary endpoints. The secondary endpoints of the PREVAIL trial were investigator-assessed rPFS, time to initiation of chemotherapy, time to prostate-specific antigen (PSA) progression, and PSA response (≥50% decline). Of 1717 patients, 148 patients were enrolled at sites in East Asia (enzalutamide 73, placebo 75). Treatment effect of enzalutamide versus placebo was consistent with that for the overall population as indicated by the HRs (95% confidence interval) of 0.38 (0.10-1.44) for centrally assessed rPFS, 0.59 (0.29-1.23) for OS, 0.33 (0.19-0.60) for time to chemotherapy, and 0.32 (0.20-0.50) for time to PSA progression. In East Asian patients, PSA responses were observed in 68.5% and 14.7% of enzalutamide- and placebo-treated patients, respectively. The enzalutamide plasma concentration ratio (East Asian:non-Asian patients) was 1.12 (90% confidence interval, 1.05-1.20) at 13 weeks. Treatment-related adverse events grade ≥ 3 occurred in 1.4% and 2.7% of enzalutamide- and placebo-treated East Asian patients, respectively. Treatment effects and safety of enzalutamide in East Asian

  9. Comparison of Alternative Androgen Receptor-axis-targeted Agent (ARATA) and Docetaxel as Second-line Therapy for Patients With Metastatic Castration-resistant Prostate Cancer With Progression After Initial ARATA in Real-world Clinical Practice in Japan.

    Science.gov (United States)

    Miyake, Hideaki; Sugiyama, Takayuki; Aki, Ryota; Matsushita, Yuto; Tamura, Keita; Motoyama, Daisuke; Ito, Toshiki; Otsuka, Atsushi

    2018-06-01

    The objective of the present study was to assess the oncologic outcomes of patients receiving second-line therapy against metastatic castration-resistant prostate cancer (mCRPC). The present study included 222 consecutive mCRPC patients with progression during initial androgen receptor-axis-targeted agent (ARATA) therapy with either abiraterone acetate (AA) or enzalutamide (Enz). Of these 222 patients, 108 subsequently received an alternative ARATA (AA-to-Enz, n = 49; Enz-to-AA, n = 59) and 114 received docetaxel (DTX; AA-to-DTX, n = 54; Enz-to-DTX, n = 60). The prostate-specific antigen (PSA) level in the 114 patients receiving DTX was significantly greater than that in the 108 patients receiving ARATA. However, no significant differences were found in the remaining parameters between the 2 groups. The PSA response rate, PSA progression-free survival (PFS), and overall survival (OS) during second-line therapy in the DTX group (n = 114) were significantly superior to those for the ARATA group (n = 108; PSA response rate, 42.1% vs. 21.3%; median PSA PFS, 7.2 vs. 4.2 months; median OS, 17.5 vs. 14.5 months). Similar trends were confirmed by comparing these outcomes among 4 therapy groups, with significant differences (PSA response rate, Enz-to-AA vs. AA-to-DTX and Enz-to-AA vs. Enz-to-DTX; PSA PFS, AA-to-Enz vs. Enz-to-AA, AA-to-Enz vs. AA-to-DTX, Enz-to-AA vs. AA-to-DTX, and Enz-to-AA vs. Enz-to-DTX; and OS, Enz-to-AA vs. AA-to-DTX and Enz-to-AA vs. Enz-to-DTX). Furthermore, the introduction of DTX was independently associated with improved PSA PFS, but not OS, on multivariate analysis. Favorable oncologic outcomes can be expected with DTX treatment, rather than with alternative ARATA, for mCRPC patients after failure of an initial ARATA. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Relationship between patient-reported outcomes and clinical outcomes in metastatic castration-resistant prostate cancer: post hoc analysis of COU-AA-301 and COU-AA-302.

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    Cella, D; Traina, S; Li, T; Johnson, K; Ho, K F; Molina, A; Shore, N D

    2018-02-01

    Patient-reported outcomes (PROs) are used to assess benefit-risk in drug development. The relationship between PROs and clinical outcomes is not well understood. We aim to elucidate the relationships between changes in PRO measures and clinical outcomes in metastatic castration-resistant prostate cancer (mCRPC). We investigated relationships between changes in self-reported fatigue, pain, functional well-being (FWB), physical well-being (PWB) and prostate cancer-specific symptoms with overall survival (OS) and radiographic progression-free survival (rPFS) after 6 and 12 months of treatment in COU-AA-301 (N = 1195) or COU-AA-302 (N = 1088). Eligible COU-AA-301 patients had progressed after docetaxel and had Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 2. Eligible COU-AA-302 patients had no prior chemotherapy and ECOG PS 0 or 1. Patients were treated with abiraterone acetate (1000 mg/day) plus prednisone (10 mg/day) or prednisone alone daily. Association between self-reported fatigue, pain and functional status, and OS and/or rPFS, using pooled data regardless of treatment, was assessed. Cox proportional hazard regression modeled time to death or radiographic progression. In COU-AA-301 patients, PRO improvements were associated with longer OS and longer time to radiographic progression versus worsening or stable PROs (P AA-302 patients, worsening PROs were associated with higher likelihood of radiographic progression (P ≤ 0.025) compared with improved or stable PROs. In multivariate models, worsening PWB remained associated with worse rPFS. The 12-month analysis confirmed the 6-month results. PROs are significantly associated with clinically relevant time-to-event efficacy outcomes in clinical trials and may complement and help predict traditional clinical practice methods for monitoring patients for disease progression. © The Author 2017. Published by Oxford University Press on behalf of the European Society for

  11. A Pharmacokinetic/Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined with Enzalutamide in Castrate-Resistant Prostate Cancer

    Science.gov (United States)

    2017-12-01

    Receptor Antagonist Mifepristone Combined with Enzalutamide in Castrate-Resistant Prostate Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER... receptor (AR) targeted therapies, prostate cancer adapts. One way it adapts is by upregulating another hormone receptor , the glucocorticoid receptor (GR...trial. 15. SUBJECT TERMS Castration resistant prostate cancer (CRPC); Androgen Receptor (AR); Glucocorticoid receptor (GR); Enzalutamide;

  12. Sox2 Is an Androgen Receptor-Repressed Gene That Promotes Castration-Resistant Prostate Cancer

    Science.gov (United States)

    Kregel, Steven; Kiriluk, Kyle J.; Rosen, Alex M.; Cai, Yi; Reyes, Edwin E.; Otto, Kristen B.; Tom, Westin; Paner, Gladell P.; Szmulewitz, Russell Z.; Vander Griend, Donald J.

    2013-01-01

    Despite advances in detection and therapy, castration-resistant prostate cancer continues to be a major clinical problem. The aberrant activity of stem cell pathways, and their regulation by the Androgen Receptor (AR), has the potential to provide insight into novel mechanisms and pathways to prevent and treat advanced, castrate-resistant prostate cancers. To this end, we investigated the role of the embryonic stem cell regulator Sox2 [SRY (sex determining region Y)-box 2] in normal and malignant prostate epithelial cells. In the normal prostate, Sox2 is expressed in a portion of basal epithelial cells. Prostate tumors were either Sox2-positive or Sox2-negative, with the percentage of Sox2-positive tumors increasing with Gleason Score and metastases. In the castration-resistant prostate cancer cell line CWR-R1, endogenous expression of Sox2 was repressed by AR signaling, and AR chromatin-IP shows that AR binds the enhancer element within the Sox2 promoter. Likewise, in normal prostate epithelial cells and human embryonic stem cells, increased AR signaling also decreases Sox2 expression. Resistance to the anti-androgen MDV3100 results in a marked increase in Sox2 expression within three prostate cancer cell lines, and in the castration-sensitive LAPC-4 prostate cancer cell line ectopic expression of Sox2 was sufficient to promote castration-resistant tumor formation. Loss of Sox2 expression in the castration-resistant CWR-R1 prostate cancer cell line inhibited cell growth. Up-regulation of Sox2 was not associated with increased CD133 expression but was associated with increased FGF5 (Fibroblast Growth Factor 5) expression. These data propose a model of elevated Sox2 expression due to loss of AR-mediated repression during castration, and consequent castration-resistance via mechanisms not involving induction of canonical embryonic stem cell pathways. PMID:23326489

  13. The Interactions between Insulin and Androgens in Progression to Castrate-Resistant Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Jennifer H. Gunter

    2012-01-01

    Full Text Available An association between the metabolic syndrome and reduced testosterone levels has been identified, and a specific inverse relationship between insulin and testosterone levels suggests that an important metabolic crosstalk exists between these two hormonal axes; however, the mechanisms by which insulin and androgens may be reciprocally regulated are not well described. Androgen-dependant gene pathways regulate the growth and maintenance of both normal and malignant prostate tissue, and androgen-deprivation therapy (ADT in patients exploits this dependence when used to treat recurrent and metastatic prostate cancer resulting in tumour regression. A major systemic side effect of ADT includes induction of key features of the metabolic syndrome and the consistent feature of hyperinsulinaemia. Recent studies have specifically identified a correlation between elevated insulin and high-grade PCa and more rapid progression to castrate resistant disease. This paper examines the relationship between insulin and androgens in the context of prostate cancer progression. Prostate cancer patients present a promising cohort for the exploration of insulin stabilising agents as adjunct treatments for hormone deprivation or enhancers of chemosensitivity for treatment of advanced prostate cancer.

  14. The Interactions between Insulin and Androgens in Progression to Castrate-Resistant Prostate Cancer

    Science.gov (United States)

    Gunter, Jennifer H.; Lubik, Amy A.; McKenzie, Ian; Pollak, Michael; Nelson, Colleen C.

    2012-01-01

    An association between the metabolic syndrome and reduced testosterone levels has been identified, and a specific inverse relationship between insulin and testosterone levels suggests that an important metabolic crosstalk exists between these two hormonal axes; however, the mechanisms by which insulin and androgens may be reciprocally regulated are not well described. Androgen-dependant gene pathways regulate the growth and maintenance of both normal and malignant prostate tissue, and androgen-deprivation therapy (ADT) in patients exploits this dependence when used to treat recurrent and metastatic prostate cancer resulting in tumour regression. A major systemic side effect of ADT includes induction of key features of the metabolic syndrome and the consistent feature of hyperinsulinaemia. Recent studies have specifically identified a correlation between elevated insulin and high-grade PCa and more rapid progression to castrate resistant disease. This paper examines the relationship between insulin and androgens in the context of prostate cancer progression. Prostate cancer patients present a promising cohort for the exploration of insulin stabilising agents as adjunct treatments for hormone deprivation or enhancers of chemosensitivity for treatment of advanced prostate cancer. PMID:22548055

  15. Health-related quality of life effects of enzalutamide in patients with metastatic castration-resistant prostate cancer: an in-depth post hoc analysis of EQ-5D data from the PREVAIL trial.

    Science.gov (United States)

    Devlin, Nancy; Herdman, Michael; Pavesi, Marco; Phung, De; Naidoo, Shevani; Beer, Tomasz M; Tombal, Bertrand; Loriot, Yohann; Ivanescu, Cristina; Parli, Teresa; Balk, Mark; Holmstrom, Stefan

    2017-06-23

    The effect of enzalutamide on health-related quality of life (HRQoL) in the PREVAIL trial in chemotherapy-naïve men with metastatic castration-resistant prostate cancer was analyzed using the generic EQ-5D instrument. Patients received oral enzalutamide 160 mg/day (n = 872) or placebo (n = 845). EQ-5D index and EQ-5D visual analogue scale (EQ-5D VAS) scores were evaluated at baseline, week 13, and every 12 weeks until week 61 due to sample size reduction thereafter. Changes on individual dimensions were assessed, and Paretian Classification of Health Change (PCHC) and time-to-event analyses were conducted. With enzalutamide, EQ-5D index and EQ-5D VAS scores declined more slowly versus placebo and time to diverge from full health was prolonged. Average decline in EQ-5D index (-0.042 vs. -0.070; P < .0001) and EQ-5D VAS (-1.3 vs. -4.4; P < .0001) was significantly smaller with enzalutamide. There were significant (P < .05) between-group differences favoring enzalutamide in Pain/Discomfort to week 37, Anxiety/Depression at week 13, and Usual Activities at week 25, but no significant differences for Mobility and Self-care. The PCHC analysis showed more enzalutamide patients reporting improvement than placebo patients at weeks 13, 25, and 49 (all P < .05) and week 37 (P = .0512). Enzalutamide was superior (P ≤ .0003) to placebo for time to diverge from full health and time to first deterioration on Pain/Discomfort and Anxiety/Depression dimensions. This in-depth post hoc analysis showed that enzalutamide delayed HRQoL deterioration and had beneficial effects on several HRQoL domains, including Pain/Discomfort and the proportion of patients in full health, compared with placebo, and may help to support future analyses of this type. NCT01212991.

  16. Effect of enzalutamide on health-related quality of life, pain, and skeletal-related events in asymptomatic and minimally symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer (PREVAIL): results from a randomised, phase 3 trial.

    Science.gov (United States)

    Loriot, Yohann; Miller, Kurt; Sternberg, Cora N; Fizazi, Karim; De Bono, Johann S; Chowdhury, Simon; Higano, Celestia S; Noonberg, Sarah; Holmstrom, Stefan; Mansbach, Harry; Perabo, Frank G; Phung, De; Ivanescu, Cristina; Skaltsa, Konstantina; Beer, Tomasz M; Tombal, Bertrand

    2015-05-01

    Enzalutamide significantly increased overall survival and radiographic progression-free survival compared with placebo in the PREVAIL trial of asymptomatic and minimally symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer. We report the effect of enzalutamide on health-related quality of life (HRQoL), pain, and skeletal-related events observed during this trial. In this phase 3, double-blind trial, patients were randomly assigned (1:1) to receive enzalutamide 160 mg/day (n=872) or placebo (n=845) orally. HRQoL was assessed at baseline and during treatment using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and EQ-5D questionnaires. Pain status was assessed at screening, baseline, week 13, and week 25 with the Brief Pain Inventory Short Form (BPI-SF). The primary analysis of HRQoL data used a mixed-effects model to test the difference between least square means change from baseline at week 61. We assessed change from baseline, percentage improvement, and time to deterioration in HRQoL and pain, the proportion of patients with a skeletal-related event, and time to first skeletal-related event. Analysis was done on the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01212991. Median treatment duration was 16·6 months (IQR 10·1-21·1) in the enzalutamide group and 4·6 months (2·8-9·7) in the placebo group. The mixed-effects model analyses showed significant treatment differences in change from baseline to week 61 with enzalutamide compared with placebo for most FACT-P endpoints and EQ-5D visual analogue scale. Median time to deterioration in FACT-P total score was 11·3 months (95% CI 11·1-13·9) in the enzalutamide group and 5·6 months (5·5-5·6) in the placebo groups (hazard ratio [HR] 0·62 [95% CI 0·54-0·72]; p<0·0001). A significantly greater proportion of patients in the enzalutamide group than in the placebo group reported clinically meaningful

  17. A combination of sorafenib and nilotinib reduces the growth of castrate-resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Archibald M

    2016-01-01

    Full Text Available Monica Archibald,1 Tara Pritchard,1 Hayley Nehoff,1 Rhonda J Rosengren,1 Khaled Greish,1,2 Sebastien Taurin1 1Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand; 2Aljawhara Centre for Molecular Medicine, Arabian Gulf University, Manama, Kingdom of Bahrain Abstract: Castrate-resistant prostate cancer (CRPC remains incurable due to the lack of effective therapies. Several tyrosine kinases have been implicated in the development and growth of CRPC, as such targeting these kinases may offer an alternative therapeutic strategy. We established the combination of two tyrosine kinase inhibitors (TKIs, sorafenib and nilotinib, as the most cytotoxic. In addtion, to improve their bioavailability and reduce their metabolism, we encapsulated sorafenib and nilotinib into styrene-co-maleic acid micelles. The micelles’ charge, size, and release rate were characterized. We assessed the effect of the combination on the cytotoxicity, cell cycle, apoptosis, protein expression, tumor spheroid integrity, migration, and invasion. The micelles exhibited a mean diameter of 100 nm, a neutral charge, and appeared highly stable. The micellar TKIs promoted greater cytotoxicity, decreased cell proliferation, and increased apoptosis relative to the free TKIs. In addition, the combination reduced the expression and activity of several tyrosine kinases and reduced tumor spheroid integrity and metastatic potential of CRPC cell lines more efficiently than the single treatments. The combination increased the therapeutic potential and demonstrated the relevance of a targeted combination therapy for the treatment of CRPC. In addition, the efficacy of the encapsulated drugs provides the basis for an in vivo preclinical testing. Keywords: sorafenib, nilotinib, castrate-resistant prostate cancer, tyrosine kinase inhibitors, nanomedicine

  18. Common structural and epigenetic changes in the genome of castration-resistant prostate cancer.

    Science.gov (United States)

    Friedlander, Terence W; Roy, Ritu; Tomlins, Scott A; Ngo, Vy T; Kobayashi, Yasuko; Azameera, Aruna; Rubin, Mark A; Pienta, Kenneth J; Chinnaiyan, Arul; Ittmann, Michael M; Ryan, Charles J; Paris, Pamela L

    2012-02-01

    Progression of primary prostate cancer to castration-resistant prostate cancer (CRPC) is associated with numerous genetic and epigenetic alterations that are thought to promote survival at metastatic sites. In this study, we investigated gene copy number and CpG methylation status in CRPC to gain insight into specific pathophysiologic pathways that are active in this advanced form of prostate cancer. Our analysis defined and validated 495 genes exhibiting significant differences in CRPC in gene copy number, including gains in androgen receptor (AR) and losses of PTEN and retinoblastoma 1 (RB1). Significant copy number differences existed between tumors with or without AR gene amplification, including a common loss of AR repressors in AR-unamplified tumors. Simultaneous gene methylation and allelic deletion occurred frequently in RB1 and HSD17B2, the latter of which is involved in testosterone metabolism. Lastly, genomic DNA from most CRPC was hypermethylated compared with benign prostate tissue. Our findings establish a comprehensive methylation signature that couples epigenomic and structural analyses, thereby offering insights into the genomic alterations in CRPC that are associated with a circumvention of hormonal therapy. Genes identified in this integrated genomic study point to new drug targets in CRPC, an incurable disease state which remains the chief therapeutic challenge. ©2012 AACR.

  19. Safety of Abiraterone Acetate in Castration-resistant Prostate Cancer Patients With Concomitant Cardiovascular Risk Factors.

    Science.gov (United States)

    Procopio, Giuseppe; Grassi, Paolo; Testa, Isabella; Verzoni, Elena; Torri, Valter; Salvioni, Roberto; Valdagni, Riccardo; de Braud, Filippo

    2015-10-01

    The aim of this study was to evaluate the safety profile of abiraterone acetate (AA) in metastatic castration-resistant prostate cancer (mCRPC) men with cardiovascular comorbidity, as little conclusive safety data are available in this patient subset. A retrospective analysis of mCRPC patients with controlled cardiovascular comorbidities, receiving AA 1000 mg administered orally once daily and prednisone 5 mg twice daily, between April 2011 and July 2012, was performed. All clinical and instrumental variables and toxicity data were analyzed by descriptive statistics: mean, standard deviation, minimum and maximum values for continuous variables, and absolute and relative frequencies for categorical variables. A total of 51 mCRPC patients were evaluated. Metastatic sites included the bone (74%), lungs, and liver (26%). All patients were previously treated with at least 2 lines of hormone and 1 docetaxel-based chemotherapy. Preexisting cardiac risk factors included hypertension (41%), cardiac ischemia (12%), arrhythmias (6%), dislipidemia (18%), and hyperglycemia (30%). No grade 3-4 adverse events were observed. Grade 1-2 adverse events included fluid retention (18%), asthenia (15%), and hypertension (16%). Median progression-free survival was 5.1 months (95% confidence interval, 0.5-12). Prostate specific antigen assessment revealed a good overall disease control rate (64%). AA appears to be safe and well tolerated even in patients with cardiovascular comorbidities or with increased risk factors for cardiovascular diseases.

  20. Antiproliferative activity of novel imidazopyridine derivatives on castration-resistant human prostate cancer cells.

    Science.gov (United States)

    Muniyan, Sakthivel; Chou, Yu-Wei; Ingersoll, Matthew A; Devine, Alexus; Morris, Marisha; Odero-Marah, Valerie A; Khan, Shafiq A; Chaney, William G; Bu, Xiu R; Lin, Ming-Fong

    2014-10-10

    Metastatic prostate cancer (mPCa) relapses after a short period of androgen deprivation therapy and becomes the castration-resistant prostate cancer (CR PCa); to which the treatment is limited. Hence, it is imperative to identify novel therapeutic agents towards this patient population. In the present study, antiproliferative activities of novel imidazopyridines were compared. Among three derivatives, PHE, AMD and AMN, examined, AMD showed the highest inhibitory activity on LNCaP C-81 cell proliferation, following dose- and time-dependent manner. Additionally, AMD exhibited significant antiproliferative effect against a panel of PCa cells, but not normal prostate epithelial cells. Further, when compared to AMD, its derivative DME showed higher inhibitory activities on PCa cell proliferation, clonogenic potential and in vitro tumorigenicity. The inhibitory activity was apparently in part due to the induction of apoptosis. Mechanistic studies indicate that AMD and DME treatments inhibited both AR and PI3K/Akt signaling. The results suggest that better understanding of inhibitory mechanisms of AMD and DME could help design novel therapeutic agents for improving the treatment of CR PCa. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  1. Development of Castration Resistant Prostate Cancer can be Predicted by a DNA Hypermethylation Profile.

    Science.gov (United States)

    Angulo, Javier C; Andrés, Guillermo; Ashour, Nadia; Sánchez-Chapado, Manuel; López, Jose I; Ropero, Santiago

    2016-03-01

    Detection of DNA hypermethylation has emerged as a novel molecular biomarker for prostate cancer diagnosis and evaluation of prognosis. We sought to define whether a hypermethylation profile of patients with prostate cancer on androgen deprivation would predict castrate resistant prostate cancer. Genome-wide methylation analysis was performed using a methylation cancer panel in 10 normal prostates and 45 tumor samples from patients placed on androgen deprivation who were followed until castrate resistant disease developed. Castrate resistant disease was defined according to EAU (European Association of Urology) guideline criteria. Two pathologists reviewed the Gleason score, Ki-67 index and neuroendocrine differentiation. Hierarchical clustering analysis was performed and relationships with outcome were investigated by Cox regression and log rank analysis. We found 61 genes that were significantly hypermethylated in greater than 20% of tumors analyzed. Three clusters of patients were characterized by a DNA methylation profile, including 1 at risk for earlier castrate resistant disease (log rank p = 0.019) and specific mortality (log rank p = 0.002). Hypermethylation of ETV1 (HR 3.75) and ZNF215 (HR 2.89) predicted disease progression despite androgen deprivation. Hypermethylation of IRAK3 (HR 13.72), ZNF215 (HR 4.81) and SEPT9 (HR 7.64) were independent markers of prognosis. Prostate specific antigen greater than 25 ng/ml, Gleason pattern 5, Ki-67 index greater than 12% and metastasis at diagnosis also predicted a negative response to androgen deprivation. Study limitations included the retrospective design and limited number of cases. Epigenetic silencing of the mentioned genes could be novel molecular markers for the prognosis of advanced prostate cancer. It might predict castrate resistance during hormone deprivation and, thus, disease specific mortality. Gene hypermethylation is associated with disease progression in patients who receive hormone therapy. It

  2. In vivo quantitative phosphoproteomic profiling identifies novel regulators of castration-resistant prostate cancer growth

    DEFF Research Database (Denmark)

    Jiang, Nan; Hjorth-Jensen, Kim; Hekmat, Omid

    2015-01-01

    Prostate cancer remains a leading cause of cancer-related mortality worldwide owing to our inability to treat effectively castration-resistant tumors. To understand the signaling mechanisms sustaining castration-resistant growth, we implemented a mass spectrometry-based quantitative proteomic app...

  3. Castration-Resistant Lgr5+ Cells Are Long-Lived Stem Cells Required for Prostatic Regeneration

    Directory of Open Access Journals (Sweden)

    Bu-er Wang

    2015-05-01

    Full Text Available The adult prostate possesses a significant regenerative capacity that is of great interest for understanding adult stem cell biology. We demonstrate that leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5 is expressed in a rare population of prostate epithelial progenitor cells, and a castration-resistant Lgr5+ population exists in regressed prostate tissue. Genetic lineage tracing revealed that Lgr5+ cells and their progeny are primarily luminal. Lgr5+ castration-resistant cells are long lived and upon regeneration, both luminal Lgr5+ cells and basal Lgr5+ cells expand. Moreover, single Lgr5+ cells can generate multilineage prostatic structures in renal transplantation assays. Additionally, Lgr5+ cell depletion revealed that the regenerative potential of the castrated adult prostate depends on Lgr5+ cells. Together, these data reveal insights into the cellular hierarchy of castration-resistant Lgr5+ cells, indicate a requirement for Lgr5+ cells during prostatic regeneration, and identify an Lgr5+ adult stem cell population in the prostate.

  4. Population-based study on use of chemotherapy in men with castration resistant prostate cancer

    OpenAIRE

    Lissbrant, Ingela Franck; Garmo, Hans; Widmark, Anders; Stattin, P?r

    2013-01-01

    Background. Chemotherapy prolongs life and relieves symptoms in men with castration resistant prostate cancer (CRPC). There is limited information on a population level on the use of chemotherapy for CRPC. Material and methods. To assess the use of chemotherapy in men with CRPC we conducted a register-based nationwide population-based study in Prostate Cancer data Base Sweden (PCBaSe) and a nationwide in-patient drug register (SALT database) between May 2009 and December 2010. We assumed that...

  5. Sortilin regulates progranulin action in castration-resistant prostate cancer cells.

    Science.gov (United States)

    Tanimoto, Ryuta; Morcavallo, Alaide; Terracciano, Mario; Xu, Shi-Qiong; Stefanello, Manuela; Buraschi, Simone; Lu, Kuojung G; Bagley, Demetrius H; Gomella, Leonard G; Scotlandi, Katia; Belfiore, Antonino; Iozzo, Renato V; Morrione, Andrea

    2015-01-01

    The growth factor progranulin is as an important regulator of transformation in several cellular systems. We have previously demonstrated that progranulin acts as an autocrine growth factor and stimulates motility, proliferation, and anchorage-independent growth of castration-resistant prostate cancer cells, supporting the hypothesis that progranulin may play a critical role in prostate cancer progression. However, the mechanisms regulating progranulin action in castration-resistant prostate cancer cells have not been characterized. Sortilin, a single-pass type I transmembrane protein of the vacuolar protein sorting 10 family, binds progranulin in neurons and negatively regulates progranulin signaling by mediating progranulin targeting for lysosomal degradation. However, whether sortilin is expressed in prostate cancer cells and plays any role in regulating progranulin action has not been established. Here, we show that sortilin is expressed at very low levels in castration-resistant PC3 and DU145 cells. Significantly, enhancing sortilin expression in PC3 and DU145 cells severely diminishes progranulin levels and inhibits motility, invasion, proliferation, and anchorage-independent growth. In addition, sortilin overexpression negatively modulates Akt (protein kinase B, PKB) stability. These results are recapitulated by depleting endogenous progranulin in PC3 and DU145 cells. On the contrary, targeting sortilin by short hairpin RNA approaches enhances progranulin levels and promotes motility, invasion, and anchorage-independent growth. We dissected the mechanisms of sortilin action and demonstrated that sortilin promotes progranulin endocytosis through a clathrin-dependent pathway, sorting into early endosomes and subsequent lysosomal degradation. Collectively, these results point out a critical role for sortilin in regulating progranulin action in castration-resistant prostate cancer cells, suggesting that sortilin loss may contribute to prostate cancer progression.

  6. Radium-223 in treatment of castration-resistant prostate cancer with skeletal metastases

    Directory of Open Access Journals (Sweden)

    V. B. Matveev

    2017-01-01

    Full Text Available More than 90 % of patients with metastatic castration-resistant prostate cancer (CRPC have radiologically confirmed skeletal metastases. Traditional treatment methods such as administration of painkillers, external beam therapy, bisphosphonates or denosumab, as well as injections of strontium-89 or samarium-153 radionuclides, have only palliative effect and in some cases can postpone development of skeletal complications. Alpha-emitter radium-223 dichloride (Ra-223; alpharadin previously is currently one of the known drugs with proven effectiveness in relation to increasing overall survival of patients with CRPC. Ra-223 was developed specifically for patients with CRPC and symptomatic skeletal metastases. The drug targets the areas of skeletal tissue remodeling. Ra-223 is the therapy of choice in patients with CRPC and skeletal metastases and without confirmed visceral metastases before and after docetaxel chemotherapy. Chemotherapy after treatment with Ra-223 is a possible and satisfactory tolerable treatment option. Combination of Ra-223 with abiraterone, enzalutamide, or denosumab is, apparently, effective and safe, but further studies are necessary.

  7. Clinical Relevance of Androgen Receptor Splice Variants in Castration-Resistant Prostate Cancer.

    Science.gov (United States)

    Maughan, Benjamin L; Antonarakis, Emmanuel S

    2015-12-01

    Metastatic castration-resistant prostate cancer (mCRPC) currently benefits from a wealth of treatment options, yet still remains lethal in the vast majority of patients. It is becoming increasingly understood that this disease entity continues to evolve over time, acquiring additional and diverse resistance mechanisms with each subsequent therapy used. This dynamic relationship between treatment pressure and disease resistance can be challenging for the managing clinician. The recent discovery of alternate splice variants of the androgen receptor (AR) is one potential mechanism of escape in mCRPC, and recognizing this resistance mechanism might be important for optimal treatment selection for our patients. AR-V7 appears to be the most relevant AR splice variant, and early clinical data suggest that it is a negative prognostic marker in mCRPC. Emerging evidence also suggests that detection of AR-V7 may be associated with resistance to novel hormonal therapy (abiraterone and enzalutamide) but may be compatible with sensitivity to taxane chemotherapy (docetaxel and cabazitaxel). Adding to this complexity is the observation that AR-V7 is a dynamic marker whose status may change across time and depending on selective pressures induced by different therapies. Finally, it is possible that AR-V7 may represent a therapeutic target in mCRPC if drugs can be designed that degrade or inhibit AR splice variants or block their transcriptional activity. Several such agents (including galeterone, EPI-506, and bromodomain/BET inhibitors) are now in clinical development.

  8. Hsp90 inhibitor 17-AAG inhibits progression of LuCaP35 xenograft prostate tumors to castration resistance.

    Science.gov (United States)

    O'Malley, Katherine J; Langmann, Gabrielle; Ai, Junkui; Ramos-Garcia, Raquel; Vessella, Robert L; Wang, Zhou

    2012-07-01

    Advanced prostate cancer is currently treated with androgen deprivation therapy (ADT). ADT initially results in tumor regression; however, all patients eventually relapse with castration-resistant prostate cancer. New approaches to delay the progression of prostate cancer to castration resistance are in desperate need. This study addresses whether targeting Heat shock protein 90 (HSP90) regulation of androgen receptor (AR) can inhibit prostate cancer progression to castration resistance. The HSP90 inhibitor 17-AAG was injected intraperitoneally into nude mice bearing LuCaP35 xenograft tumors to determine the effect of HSP90 inhibition on prostate cancer progression to castration resistance and host survival. Administration of 17-AAG maintained androgen-sensitivity, delayed the progression of LuCaP35 xenograft tumors to castration resistance, and prolonged the survival of host. In addition, 17-AAG prevented nuclear localization of endogenous AR in LuCaP35 xenograft tumors in castrated nude mice. Targeting Hsp90 or the mechanism by which HSP90 regulates androgen-independent AR nuclear localization and activation may lead to new approaches to prevent and/or treat castration-resistant prostate cancer. Copyright © 2011 Wiley Periodicals, Inc.

  9. Non-Coding RNAs in Castration-Resistant Prostate Cancer: Regulation of Androgen Receptor Signaling and Cancer Metabolism.

    Science.gov (United States)

    Shih, Jing-Wen; Wang, Ling-Yu; Hung, Chiu-Lien; Kung, Hsing-Jien; Hsieh, Chia-Ling

    2015-12-04

    Hormone-refractory prostate cancer frequently relapses from therapy and inevitably progresses to a bone-metastatic status with no cure. Understanding of the molecular mechanisms conferring resistance to androgen deprivation therapy has the potential to lead to the discovery of novel therapeutic targets for type of prostate cancer with poor prognosis. Progression to castration-resistant prostate cancer (CRPC) is characterized by aberrant androgen receptor (AR) expression and persistent AR signaling activity. Alterations in metabolic activity regulated by oncogenic pathways, such as c-Myc, were found to promote prostate cancer growth during the development of CRPC. Non-coding RNAs represent a diverse family of regulatory transcripts that drive tumorigenesis of prostate cancer and various other cancers by their hyperactivity or diminished function. A number of studies have examined differentially expressed non-coding RNAs in each stage of prostate cancer. Herein, we highlight the emerging impacts of microRNAs and long non-coding RNAs linked to reactivation of the AR signaling axis and reprogramming of the cellular metabolism in prostate cancer. The translational implications of non-coding RNA research for developing new biomarkers and therapeutic strategies for CRPC are also discussed.

  10. Overcoming Autophagy to Induce Apoptosis in Castration Resistant Prostate Cancer

    Science.gov (United States)

    2015-10-01

    et al., Skp2 regulates androgen receptor through ubiquitin-mediated degradation independent of Akt /mTOR pathways in prostate cancer. Prostate, 2014...I remained fairly steady with only marginal production of LC-3 II, so did the p- Akt . Because of the relative stable AR expression and yet...show ubiquitination of AR via co- immunoprecipitation of AR and ubiquitin. LNCaP C4-2B cells were treated with metformin alone or in combinations

  11. Phase II Study of Pomalidomide in Patients with Castration-Resistant Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Amato, Robert J., E-mail: robert.amato@uth.tmc.edu [Memorial Hermann Cancer Center, University of Texas, 6410 Fannin Street, Suite 830, Houston, TX 77030 (United States); Glode, L. Michael [Health Science Center, University of Colorado, Denver, CO 80217 (United States); University of Colorado Cancer Center, Aurora, CO 80045 (United States); Podolnick, Jeremy [Memorial Hermann Cancer Center, University of Texas, 6410 Fannin Street, Suite 830, Houston, TX 77030 (United States); Knight, Robert [Celgene Corporation, Summit, NJ 07901-3915 (United States); Crawford, David [Health Science Center, University of Colorado, Denver, CO 80217 (United States); University of Colorado Cancer Center, Aurora, CO 80045 (United States)

    2011-09-02

    Pomalidomide is a distinct immunomodulatory agent that also displays anti-proliferative and proapoptotic activity. The purpose of this study was to assess the efficacy and safety of pomalidomide for the treatment of chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (CRPC). Methods: Pomalidomide was administered orally in doses of 1 or 2 mg/day without interruption. Follow ups were conducted every 4 weeks with evaluation of study outcomes at 12 weeks. The principal study outcomes were PSA response, time to progression (TTP) using RECIST, overall survival (OS), and safety. A total of 32 patients were enrolled: 15 in the 1 mg/day cohort (median baseline PSA level of 12.30 ng/mL [0.8–236.0]), and 17 in the 2 mg/day cohort (median baseline PSA level of 12.50 ng/mL [0.6–191.8]). Results: In the 1 mg cohort disease was stabilized for ≥28 days in eight patients, and median TTP was 2.90 months. In the 2 mg cohort, PSA decreased ≥50% in three patients, disease was stabilized for ≥28 days in seven patients, and median TTP was 5.87 months. Toxicity in both cohorts was predominantly grade 1 or 2; 2 grade 3 toxicity (fatigue) occurred in the 1 mg cohort, and 5 grade 3 toxicities (chest pain, diarrhea, epigastric pain, impaction, pain) occurred in the 2 mg cohort. One grade 4 toxicity of cardiac ischemia occurred. Conclusions: Pomalidomide shows promising activity in patients with CRPC and has an acceptable safety profile.

  12. Phase II Study of Pomalidomide in Patients with Castration-Resistant Prostate Cancer

    International Nuclear Information System (INIS)

    Amato, Robert J.; Glode, L. Michael; Podolnick, Jeremy; Knight, Robert; Crawford, David

    2011-01-01

    Pomalidomide is a distinct immunomodulatory agent that also displays anti-proliferative and proapoptotic activity. The purpose of this study was to assess the efficacy and safety of pomalidomide for the treatment of chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (CRPC). Methods: Pomalidomide was administered orally in doses of 1 or 2 mg/day without interruption. Follow ups were conducted every 4 weeks with evaluation of study outcomes at 12 weeks. The principal study outcomes were PSA response, time to progression (TTP) using RECIST, overall survival (OS), and safety. A total of 32 patients were enrolled: 15 in the 1 mg/day cohort (median baseline PSA level of 12.30 ng/mL [0.8–236.0]), and 17 in the 2 mg/day cohort (median baseline PSA level of 12.50 ng/mL [0.6–191.8]). Results: In the 1 mg cohort disease was stabilized for ≥28 days in eight patients, and median TTP was 2.90 months. In the 2 mg cohort, PSA decreased ≥50% in three patients, disease was stabilized for ≥28 days in seven patients, and median TTP was 5.87 months. Toxicity in both cohorts was predominantly grade 1 or 2; 2 grade 3 toxicity (fatigue) occurred in the 1 mg cohort, and 5 grade 3 toxicities (chest pain, diarrhea, epigastric pain, impaction, pain) occurred in the 2 mg cohort. One grade 4 toxicity of cardiac ischemia occurred. Conclusions: Pomalidomide shows promising activity in patients with CRPC and has an acceptable safety profile

  13. Phase I/II trials of {sup 186}Re-HEDP in metastatic castration-resistant prostate cancer: post-hoc analysis of the impact of administered activity and dosimetry on survival

    Energy Technology Data Exchange (ETDEWEB)

    Denis-Bacelar, Ana M.; Chittenden, Sarah J.; Divoli, Antigoni; Flux, Glenn D. [The Institute of Cancer Research and The Royal Marsden Hospital NHS Foundation Trust, Joint Department of Physics, London (United Kingdom); Dearnaley, David P.; Johnson, Bernadette [The Institute of Cancer Research and The Royal Marsden Hospital NHS Foundation Trust, Division of Radiotherapy and Imaging, London (United Kingdom); O' Sullivan, Joe M. [Queen' s University Belfast, Centre for Cancer Research and Cell Biology, Belfast (United Kingdom); McCready, V.R. [Brighton and Sussex University Hospitals NHS Trust, Department of Nuclear Medicine, Brighton (United Kingdom); Du, Yong [The Royal Marsden Hospital NHS Foundation Trust, Department of Nuclear Medicine and PET/CT, London (United Kingdom)

    2017-04-15

    To investigate the role of patient-specific dosimetry as a predictive marker of survival and as a potential tool for individualised molecular radiotherapy treatment planning of bone metastases from castration-resistant prostate cancer, and to assess whether higher administered levels of activity are associated with a survival benefit. Clinical data from 57 patients who received 2.5-5.1 GBq of {sup 186}Re-HEDP as part of NIH-funded phase I/II clinical trials were analysed. Whole-body and SPECT-based absorbed doses to the whole body and bone lesions were calculated for 22 patients receiving 5 GBq. The patient mean absorbed dose was defined as the mean of all bone lesion-absorbed doses in any given patient. Kaplan-Meier curves, log-rank tests, Cox's proportional hazards model and Pearson's correlation coefficients were used for overall survival (OS) and correlation analyses. A statistically significantly longer OS was associated with administered activities above 3.5 GBq in the 57 patients (20.1 vs 7.1 months, hazard ratio: 0.39, 95 % CI: 0.10-0.58, P = 0.002). A total of 379 bone lesions were identified in 22 patients. The mean of the patient mean absorbed dose was 19 (±6) Gy and the mean of the whole-body absorbed dose was 0.33 (±0.11) Gy for the 22 patients. The patient mean absorbed dose (r = 0.65, P = 0.001) and the whole-body absorbed dose (r = 0.63, P = 0.002) showed a positive correlation with disease volume. Significant differences in OS were observed for the univariate group analyses according to disease volume as measured from SPECT imaging of {sup 186}Re-HEDP (P = 0.03) and patient mean absorbed dose (P = 0.01), whilst only the disease volume remained significant in a multivariable analysis (P = 0.004). This study demonstrated that higher administered activities led to prolonged survival and that for a fixed administered activity, the whole-body and patient mean absorbed doses correlated with the extent of disease, which, in turn, correlated

  14. Prostate Cancer Stem-like Cells Contribute to the Development of Castration-Resistant Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Diane Ojo

    2015-11-01

    Full Text Available Androgen deprivation therapy (ADT has been the standard care for patients with advanced prostate cancer (PC since the 1940s. Although ADT shows clear benefits for many patients, castration-resistant prostate cancer (CRPC inevitably occurs. In fact, with the two recent FDA-approved second-generation anti-androgens abiraterone and enzalutamide, resistance develops rapidly in patients with CRPC, despite their initial effectiveness. The lack of effective therapeutic solutions towards CRPC largely reflects our limited understanding of the underlying mechanisms responsible for CRPC development. While persistent androgen receptor (AR signaling under castration levels of serum testosterone (<50 ng/mL contributes to resistance to ADT, it is also clear that CRPC evolves via complex mechanisms. Nevertheless, the physiological impact of individual mechanisms and whether these mechanisms function in a cohesive manner in promoting CRPC are elusive. In spite of these uncertainties, emerging evidence supports a critical role of prostate cancer stem-like cells (PCSLCs in stimulating CRPC evolution and resistance to abiraterone and enzalutamide. In this review, we will discuss the recent evidence supporting the involvement of PCSLC in CRPC acquisition as well as the pathways and factors contributing to PCSLC expansion in response to ADT.

  15. Abiraterone acetate: oral androgen biosynthesis inhibitor for treatment of castration-resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Rosenberg JE

    2012-01-01

    Full Text Available Yasser Rehman1, Jonathan E Rosenberg21Division of Hospital Medicine, UMass Memorial Healthcare, Worcester, MA, USA; 2Lank Center for Genitourinary Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USAAbstract: Prostate cancer is the second leading cause of cancer death in men in the US and Europe. The treatment of advanced-stage prostate cancer has been androgen deprivation. Medical castration leads to decreased production of testosterone and dihydrotestosterone by the testes, but adrenal glands and even prostate cancer tissue continue to produce androgens, which eventually leads to continued prostate cancer growth despite castrate level of androgens. This stage is known as castrate-resistant prostate cancer (CRPC, which continues to be a challenge to treat. Addition of androgen antagonists to hormonal deprivation has been successful in lowering the prostate-specific antigen levels further, but has not actually translated into life-prolonging options. The results of several contemporary studies have continued to demonstrate activation of the androgen receptor as being the key factor in the continued growth of prostate cancer. Blockade of androgen production by nongonadal sources has led to clinical benefit in this setting. One such agent is abiraterone acetate, which significantly reduces androgen production by blocking the enzyme, cytochrome P450 17 alpha-hydroxylase (CYP17. This has provided physicians with another treatment option for patients with CRPC. The landscape for prostate cancer treatment has changed with the approval of cabazitaxel, sipuleucel-T and abiraterone. Here we provide an overview of abiraterone acetate, its mechanism of action, and its potential place for therapy in CRPC.Keywords: CRPC, abiraterone, CYP17, inhibitors, androgens, castration resistant prostate cancer

  16. YAP1 regulates prostate cancer stem cell-like characteristics to promote castration resistant growth

    DEFF Research Database (Denmark)

    Jiang, Ning; Ke, Binghu; Hjort-Jensen, Kim

    2017-01-01

    Castration resistant prostate cancer (CRPC) is a stage of relapse that arises after various forms of androgen ablation therapy (ADT) and causes significant morbidity and mortality. However, the mechanism underlying progression to CRPC remains poorly understood. Here, we report that YAP1, which...... is negatively regulated by AR, influences prostate cancer (PCa) cell self-renewal and CRPC development. Specifically, we found that AR directly regulates the methylation of YAP1 gene promoter via the formation of a complex with Polycomb group protein EZH2 and DNMT3a. In normal conditions, AR recruits EZH2......-differentiation of PCa cells to stem/progenitor-like cells (PCSC), which potentially contribute to disease recurrence. Finally, the knock down of YAP1 expression or the inhibition of YAP1 function by Verteporfin in TRAMP prostate cancer mice significantly suppresses tumor recurrence following castration. In conclusion...

  17. Androgen Receptor Antagonism By Divalent Ethisterone Conjugates In Castrate-Resistant Prostate Cancer Cells

    Science.gov (United States)

    Levine, Paul M.; Lee, Eugine; Greenfield, Alex; Bonneau, Richard; Logan, Susan K.; Garabedian, Michael J.; Kirshenbaum, Kent

    2013-01-01

    Sustained treatment of prostate cancer with Androgen Receptor (AR) antagonists can evoke drug resistance, leading to castrate-resistant disease. Elevated activity of the AR is often associated with this highly aggressive disease state. Therefore, new therapeutic regimens that target and modulate AR activity could prove beneficial. We previously introduced a versatile chemical platform to generate competitive and non-competitive multivalent peptoid oligomer conjugates that modulate AR activity. In particular, we identified a linear and a cyclic divalent ethisterone conjugate that exhibit potent anti-proliferative properties in LNCaP-abl cells, a model of castrate-resistant prostate cancer. Here, we characterize the mechanism of action of these compounds utilizing confocal microscopy, time-resolved fluorescence resonance energy transfer, chromatin immunoprecipitation, flow cytometry, and microarray analysis. The linear conjugate competitively blocks AR action by inhibiting DNA binding. In addition, the linear conjugate does not promote AR nuclear localization or co-activator binding. In contrast, the cyclic conjugate promotes AR nuclear localization and induces cell-cycle arrest, despite its inability to compete against endogenous ligand for binding to AR in vitro. Genome-wide expression analysis reveals that gene transcripts are differentially affected by treatment with the linear or cyclic conjugate. Although the divalent ethisterone conjugates share extensive chemical similarities, we illustrate that they can antagonize the AR via distinct mechanisms of action, establishing new therapeutic strategies for potential applications in AR pharmacology. PMID:22871957

  18. Cost-effectiveness of abiraterone treatment in patients with castration-resistant prostate cancer who previously received docetaxel therapy

    Directory of Open Access Journals (Sweden)

    A. V. Rudakova

    2014-01-01

    Full Text Available Background. Therapy for metastatic castration-resistant prostate cancer (CRPC is a serious problem that requires significant public health care expenditures.Objective: to evaluate the cost-effectiveness of abiraterone treatment in patients with metastatic CRPC who previously received docetaxel under the conditions of the budgetary public health system of the Russian Federation.Material and methods. Markovian simulation based on the COU-AA-301 randomized placebo-controlled Phase III study was used. Survival analysis was made in 70-year-old patients. The cost of abiraterone therapy corresponded to that of the 2013 auctions.Results. Abiraterone therapy in patients who have previously received docetaxel therapy causes an increase in average life expectancy by an average of 4.6 months and progression-free survival by 2.0 months. Moreover, the cost calculated with reference to one year of additional life will account for about 3.6 million rubles and that to one additional quality-adjusted life year will be about 5.45 million rubles.Conclusion. The cost-effectiveness of abiraterone therapy for metastatic CRPC in patients who have previously received docetaxel therapy is similar to that of other medicaments used in oncological practice under the conditions of the budgetary public health system of the Russian Federation. In this connection, abiraterone may be considered as an economically acceptable medical intervention in this clinical situation.

  19. Cost-effectiveness of abiraterone treatment in patients with castration-resistant prostate cancer who previously received docetaxel therapy

    Directory of Open Access Journals (Sweden)

    A. V. Rudakova

    2014-11-01

    Full Text Available Background. Therapy for metastatic castration-resistant prostate cancer (CRPC is a serious problem that requires significant public health care expenditures.Objective: to evaluate the cost-effectiveness of abiraterone treatment in patients with metastatic CRPC who previously received docetaxel under the conditions of the budgetary public health system of the Russian Federation.Material and methods. Markovian simulation based on the COU-AA-301 randomized placebo-controlled Phase III study was used. Survival analysis was made in 70-year-old patients. The cost of abiraterone therapy corresponded to that of the 2013 auctions.Results. Abiraterone therapy in patients who have previously received docetaxel therapy causes an increase in average life expectancy by an average of 4.6 months and progression-free survival by 2.0 months. Moreover, the cost calculated with reference to one year of additional life will account for about 3.6 million rubles and that to one additional quality-adjusted life year will be about 5.45 million rubles.Conclusion. The cost-effectiveness of abiraterone therapy for metastatic CRPC in patients who have previously received docetaxel therapy is similar to that of other medicaments used in oncological practice under the conditions of the budgetary public health system of the Russian Federation. In this connection, abiraterone may be considered as an economically acceptable medical intervention in this clinical situation.

  20. Epigenetic Machinery Regulates Alternative Splicing of Androgen Receptor (AR) Gene in Castration-Resistant Prostate Cancer (CRPC)

    Science.gov (United States)

    2017-09-01

    Splicing of Androgen Receptor (AR) Gene in Castration-Resistant Prostate Cancer (CRPC) 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Jer...Epigenetic regulation of androgen receptor signaling in prostate cancer . Epigenetics. 5, 100-104. 2. Duan LL, Rai G , Roggero C, Zhang Q-J, Wei Q... Prostate Cancer (CRPC) PRINCIPAL INVESTIGATOR: Hsieh, Jer-Tsong CONTRACTING ORGANIZATION: University of Texas Southwestern Medical Center

  1. Cotargeting of Androgen Synthesis and Androgen Receptor Expression as a Novel Treatment for Castration Resistant Prostate Cancer

    Science.gov (United States)

    2017-08-01

    disease [2-4]. The major mechanism underlying the development of CRPC is the reactivation of the androgen receptor (AR), the driver of prostate cancer ...Epigenetic Activator of Androgen Receptor Expression in Castration- Resistant Prostate Cancer . Indiana Basic Urological Research (IBUR) Symposium...principal discipline(s) of the project? Androgen receptor (AR) is the driver of prostate cancer development and progression and is the validated

  2. Androgen receptor expression in Circulating Tumor Cells from castration-resistant prostate cancer patients with novel endocrine agents

    NARCIS (Netherlands)

    Crespo, M.; van Dalum, Guus; Ferraldeschi, R.; Zafeiriou, Z.; Sideris, S.; Lorente, D.; Bianchini, D.; Rodrigues, D.N.; Rijsnaes, R.; Miranda, S.; Figueiredo, I.; Flohr, P.; Nowakowska, K.; de Bono, J.S.; Terstappen, Leonardus Wendelinus Mathias Marie; Attard, G.

    2015-01-01

    Background: Abiraterone and enzalutamide are novel endocrine treatments that abrogate androgen receptor (AR) signalling in castration-resistant prostate cancer (CRPC). Here, we developed a circulating tumour cells (CTCs)-based assay to evaluate AR expression in real-time in CRPC and investigated

  3. Development of a New Class of Drugs To Inhibit All Forms of Androgen Receptor in Castration Resistant Prostate Cancers

    Science.gov (United States)

    2016-10-01

    receptor, castration-resistant prostate cancer, DNA binding domain, androgen response element, AR inhibitor, chromatin, x-ray crystallography , pre-clinical...14228 (months 1-30) 3.2. Synthesis of derivatives of our lead compounds (months 6-30). 3.3.Experimental evaluation of the developed synthetic

  4. FOXA1 promotes tumor progression in prostate cancer and represents a novel hallmark of castration-resistant prostate cancer.

    Science.gov (United States)

    Gerhardt, Josefine; Montani, Matteo; Wild, Peter; Beer, Marc; Huber, Fabian; Hermanns, Thomas; Müntener, Michael; Kristiansen, Glen

    2012-02-01

    Forkhead box protein A1 (FOXA1) modulates the transactivation of steroid hormone receptors and thus may influence tumor growth and hormone responsiveness in prostate cancer. We therefore investigated the correlation of FOXA1 expression with clinical parameters, prostate-specific antigen (PSA) relapse-free survival, and hormone receptor expression in a large cohort of prostate cancer patients at different disease stages. FOXA1 expression did not differ significantly between benign glands from the peripheral zone and primary peripheral zone prostate carcinomas. However, FOXA1 was overexpressed in metastases and particularly in castration-resistant cases, but was expressed at lower levels in both normal and neoplastic transitional zone tissues. FOXA1 levels correlated with higher pT stages and Gleason scores, as well as with androgen (AR) and estrogen receptor expression. Moreover, FOXA1 overexpression was associated with faster biochemical disease progression, which was pronounced in patients with low AR levels. Finally, siRNA-based knockdown of FOXA1 induced decreased cell proliferation and migration. Moreover, in vitro tumorigenicity was inducible by ARs only in the presence of FOXA1, substantiating a functional cooperation between FOXA1 and AR. In conclusion, FOXA1 expression is associated with tumor progression, dedifferentiation of prostate cancer cells, and poorer prognosis, as well as with cellular proliferation and migration and with AR signaling. These findings suggest FOXA1 overexpression as a novel mechanism inducing castration resistance in prostate cancer. Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  5. Vimentin and Ki67 expression in circulating tumour cells derived from castrate-resistant prostate cancer.

    Science.gov (United States)

    Lindsay, C R; Le Moulec, S; Billiot, F; Loriot, Y; Ngo-Camus, M; Vielh, P; Fizazi, K; Massard, C; Farace, F

    2016-02-29

    High circulating tumor cell (CTC) counts are associated with poor prognosis in advanced prostate cancer, and recently CTC number was suggested to be a surrogate for survival in metastatic castrate-resistant prostate cancer (mCRPC). Ki67 and vimentin are well-characterised markers of tumour cell proliferation and the epithelial-mesenchymal transition (EMT), respectively. Here we asked if the expression of vimentin and Ki67 in CTCs offered prognostic or predictive information in mCRPC. In two separate patient cohorts, anti-vimentin or anti-Ki67 antibodies were added to the free channel in the CellSearch® system for analysis of peripheral blood samples. For each cohort, association of CTC number with clinical characteristics were assessed using Fisher's exact, Mann-Whitney and chi-squared tests. Kaplan-Meier method and log-rank tests were used to analyse overall survival (OS) of vimentin-expressing and Ki67-expressing CTC patient cohorts. In this retrospective analysis, CTC vimentin expression was analysed in 142 blood samples from 93 patients, and CTC Ki67 expression was analysed in 90 blood samples from 51 patients. In the vimentin cohort, 80/93 (86 %) of baseline samples from patients were CTC-positive overall (≥1 total CTC per 7.5 mls blood), and 30/93 (32.3 %) vimentin CTC-positive (≥1 vimentin-positive CTC per 7.5 mls blood). 41/51 (80.4 %) of baseline samples from patients in the Ki67 cohort were CTC-positive overall, and 23/51 (45.1 %) Ki67 CTC-positive (≥1 Ki67-positive CTC per 7.5 mls blood). There was no significant difference in baseline PSA in patients with vimentin-positive CTC at baseline versus those with no vimentin-positive CTC at baseline (p = 0.33). A significant reduction in OS was shown in patients with vimentin-positive CTC compared to those without vimentin-positive CTC (median 305 days vs 453 days, p = 0.0293). There was no significant difference in baseline PSA in patients with Ki67-positive CTC at baseline versus those without Ki67

  6. Vimentin and Ki67 expression in circulating tumour cells derived from castrate-resistant prostate cancer

    International Nuclear Information System (INIS)

    Lindsay, C. R.; Le Moulec, S.; Billiot, F.; Loriot, Y.; Ngo-Camus, M.; Vielh, P.; Fizazi, K.; Massard, C.; Farace, F.

    2016-01-01

    High circulating tumor cell (CTC) counts are associated with poor prognosis in advanced prostate cancer, and recently CTC number was suggested to be a surrogate for survival in metastatic castrate-resistant prostate cancer (mCRPC). Ki67 and vimentin are well-characterised markers of tumour cell proliferation and the epithelial-mesenchymal transition (EMT), respectively. Here we asked if the expression of vimentin and Ki67 in CTCs offered prognostic or predictive information in mCRPC. In two separate patient cohorts, anti-vimentin or anti-Ki67 antibodies were added to the free channel in the CellSearch® system for analysis of peripheral blood samples. For each cohort, association of CTC number with clinical characteristics were assessed using Fisher’s exact, Mann-Whitney and chi-squared tests. Kaplan-Meier method and log-rank tests were used to analyse overall survival (OS) of vimentin-expressing and Ki67-expressing CTC patient cohorts. In this retrospective analysis, CTC vimentin expression was analysed in 142 blood samples from 93 patients, and CTC Ki67 expression was analysed in 90 blood samples from 51 patients. In the vimentin cohort, 80/93 (86 %) of baseline samples from patients were CTC-positive overall (≥1 total CTC per 7.5 mls blood), and 30/93 (32.3 %) vimentin CTC-positive (≥1 vimentin-positive CTC per 7.5 mls blood). 41/51 (80.4 %) of baseline samples from patients in the Ki67 cohort were CTC-positive overall, and 23/51 (45.1 %) Ki67 CTC-positive (≥1 Ki67-positive CTC per 7.5 mls blood). There was no significant difference in baseline PSA in patients with vimentin-positive CTC at baseline versus those with no vimentin-positive CTC at baseline (p = 0.33). A significant reduction in OS was shown in patients with vimentin-positive CTC compared to those without vimentin-positive CTC (median 305 days vs 453 days, p = 0.0293). There was no significant difference in baseline PSA in patients with Ki67-positive CTC at baseline versus those without Ki67

  7. Cholesterol biosynthesis inhibitor RO 48-8071 suppresses growth of hormone-dependent and castration-resistant prostate cancer cells

    Directory of Open Access Journals (Sweden)

    Liang Y

    2016-05-01

    Full Text Available Yayun Liang,1 Benford Mafuvadze,1 Johannes D Aebi,2 Salman M Hyder1 1Dalton Cardiovascular Research Center and Department of Biomedical Sciences, University of Missouri-Columbia, Columbia, MO, USA; 2Medicinal Chemistry, Roche Pharma Research and Early Development (pRED, Roche Innovation Center Basel, F Hoffmann-La Roche Ltd., Basel, Switzerland Abstract: Standard treatment for primary prostate cancer includes systemic exposure to chemotherapeutic drugs that target androgen receptor or antihormone therapy (chemical castration; however, drug-resistant cancer cells generally emerge during treatment, limiting the continued use of systemic chemotherapy. Patients are then treated with more toxic standard therapies. Therefore, there is an urgent need for novel and more effective treatments for prostate cancer. The cholesterol biosynthetic pathway is an attractive therapeutic target for treating endocrine-dependent cancers because cholesterol is an essential structural and functional component of cell membranes as well as the metabolic precursor of endogenous steroid hormones. In this study, we have examined the effects of RO 48-8071 (4'-[6-(allylmethylaminohexyloxy]-4-bromo-2'-fluorobenzophenone fumarate; Roche Pharmaceuticals internal reference: RO0488071 (RO, which is an inhibitor of 2, 3-oxidosqualene cyclase (a key enzyme in the cholesterol biosynthetic pathway, on prostate cancer cells. Exposure of both hormone-dependent and castration-resistant human prostate cancer cells to RO reduced prostate cancer cell viability and induced apoptosis in vitro. RO treatment reduced androgen receptor protein expression in hormone-dependent prostate cancer cells and increased estrogen receptor β (ERβ protein expression in both hormone-dependent and castration-resistant prostate cancer cell lines. Combining RO with an ERβ agonist increased its ability to reduce castration-resistant prostate cancer cell viability. In addition, RO effectively suppressed the

  8. A gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer.

    Science.gov (United States)

    Chang, Kai-Hsiung; Li, Rui; Kuri, Barbara; Lotan, Yair; Roehrborn, Claus G; Liu, Jiayan; Vessella, Robert; Nelson, Peter S; Kapur, Payal; Guo, Xiaofeng; Mirzaei, Hamid; Auchus, Richard J; Sharifi, Nima

    2013-08-29

    Growth of prostate cancer cells is dependent upon androgen stimulation of the androgen receptor (AR). Dihydrotestosterone (DHT), the most potent androgen, is usually synthesized in the prostate from testosterone secreted by the testis. Following chemical or surgical castration, prostate cancers usually shrink owing to testosterone deprivation. However, tumors often recur, forming castration-resistant prostate cancer (CRPC). Here, we show that CRPC sometimes expresses a gain-of-stability mutation that leads to a gain-of-function in 3β-hydroxysteroid dehydrogenase type 1 (3βHSD1), which catalyzes the initial rate-limiting step in conversion of the adrenal-derived steroid dehydroepiandrosterone to DHT. The mutation (N367T) does not affect catalytic function, but it renders the enzyme resistant to ubiquitination and degradation, leading to profound accumulation. Whereas dehydroepiandrosterone conversion to DHT is usually very limited, expression of 367T accelerates this conversion and provides the DHT necessary to activate the AR. We suggest that 3βHSD1 is a valid target for the treatment of CRPC. Copyright © 2013 Elsevier Inc. All rights reserved.

  9. Estradiol suppresses tissue androgens and prostate cancer growth in castration resistant prostate cancer

    International Nuclear Information System (INIS)

    Montgomery, Bruce; Nelson, Peter S; Vessella, Robert; Kalhorn, Tom; Hess, David; Corey, Eva

    2010-01-01

    Estrogens suppress tumor growth in prostate cancer which progresses despite anorchid serum androgen levels, termed castration resistant prostate cancers (CRPC), although the mechanisms are unclear. We hypothesize that estrogen inhibits CRPC in anorchid animals by suppressing tumoral androgens, an effect independent of the estrogen receptor. The human CRPC xenograft LuCaP 35V was implanted into orchiectomized male SCID mice and established tumors were treated with placebo, 17β-estradiol or 17β-estradiol and estrogen receptor antagonist ICI 182,780. Effects of 17β-estradiol on tumor growth were evaluated and tissue testosterone (T) and dihydrotestosterone (DHT) evaluated by mass spectrometry. Treatment of LuCaP 35V with 17β-estradiol slowed tumor growth compared to controls (tumor volume at day 21: 785 ± 81 mm 3 vs. 1195 ± 84 mm 3 , p = 0.002). Survival was also significantly improved in animals treated with 17β-estradiol (p = 0.03). The addition of the estrogen receptor antagonist ICI 182,780 did not significantly change survival or growth. 17β-estradiol in the presence and absence of ICI 182,780 suppressed tumor testosterone (T) and dihydrotestosterone (DHT) as assayed by mass spectrometry. Tissue androgens in placebo treated LuCaP 35V xenografts were; T = 0.71 ± 0.28 pg/mg and DHT = 1.73 ± 0.36 pg/mg. In 17β-estradiol treated LuCaP35V xenografts the tissue androgens were, T = 0.20 ± 0.10 pg/mg and DHT = 0.15 ± 0.15 pg/mg, (p < 0.001 vs. controls). Levels of T and DHT in control liver tissue were < 0.2 pg/mg. CRPC in anorchid animals maintains tumoral androgen levels despite castration. 17β-estradiol significantly suppressed tumor T and DHT and inhibits growth of CRPC in an estrogen receptor independent manner. The ability to manipulate tumoral androgens will be critical in the development and testing of agents targeting CRPC through tissue steroidogenesis

  10. DBC1 promotes castration-resistant prostate cancer by positively regulating DNA binding and stability of AR-V7.

    Science.gov (United States)

    Moon, Sue Jin; Jeong, Byong Chang; Kim, Hwa Jin; Lim, Joung Eun; Kwon, Ghee Young; Kim, Jeong Hoon

    2018-03-01

    Constitutively active AR-V7, one of the major androgen receptor (AR) splice variants lacking the ligand-binding domain, plays a key role in the development of castration-resistant prostate cancer (CRPC) and anti-androgen resistance. However, our understanding of the regulatory mechanisms of AR-V7-driven transcription is limited. Here we report DBC1 as a key regulator of AR-V7 transcriptional activity and stability in CRPC cells. DBC1 functions as a coactivator for AR-V7 and is required for the expression of AR-V7 target genes including CDH2, a mesenchymal marker linked to CRPC progression. DBC1 is required for recruitment of AR-V7 to its target enhancers and for long-range chromatin looping between the CDH2 enhancer and promoter. Mechanistically, DBC1 enhances DNA-binding activity of AR-V7 by direct interaction and inhibits CHIP E3 ligase-mediated ubiquitination and degradation of AR-V7 by competing with CHIP for AR-V7 binding, thereby stabilizing and activating AR-V7. Importantly, DBC1 depletion suppresses the tumorigenic and metastatic properties of CRPC cells. Our results firmly establish DBC1 as a critical AR-V7 coactivator that plays a key role in the regulation of DNA binding and stability of AR-V7 and has an important physiological role in CRPC progression.

  11. Bladder outlet obstruction (BOO) in men with castration-resistant prostate cancer.

    Science.gov (United States)

    Rom, Maximilian; Waldert, Matthias; Schatzl, Georg; Swietek, Natalia; Shariat, Shahrokh F; Klatte, Tobias

    2014-07-01

    To evaluate the frequency of bladder outlet obstruction (BOO) and detrusor overactivity (DO) in patients with castration-resistant prostate cancer (CRPC) and lower urinary tract symptoms (LUTS). Our prospective urodynamics database was queried. Inclusion criteria were CRPC and an International Prostate Symptom Score (IPSS) ≥ 20. Exclusion criteria were previous local therapy to the prostate gland, known urethral stricture disease, and a neurological component of LUTS. Twenty-one patients were identified. Urodynamic findings were analysed and compared with those of a matched cohort of 42 patients with benign prostatic enlargement (BPE). The median age of patients in the CRPC group was 74 years, and the median prostate-specific antigen (PSA) level at the time of the urodynamic study was 90 ng/mL. According to the BOO index, three patients (14%) were obstructed, three were equivocally obstructed (14%) and 15 were unobstructed. DO was seen in 12 patients (57%). Compared with the BPE group, patients with CRPC had lower cystometric bladder capacities (P = 0.003), were less likely to have BOO (14 vs 43%, P = 0.009) and more likely to have DO (57 vs 29%, P = 0.028). This study generates the hypothesis that only a minority of CRPC patients with LUTS have BOO, and that more than half of patients have DO. LUTS in CRPC may therefore be seldom attributable to BOO, but are, at least in part, related to DO and reduced cystometric capacity. A urodynamic investigation may be necessary before palliative transurethral resection of the prostate to select appropriate candidates. Larger prospective studies are needed to confirm our findings. © 2013 The Authors. BJU International © 2013 BJU International.

  12. Curcumin induces apoptosis and protective autophagy in castration-resistant prostate cancer cells through iron chelation

    Directory of Open Access Journals (Sweden)

    Yang C

    2017-02-01

    Full Text Available Chunguang Yang,1,* Xueyou Ma,1,* Zhihua Wang,1 Xing Zeng,1 Zhiquan Hu,1 Zhangqun Ye,1 Guanxin Shen2 1Department of Urology, Tongji Hospital, 2Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China *These authors contributed equally to this work Background: Curcumin induces apoptosis and autophagy in different cancer cells. Moreover, chemical and biological experiments have evidenced that curcumin is a biologically active iron chelator and induces cytotoxicity through iron chelation. We thus hypothesized that curcumin may induce apoptosis and autophagy in castration-resistant prostate cancer (CRPC cells through its iron-chelating properties.Materials and methods: CRPC cells were loaded with curcumin alone or in combination with ferric ammonium citrate (FAC. Cytotoxicity was measured by 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT assay. Apoptosis was assessed by flow cytometry, terminal deoxynucleotidyl transferase nick end labeling (TUNEL assay and caspase activity. Autophagy status was analyzed by the detection of autophagosomes and light chain 3-II (LC3-II using transmission electron microscopy and Western blot. Iron-binding activity of curcumin was assessed by spectrophotometry and MTT assay. The expression levels of transferrin receptor 1 (TfR1 and iron regulatory protein 1 (IRP1 were examined by Western blot.Results: Curcumin induced apoptosis and autophagy in CRPC cells. Combining curcumin with autophagy inhibitors (3-methyladenine [3-MA] synergized the apoptotic effect of curcumin. Moreover, curcumin bound to FAC at a ratio of ~1:1, as assessed by spectrophotometry and MTT assay. Apoptosis and autophagy induced by curcumin were counteracted by equal amounts of FAC. At apoptosis- and autophagy-inducing concentrations, curcumin enhanced the expression levels of TfR1 and IRP1, indicative of iron deprivation induced by curcumin

  13. Targeting Siah2 as Novel Therapy for Metastatic Prostate Cancer

    Science.gov (United States)

    2017-12-01

    deprivation therapy (ADT) or androgen receptor (AR) pathway inhibition (ARPI) but eventually develops into lethal castration resistance prostate cancer ...AWARD NUMBER: W81XWH-14-1-0553 TITLE: Targeting Siah2 as Novel Therapy for Metastatic Prostate Cancer PRINCIPAL INVESTIGATOR: Martin Gleave...Siah2 as Novel Therapy for Metastatic Prostate Cancer 5b. GRANT NUMBER W81XWH-14-1-0553 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Martin Gleave 5d

  14. Lymphocyte function following radium-223 therapy in patients with metastasized, castration-resistant prostate cancer

    International Nuclear Information System (INIS)

    Barsegian, Vahe; Moeckel, Daniel; Mueller, Stefan P.; Bockisch, Andreas; Horn, Peter A.; Lindemann, Monika

    2017-01-01

    Therapy with the alpha-emitter radium-223 chloride ("2"2"3Ra) is an innovative therapeutic option in patients with metastasized, castration-resistant prostate cancer. However, radiotherapy can lead to hematopoietic toxicity. The aim of this study was to determine if "2"2"3Ra therapy induces an impairment of cellular antimicrobial immune responses. In 11 patients receiving "2"2"3Ra treatment, lymphocyte proliferation and the production of pro- and anti-inflammatory cytokines (interferon-γ and interleukin-10) were determined, using lymphocyte transformation testing and ELISpot, respectively. Lymphocyte function after stimulation with mitogens and microbial antigens was assessed prior to therapy and at day 1, 7 and 28 after therapy. Lymphocyte proliferation and the production of interferon-γ and interleukin-10 towards mitogens and antigens remained unchanged after therapy. Consistent with these in vitro data, we did not observe infectious complications after treatment. The results argue against an impairment of lymphocyte function after "2"2"3Ra therapy. Thus, immune responses against pathogens should remain unaffected. (orig.)

  15. Lymphocyte function following radium-223 therapy in patients with metastasized, castration-resistant prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Barsegian, Vahe; Moeckel, Daniel [Helios Kliniken, Institute of Nuclear Medicine, Schwerin (Germany); Mueller, Stefan P.; Bockisch, Andreas [University Hospital Essen, Department of Nuclear Medicine, Essen (Germany); Horn, Peter A.; Lindemann, Monika [University Hospital Essen, Institute for Transfusion Medicine, Essen (Germany)

    2017-02-15

    Therapy with the alpha-emitter radium-223 chloride ({sup 223}Ra) is an innovative therapeutic option in patients with metastasized, castration-resistant prostate cancer. However, radiotherapy can lead to hematopoietic toxicity. The aim of this study was to determine if {sup 223}Ra therapy induces an impairment of cellular antimicrobial immune responses. In 11 patients receiving {sup 223}Ra treatment, lymphocyte proliferation and the production of pro- and anti-inflammatory cytokines (interferon-γ and interleukin-10) were determined, using lymphocyte transformation testing and ELISpot, respectively. Lymphocyte function after stimulation with mitogens and microbial antigens was assessed prior to therapy and at day 1, 7 and 28 after therapy. Lymphocyte proliferation and the production of interferon-γ and interleukin-10 towards mitogens and antigens remained unchanged after therapy. Consistent with these in vitro data, we did not observe infectious complications after treatment. The results argue against an impairment of lymphocyte function after {sup 223}Ra therapy. Thus, immune responses against pathogens should remain unaffected. (orig.)

  16. AR copy number and AR signaling-directed therapies in castration-resistant prostate cancer.

    Science.gov (United States)

    Salvi, Samanta; Conteduca, Vincenza; Lolli, Cristian; Testoni, Sara; Casadio, Valentina; Zaccheroni, Andrea; Rossi, Lorena; Burgio, Salvatore Luca; Menna, Cecilia; Schepisi, Giuseppe; De Giorgi, Ugo

    2017-11-22

    Adaptive upregulation of androgen receptor (AR) is the most common event involved in the progression from hormone sensitive to castration-resistant prostate cancer (CRPC). AR signaling remains the main target of new AR signalling-directed therapies such as abiraterone and enzalutamide in CRPC patients. In this review, we discuss general mechanisms of resistance to AR-targeted therapies, with a focus on the role of AR copy number (CN). We reported methods and clinical applications of AR CN evaluation in tissue and liquid biopsy, thus to have a complete information regarding its role as predictive and prognostic biomarker. Outcomes of CRPC patients are reported to be highly variable as consequence of tumor heterogeneity. AR CN could contribute to patient selection and tumor monitoring in CRPC treated with new anti-cancer treatment as abiraterone and enzalutamide. Further studies to investigate AR CN effect to these agents and its potential combination with other prognostic or predictive clinical factors are necessary in the context of harmonized clinical trial design. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  17. Resistance to BET Inhibitor Leads to Alternative Therapeutic Vulnerabilities in Castration-Resistant Prostate Cancer.

    Science.gov (United States)

    Pawar, Aishwarya; Gollavilli, Paradesi Naidu; Wang, Shaomeng; Asangani, Irfan A

    2018-02-27

    BRD4 plays a major role in the transcription networks orchestrated by androgen receptor (AR) in castration-resistant prostate cancer (CRPC). Several BET inhibitors (BETi) that displace BRD4 from chromatin are being evaluated in clinical trials for CRPC. Here, we describe mechanisms of acquired resistance to BETi that are amenable to targeted therapies in CRPC. BETi-resistant CRPC cells displayed cross-resistance to a variety of BETi in the absence of gatekeeper mutations, exhibited reduced chromatin-bound BRD4, and were less sensitive to BRD4 degraders/knockdown, suggesting a BRD4-independent transcription program. Transcriptomic analysis revealed reactivation of AR signaling due to CDK9-mediated phosphorylation of AR, resulting in sensitivity to CDK9 inhibitors and enzalutamide. Additionally, increased DNA damage associated with PRC2-mediated transcriptional silencing of DDR genes was observed, leading to PARP inhibitor sensitivity. Collectively, our results identify the therapeutic limitation of BETi as a monotherapy; however, our BETi resistance data suggest unique opportunities for combination therapies in treating CRPC. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

  18. Differences in clinical outcome between docetaxel and abiraterone acetate as the first-line treatment in chemo-naïve metastatic castration-resistant prostate cancer patients with or without the ineligible clinical factors of the COU-AA-302 study.

    Science.gov (United States)

    Poon, Darren M C; Chan, Kuen; Lee, Siu H; Chan, Tim W; Sze, Henry; Lee, Eric K C; Lam, Daisy; Chan, Michelle F T

    2018-03-01

    This study aimed to compare the efficacy of abiraterone acetate (AA) versus docetaxel (T) as first-line treatment in chemo-naïve metastatic castration-resistant prostate cancer (mCRPC) patients with or without the ineligible factors of the COU-AA-302 study (presence of visceral metastases, symptomatic disease, and/or Eastern Cooperative Oncology Group performance status ≥ 2). The clinical records of chemo-naïve mCRPC patients who received AA in six public oncology centers or T in two of these centers between 2003 and 2014 were reviewed. The survival time was compared among four subgroups of patients: those with ineligible factors administered AA (Group Ineligible-AA) or T (Group Ineligible-T), and those without ineligible factors and administered AA (Group Eligible-AA) or T (Group Eligible-T). During the study period, we identified 115 mCRPC patients who received AA or T, among whom 29, 36, 29, and 21 patients were classified as Groups Ineligible-AA, Ineligible-T, Eligible-AA, and Eligible-T, respectively. Both Group Ineligible-AA and Group Eligible-AA had significantly longer progression-free survival (PFS) and similar overall survival (OS) as Group Ineligible-T and Group Eligible-T (Ineligible, PFS: 6.3 vs. 5.9 months, P  = 0.0234, OS: 7.8 vs. 15.7 months, P  = 0.1601; Eligible, PFS: 9.8 vs. 5.6 months, P  = 0.0437, OS: 20.5 vs. 18.2 months, P  = 0.7820). Compared to T, AA treatment resulted in longer PFS and similar OS in chemo-naïve mCRPC patients, irrespective of the presence of ineligible factors, suggesting that the initial treatment by AA may still be beneficial to those with the aforementioned ineligible factors.

  19. A randomised, phase II study of repeated rhenium-188-HEDP combined with docetaxel and prednisone versus docetaxel and prednisone alone in castration-resistant prostate cancer (CRPC) metastatic to bone; the Taxium II trial

    Energy Technology Data Exchange (ETDEWEB)

    Dodewaard-de Jong, Joyce M. van [VU University Medical Centre, Department of Medical Oncology, Amsterdam (Netherlands); Meander Medical Centre, Department of Medical Oncology, Amersfoort (Netherlands); Klerk, John M.H. de [Meander Medical Centre, Department of Nuclear Medicine, Amersfoort (Netherlands); Bloemendal, Haiko J. [Meander Medical Centre, Department of Medical Oncology, Amersfoort (Netherlands); University Medical Centre Utrecht, Department of Medical Oncology, Utrecht (Netherlands); Oprea-Lager, Daniela E.; Hoekstra, Otto S. [VU University Medical Centre, Department of Radiology and Nuclear Medicine, Amsterdam (Netherlands); Berg, H.P. van den [Tergooi Medical Hospital, Department of Medical Oncology, Hilversum (Netherlands); Los, Maartje [St Antonius Hospital Utrecht, Department of Medical Oncology, Utrecht (Netherlands); Beeker, Aart [Spaarne Gasthuis, Department of Medical Oncology, Hoofddorp (Netherlands); Jonker, Marianne A. [VU University Medical Centre, Department of Epidemiology and Biostatistics, Amsterdam (Netherlands); O' Sullivan, Joe M. [Queen' s University Belfast, Centre for Cancer Research and Cell Biology, Belfast, Northern Ireland (United Kingdom); Verheul, Henk M.W.; Eertwegh, Alfons J.M. van den [VU University Medical Centre, Department of Medical Oncology, Amsterdam (Netherlands)

    2017-08-15

    Rhenium-188-HEDP is a beta-emitting radiopharmaceutical used for palliation of metastatic bone pain. We investigated whether the addition of rhenium-188-HEDP to docetaxel/prednisone improved efficacy of chemotherapy in patients with CRPC. Patients with progressive CRPC and osteoblastic bone metastases were randomised for first-line docetaxel 75 mg/m{sup 2} 3-weekly plus prednisone with or without 2 injections of rhenium-188-HEDP after the third (40 MBq/kg) and after the sixth (20 MBq/kg) cycle of docetaxel. Primary endpoint was progression-free survival (PFS), defined as either PSA, radiographic or clinical progression. Patients were stratified by extent of bone metastases and hospital. Forty-two patients were randomised for standard treatment and 46 patients for combination therapy. Median number of cycles of docetaxel was 9 in the control group and 8 in the experimental group. Median follow-up was 18.4 months. Two patients from the experimental group did not start treatment after randomisation. In the intention to treat analysis no differences in PFS, survival and PSA became apparent between the two groups. In an exploratory per-protocol analysis median overall survival was significantly longer in the experimental group (33.8 months (95%CI 31.75-35.85)) than in the control group (21.0 months (95%CI 13.61-28.39); p 0.012). Also median PFS in patients with a baseline phosphatase >220U/L was significantly better with combination treatment (9.0 months (95%CI 3.92-14.08) versus 6.2 months (95%CI 3.08-9.32); log rank p 0.005). As expected, thrombocytopenia (grade I/II) was reported more frequently in the experimental group (25% versus 0%). Combined treatment with rhenium-188-HEDP and docetaxel did not prolong PFS in patients with CRPC. The observed survival benefit in the per-protocol analysis warrants further studies in the combined treatment of chemotherapy and radiopharmaceuticals. (orig.)

  20. Abiraterone in metastatic prostate cancer without previous chemotherapy

    NARCIS (Netherlands)

    Ryan, Charles J.; Smith, Matthew R.; de Bono, Johann S.; Molina, Arturo; Logothetis, Christopher J.; de Souza, Paul; Fizazi, Karim; Mainwaring, Paul; Piulats, Josep M.; Ng, Siobhan; Carles, Joan; Mulders, Peter F. A.; Basch, Ethan; Small, Eric J.; Saad, Fred; Schrijvers, Dirk; van Poppel, Hendrik; Mukherjee, Som D.; Suttmann, Henrik; Gerritsen, Winald R.; Flaig, Thomas W.; George, Daniel J.; Yu, Evan Y.; Efstathiou, Eleni; Pantuck, Allan; Winquist, Eric; Higano, Celestia S.; Taplin, Mary-Ellen; Park, Youn; Kheoh, Thian; Griffin, Thomas; Scher, Howard I.; Rathkopf, Dana E.; Boyce, A.; Costello, A.; Davis, I.; Ganju, V.; Horvath, L.; Lynch, R.; Marx, G.; Parnis, F.; Shapiro, J.; Singhal, N.; Slancar, M.; van Hazel, G.; Wong, S.; Yip, D.; Carpentier, P.; Luyten, D.; de Reijke, T.

    2013-01-01

    Abiraterone acetate, an androgen biosynthesis inhibitor, improves overall survival in patients with metastatic castration-resistant prostate cancer after chemotherapy. We evaluated this agent in patients who had not received previous chemotherapy. In this double-blind study, we randomly assigned

  1. Orphan nuclear receptor TLX contributes to androgen insensitivity in castration-resistant prostate cancer via its repression of androgen receptor transcription.

    Science.gov (United States)

    Jia, Lin; Wu, Dinglan; Wang, Yuliang; You, Wenxing; Wang, Zhu; Xiao, Lijia; Cai, Ganhui; Xu, Zhenyu; Zou, Chang; Wang, Fei; Teoh, Jeremy Yuen-Chun; Ng, Chi-Fai; Yu, Shan; Chan, Franky L

    2018-03-20

    The metastatic castration-resistant prostate cancer (CRPC) is a lethal form of prostate cancer, in which the expression of androgen receptor (AR) is highly heterogeneous. Indeed, lower AR expression and attenuated AR signature activity is shown in CRPC tissues, especially in the subset of neuroendocrine prostate cancer (NEPC) and prostate cancer stem-like cells (PCSCs). However, the significance of AR downregulation in androgen insensitivity and de-differentiation of tumor cells in CRPC is poorly understood and much neglected. Our previous study shows that the orphan nuclear receptor TLX (NR2E1), which is upregulated in prostate cancer, plays an oncogenic role in prostate carcinogenesis by suppressing oncogene-induced senescence. In the present study, we further established that TLX exhibited an increased expression in metastatic CRPC. Further analyses showed that overexpression of TLX could confer resistance to androgen deprivation and anti-androgen in androgen-dependent prostate cancer cells in vitro and in vivo, whereas knockdown of endogenous TLX could potentiate the sensitivity to androgen deprivation and anti-androgen in prostate cancer cells. Our study revealed that the TLX-induced resistance to androgen deprivation and anti-androgen was mediated through its direct suppression of AR gene transcription and signaling in both androgen-stimulated and -unstimulated prostate cancer cells. We also characterized that TLX could bind directly to AR promoter and repress AR transcription by recruitment of histone modifiers, including HDAC1, HDAC3, and LSD1. Together, our present study shows, for the first time, that TLX can contribute to androgen insensitivity in CRPC via repression of AR gene transcription and signaling, and also implicates that targeting the druggable TLX may have a potential therapeutic significance in CRPC management, particularly in NEPC and PCSCs.

  2. Emerging Therapies in Metastatic Prostate Cancer.

    Science.gov (United States)

    Sonnenburg, Daniel W; Morgans, Alicia K

    2018-04-11

    In the last decade, there have been multiple landmark therapeutic advances for the treatment of metastatic prostate cancer, both in the castration-resistant and hormone-sensitive setting. In this review, we highlight recent progress and ongoing trials for metastatic prostate cancer, including advances in chemotherapy, androgen receptor-directed therapy, targeted therapies, and immunotherapy. Several landmark studies for men with metastatic hormone-sensitive prostate cancer demonstrated improvement in overall survival with the addition of docetaxel chemotherapy or abiraterone acetate to standard androgen deprivation therapy. A single-arm phase 2 study of the PARP inhibitor olaparib demonstrated high response rates and more favorable progression-free and overall survival for men with metastatic castration-resistant prostate cancer and DNA repair defects treated with olaparib compared with men without DNA repair defects. Multiple ongoing clinical trials are investigating novel hormonal therapies and combinations of chemotherapy, targeted small molecules, immunotherapy, and radiopharmaceuticals. Progress continues to be made in the treatment of metastatic prostate cancer, and ongoing clinical trials continue to investigate novel agents and approaches to treatment.

  3. Targeting Mitochondrial Inhibitors for Metastatic Castrate-Resistant Prostate Cancer

    Science.gov (United States)

    2017-09-01

    described previously, authenticity documented by 1H and 13C NMR and mass spectrometry , and coupled using ethylene diamine derivatives as the self-cleaving...synthesizes all of the compounds proposed in this application. He uses 1H and 13C NMR and mass spectrometry for the quality assurance for each...time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this

  4. Targeting Mitochondrial Inhibitors for Metastatic Castrate Resistant Prostate Cancer

    Science.gov (United States)

    2017-09-01

    reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215...enzymatically active PSA within extracellular fluid (ECF) at sites of mCRPC. The advantage of ECF hydrolysis is that only a fraction of cancer cells need to...hydrolysis is that only a fraction of cancer cells need to secrete PSA since its enzymatic activity amplifies the level of liberated cell penetrant MTs

  5. State-of-the-Art Management for the Patient with Castration-Resistant Prostate Cancer in 2012.

    Science.gov (United States)

    Sartor, Oliver

    2012-01-01

    Much progress has been made in metastatic castration-resistant prostate cancer (CRPC), and multiple new U.S. Food and Drug Administration (FDA)-approved survival-prolonging drugs are now available. In 2004, docetaxel/prednisone was the first therapy shown to prolong survival. In 2010 and 2011, sipuleucel-T, cabazitaxel/prednisone, and abiraterone/prednisone were FDA approved. Two new agents, radium-223 and MDV-3100, have recently reported large phase III trials prolonging overall survival and will be submitted for regulatory approval in 2012. One can now begin to ask, is there an optimal sequence for therapies in metastatic CRPC? Despite the recent progress, there is much we do not know and virtually no information on this important question. We know that abiraterone/prednisone and cabazitaxel/prednisone are appropriate choices for a patient after receiving docetaxel, but we do not know what, if anything, represents the optimal sequence for abiraterone and cabazitaxel. In fact we do not understand how one therapy may affect the response to a subsequent therapy. We are also aware that the pre- and postdocetaxel spaces represent regulatory rather than biologic divisions. In addition, despite the proven role of docetaxel/prednisone, many patients with CRPC are not considered to be suitable for chemotherapy, and worldwide many never receive any form of chemotherapy. What is the optimal management for these patients? Taken together it is reasonable to assess patient preferences, prior therapies and response/tolerance to prior therapies, burden of disease, comorbidities, current symptoms, drug toxicities, out-of-pocket costs, etc., in clinical decision making. Given the many factors we do not know, it is hard to be dogmatic in approaching the therapeutic options for the patient with CRPC. We will likely soon move beyond the current sequencing paradigm and begin to assess new combinations in a systematic and rational fashion. Perhaps one day, in the not too distant future

  6. Pain in castration-resistant prostate cancer with bone metastases: a qualitative study

    Directory of Open Access Journals (Sweden)

    Gater Adam

    2011-10-01

    Full Text Available Abstract Background Bone metastases are a common painful and debilitating consequence of castration-resistant prostate cancer (CPRC. Bone pain may predict patients' prognosis and there is a need to further explore CRPC patients' experiences of bone pain in the overall context of disease pathology. Due to the subjective nature of pain, assessments of pain severity, onset and progression are reliant on patient assessment. Patient reported outcome (PRO measures, therefore, are commonly used as key endpoints for evaluating the efficacy of CRPC treatments. Evidence of the content validity of leading PRO measures of pain severity used in CRPC clinical trials is, however, limited. Methods To document patients' experience of CRPC symptoms including pain, and their impact on health-related quality of life (HRQL, semi-structured in-depth qualitative interviews were conducted with 17 patients with CRPC and bone metastases. The content validity of the Present Pain Intensity (PPI scale from the McGill Pain Questionnaire (MPQ, and the 'Average Pain' and 'Worst Pain' items of the Brief Pain Inventory Short-Form (BPI-SF was also assessed. Results Patients with CRPC and bone metastases present with a constellation of symptoms that can have a profound effect on HRQL. For patients in this study, bone pain was the most prominent and debilitating symptom associated with their condition. Bone pain was chronic and, despite being generally well-managed by analgesic medication, instances of breakthrough cancer pain (BTcP were common. Cognitive debriefing of the selected PRO measures of pain severity highlighted difficulties among patients in understanding the verbal response scale (VRS of the MPQ PPI scale. There were also some inconsistencies in the way in which the BPI-SF 'Average Pain' item was interpreted by patients. In contrast, the BPI-SF 'Worst Pain' item was well understood and interpreted consistently among patients. Conclusions Study findings support the

  7. Study the Origin and Mechanisms of Castration Resistance Characterized by Outgrowth of Prostate Cancer Cells with Low/Negative Androgen Receptor

    Science.gov (United States)

    2017-12-01

    Prostate Cancer Cells with Low/Negative Androgen Receptor 5b. GRANT NUMBER W81XWH-15-1-0540 5c. PROGRAM...role of androgen receptor (AR) signaling in disease progression, the current approach to treat prostate cancer is AR-targeted therapy. While this... Prostate cancer ; Androgen receptor ; Castration-resistant prostate cancer (CRPC); Enzalutamide resistance; GREB1; p300 6 Accomplishments Specific

  8. Investigating Genomic Mechanisms of Treatment Resistance in Castration ResistantProstate Cancer

    Science.gov (United States)

    2017-07-01

    bladder cancer which has been a time intensive but fruitful process. Additionally I have taken on a number of extramural responsibilities including...advancement. Led ASCO 2017 Annual Meeting Prostate Program Committee, served on ASCO 2017 Educational Committee, NCCN panel member ( bladder cancer ...pancreatic cancer . Cancer Lett. 2016 Sep 28; 380(1):144-52. PMID: 27343980 4. Anantharaman A, Friedlander TW. Targeting the androgen receptor in metastatic

  9. Enzalutamide in metastatic prostate cancer before chemotherapy

    DEFF Research Database (Denmark)

    Beer, Tomasz M; Armstrong, Andrew J; Rathkopf, Dana E

    2014-01-01

    BACKGROUND: Enzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer in whom the disease has progressed after chemotherapy. New treatment options are needed for patients with metastatic prostate cancer who have...... the most common clinically relevant adverse events associated with enzalutamide treatment. CONCLUSIONS: Enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer. (Funded by Medivation and Astellas...... skeletal-related event (hazard ratio, 0.72), a complete or partial soft-tissue response (59% vs. 5%), the time until prostate-specific antigen (PSA) progression (hazard ratio, 0.17), and a rate of decline of at least 50% in PSA (78% vs. 3%) (P

  10. Identification and Targeting of Candidate Pre-Existing Lurker Cells that Give Rise to Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2015-10-01

    castration-resistance of each subset in humans. We also measured castration-resistance of isolated subsets in vitro in the presence or absence of DHT in...microns). In vitro growth in the absence of DHT also demonstrates castration-resistant properties of the intermediate/luminal progenitor cells...subsets without DHT compared to DHT -containing media, demonstrating castration-resistance). 4 4) other achievements: We found that tumors

  11. {sup 11}C-Choline PET/CT in castration-resistant prostate cancer patients treated with docetaxel

    Energy Technology Data Exchange (ETDEWEB)

    Ceci, Francesco [University of Bologna, Service of Nuclear Medicine, S. Orsola-Malpighi Hospital, Bologna (Italy); Azienda Ospedaliero-Universitaria di Bologna, Policlinico S. Orsola-Malpighi, UO Medicina Nucleare PAD. 30, Bologna (Italy); Castellucci, Paolo; Graziani, Tiziano; Renzi, Riccardo; Fanti, Stefano [University of Bologna, Service of Nuclear Medicine, S. Orsola-Malpighi Hospital, Bologna (Italy); Schiavina, Riccardo; Borghesi, Marco; Brunocilla, Eugenio [University of Bologna, Department of Urology, S. Orsola-Malpighi Hospital, Bologna (Italy); Di Tullio, Piergiorgio; Ardizzoni, Andrea [University of Bologna, Department of Oncology, S. Orsola-Malpighi Hospital, Bologna (Italy)

    2016-01-15

    To investigate the role of {sup 11}C-choline PET/CT for evaluating the response to treatment in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with docetaxel in comparison with PSA response. Inclusion criteria were (a) proven mCRPC, (b) docetaxel as first line of chemotherapy (docetaxel 75 mg/m{sup 2} + prednisone 5 mg), and (c) {sup 11}C-choline PET/CT and PSA values assessed before and after docetaxel administration. A total of 61 patients were retrospectively enrolled (mean age 68.9 years, range 57 - 84 years). {sup 11}C-Choline PET/CT was performed at baseline before docetaxel treatment (PET1) and after the end of treatment (PET2). PSA values were measured before treatment (PSA1) and after treatment (PSA2). PET2 was reported as complete response (CR), partial response (PR) or stable disease (SD). Progressive disease (PD) was considered if a new lesion was seen. PSA trend was calculated from the change in absolute values between PSA1 and PSA2. A decrease of ≥50 % between PSA1 and PSA2 was considered a PSA response. Clinical, radiological and laboratory follow-up ranged from 6 to 53 months (mean 13.5 months). Of the 61 patients, 40 (65.5 %) showed PD on PET2, 13 (21.3 %) showed SD, 2 (3.4 %) showed PR, and 6 (9.8 %) showed CR. An increasing PSA trend was seen in 29 patients (47.5 %) and a decreasing PSA trend in 32 patients (52.5 %). A PSA response of ≥50 % was seen in 25 patients (41 %). Radiological PD was seen in 23 of the 29 patients (79.3 %) with an increasing PSA trend, in 16 of the 32 patients (50 %) with a decreasing PSA trend, and in 11 of the 25 patients (44 %) with a PSA response of ≥50 %. In the multivariate statistical analysis, the presence of more than ten bone lesions detected on PET1 was significantly associated with an increased probability of PD on PET2. No association was observed between PSA level and PD on PET2. Our results suggest that an increasing PSA trend measured after docetaxel treatment could be

  12. AR-V7 in Peripheral Whole Blood of Patients with Castration-resistant Prostate Cancer: Association with Treatment-specific Outcome Under Abiraterone and Enzalutamide.

    Science.gov (United States)

    Seitz, Anna Katharina; Thoene, Silvia; Bietenbeck, Andreas; Nawroth, Roman; Tauber, Robert; Thalgott, Mark; Schmid, Sebastian; Secci, Ramona; Retz, Margitta; Gschwend, Jürgen E; Ruland, Jürgen; Winter, Christof; Heck, Matthias M

    2017-11-01

    It has been demonstrated that androgen receptor splice variant 7 (AR-V7) expression in circulating tumor cells (CTCs) predicts poor treatment response in metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone or enzalutamide. To develop a practical and robust liquid profiling approach for direct quantification of AR-V7 in peripheral whole blood without the need for CTC capture and to determine its potential for predicting treatment response in mCRPC patients. Whole blood samples from a prospective biorepository of 85 mCRPC patients before treatment initiation with abiraterone (n=56) or enzalutamide (n=29) were analyzed via droplet digital polymerase chain reaction. The association of AR-V7 status with prostate-specific antigen (PSA) response defined by PSA decline ≥50% and with PSA-progression-free survival (PSA-PFS), clinical PFS, and overall survival (OS) was assessed. High AR-V7 expression levels in whole blood were detectable in 18% (15/85) of patients. No patient with high AR-V7 expression achieved a PSA response, and AR-V7 status was an independent predictor of PSA response in multivariable logistic regression analysis (p=0.03). High AR-V7 expression was associated with shorter PSA-PFS (median 2.4 vs 3.7 mo; pAR-V7 expression remained an independent predictor of shorter PSA-PFS (hazard ratio [HR] 7.0, 95% confidence interval [CI] 2.3-20.7; pAR-V7 mRNA levels in whole blood is a simple and promising approach to predict poor treatment outcome in mCRPC patients receiving abiraterone or enzalutamide. We established a method for determining AR-V7 status in whole blood. This test predicted treatment resistance in patients with metastatic castration-resistant prostate cancer undergoing treatment with abiraterone or enzalutamide. Prospective validation is needed before application to clinical practice. Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

  13. Can palliative radiotherapy influence prostate-specific antigen response in patients with castrate-resistant prostate cancer treated with systemic therapy (chemotherapy or abiraterone)?—a report of three cases

    International Nuclear Information System (INIS)

    Hingorani, Mohan; Dixit, Sanjay; Pugazhenthi, Pattu; Hawkyard, Simon; Robertson, Andrew; Khafagy, Richard

    2015-01-01

    Palliative radiotherapy (pRT) is primarily employed for palliation of bone pain in patients with castrate-resistant prostate cancer (CRPC). However, evidence that pRT influences prostate-specific antigen response in patients with CRPC on systemic therapy is lacking. We describe three cases of CRPC progressing after treatment with docetaxel (n=2) and abiraterone (n=1), who responded unusually after pRT for bone pain with the development of a significant biochemical response and restoration of response to systemic therapy. The possibility of pRT influencing metastatic disease in CRPC has not been previously reported, and raises the possibility of radiation-induced modulation of anti-tumor immune response mechanisms that may play a role in the restoration of response to systemic treatment

  14. 5alphaDH-DOC (5alpha-dihydro-deoxycorticosterone) activates androgen receptor in castration-resistant prostate cancer.

    Science.gov (United States)

    Uemura, Motohide; Honma, Seijiro; Chung, Suyoun; Takata, Ryo; Furihata, Mutsuo; Nishimura, Kazuo; Nonomura, Norio; Nasu, Yasutomo; Miki, Tsuneharu; Shuin, Taro; Fujioka, Tomoaki; Okuyama, Akihiko; Nakamura, Yusuke; Nakagawa, Hidewaki

    2010-08-01

    Prostate cancer often relapses during androgen-depletion therapy, even under the castration condition in which circulating androgens are drastically reduced. High expressions of androgen receptor (AR) and genes involved in androgen metabolism indicate a continued role for AR in castration-resistant prostate cancers (CRPCs). There is increasing evidence that some amounts of 5alpha-dihydrotestosterone (DHT) and other androgens are present sufficiently to activate AR within CRPC tissues, and enzymes involved in the androgen and steroid metabolism, such as 5alpha-steroid reductases, are activated in CRPCs. In this report, we screened eight natural 5alphaDH-steroids to search for novel products of 5alpha-steroid reductases, and identified 11-deoxycorticosterone (DOC) as a novel substrate for 5alpha-steroid reductases in CRPCs. 11-Deoxycorticosterone (DOC) and 5alpha-dihydro-deoxycorticosterone (5alphaDH-DOC) could promote prostate cancer cell proliferation through AR activation, and type 1 5alpha-steroid reductase (SRD5A1) could convert from DOC to 5alphaDH-DOC. Sensitive liquid chromatography-tandem mass spectrometric analysis detected 5alphaDH-DOC in some clinical CRPC tissues. These findings implicated that under an extremely low level of DHT, 5alphaDH-DOC and other products of 5alpha-steroid reductases within CRPC tissues might activate the AR pathway for prostate cancer cell proliferation and survival under castration.

  15. Enzalutamide in Patients With Castration-Resistant Prostate Cancer Progressing After Docetaxel: Retrospective Analysis of the Swiss Enzalutamide Named Patient Program.

    Science.gov (United States)

    Papazoglou, Dimitrios; Wannesson, Luciano; Berthold, Dominik; Cathomas, Richard; Gillessen, Silke; Rothermundt, Christian; Hasler, Loretta; Winterhalder, Ralph; Barth, Andreas; Mingrone, Walter; Nussbaum, Catrina Uhlmann; von Rohr, Lukas; von Burg, Philippe; Schmid, Mathias; Richner, Jürg; Baumann, Sylvia; Kühne, Reto; Stenner, Frank; Rothschild, Sacha I

    2017-06-01

    Enzalutamide is a second-generation androgen receptor (AR) inhibitor that binds to and blocks the AR with higher affinity than previously available AR inhibitors. High activity has been proven in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel and in chemotherapy-naive patients with mCRPC. However, its activity in patients previously treated with other novel agents (for example, abiraterone and/or cabazitaxel), remains controversial. The aim of this retrospective analysis of the Swiss Enzalutamide Named Patient Program was to evaluate clinical efficacy and safety of enzalutamide treatment in patients with mCRPC progressing after docetaxel and other lines of therapy considering different treatment sequences. We report on 44 patients treated with enzalutamide. The median survival time from diagnosis of CPRC was 41.1 months (95% confidence interval [CI], 32.3-49.8 months). Enzalutamide was used as a second, third, fourth, fifth, sixth, or seventh-line therapy in 13%, 20%, 31%, 20%, 11%, and 2% of patients. The median duration of enzalutamide treatment was 3.0 months (range, 1-21 months). Median progression-free survival was 3.0 months (95% CI, 2.4-3.7 months). The estimated median overall survival was 6.3 months (95% CI, 4.6-8.1 months). Sixteen patients (36.4%) had a prostate-specific antigen decrease of ≥ 30%, and 11 patients (25.0%) of ≥ 50%, respectively. In multivariate analysis, the absence of previous therapy with abiraterone and a prostate-specific antigen response of ≥ 50% on enzalutamide therapy were significantly associated with overall survival on enzalutamide treatment. Our results show that enzalutamide has modest activity in extensively pretreated patients. However, there is a subgroup of patients achieving benefit from enzalutamide therapy even after pretreatment with abiraterone. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Second-Line Hormonal Therapy for Men With Chemotherapy-Naïve, Castration-Resistant Prostate Cancer: American Society of Clinical Oncology Provisional Clinical Opinion.

    Science.gov (United States)

    Virgo, Katherine S; Basch, Ethan; Loblaw, D Andrew; Oliver, Thomas K; Rumble, R Bryan; Carducci, Michael A; Nordquist, Luke; Taplin, Mary-Ellen; Winquist, Eric; Singer, Eric A

    2017-06-10

    Purpose ASCO provisional clinical opinions (PCOs) offer direction to the ASCO membership after publication or presentation of potential practice-changing data. This PCO addresses second-line hormonal therapy for chemotherapy-naïve men with castration-resistant prostate cancer (CRPC) who range from being asymptomatic with only biochemical evidence of CRPC to having documented metastases but minimal symptoms. Clinical Context The treatment goal for CRPC is palliation. Despite resistance to initial androgen deprivation therapy, most men respond to second-line hormonal therapies. However, guidelines have neither addressed second-line hormonal therapy for nonmetastatic CRPC nor provided specific guidance with regard to the chemotherapy-naïve population. Recent Data Six phase III randomized controlled trials and expert consensus opinion inform this PCO. Provisional Clinical Opinion For men with CRPC, a castrate state should be maintained indefinitely. Second-line hormonal therapy (eg, antiandrogens, CYP17 inhibitors) may be considered in patients with nonmetastatic CRPC at high risk for metastatic disease (rapid prostate-specific antigen doubling time or velocity) but otherwise is not suggested. In patients with radiographic evidence of metastases and minimal symptoms, enzalutamide or abiraterone plus prednisone should be offered after discussion with patients about potential harms, benefits, costs, and patient preferences. Radium-223 and sipuleucel-T also are options. No evidence provides guidance about the optimal order of hormonal therapies for CRPC beyond second-line treatment. Prostate-specific antigen testing every 4 to 6 months is reasonable for men without metastases. Routine radiographic restaging generally is not suggested but can be considered for patients at risk for metastases or who exhibit symptoms or other evidence of progression. Additional information is available at www.asco.org/genitourinary-cancer-guidelines and www.asco.org/guidelineswiki .

  17. LncRNA HOTAIR Enhances the Androgen-Receptor-Mediated Transcriptional Program and Drives Castration-Resistant Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Ali Zhang

    2015-10-01

    Full Text Available Understanding the mechanisms of androgen receptor (AR activation in the milieu of low androgen is critical to effective treatment of castration-resistant prostate cancer (CRPC. Here, we report HOTAIR as an androgen-repressed lncRNA, and, as such, it is markedly upregulated following androgen deprivation therapies and in CRPC. We further demonstrate a distinct mode of lncRNA-mediated gene regulation, wherein HOTAIR binds to the AR protein to block its interaction with the E3 ubiquitin ligase MDM2, thereby preventing AR ubiquitination and protein degradation. Consequently, HOTAIR expression is sufficient to induce androgen-independent AR activation and drive the AR-mediated transcriptional program in the absence of androgen. Functionally, HOTAIR overexpression increases, whereas HOTAIR knockdown decreases, prostate cancer cell growth and invasion. Taken together, our results provide compelling evidence of lncRNAs as drivers of androgen-independent AR activity and CRPC progression, and they support the potential of lncRNAs as therapeutic targets.

  18. Inhibition of Androgen Receptor Nuclear Localization and Castration-Resistant Prostate Tumor Growth by Pyrroloimidazole-based Small Molecules.

    Science.gov (United States)

    Masoodi, Khalid Z; Xu, Yadong; Dar, Javid A; Eisermann, Kurtis; Pascal, Laura E; Parrinello, Erica; Ai, Junkui; Johnston, Paul A; Nelson, Joel B; Wipf, Peter; Wang, Zhou

    2017-10-01

    The androgen receptor (AR) is a ligand-dependent transcription factor that controls the expression of androgen-responsive genes. A key step in androgen action, which is amplified in castration-resistant prostate cancer (CRPC), is AR nuclear translocation. Small molecules capable of inhibiting AR nuclear localization could be developed as novel therapeutics for CRPC. We developed a high-throughput screen and identified two structurally-related pyrroloimidazoles that could block AR nuclear localization in CRPC cells. We show that these two small molecules, 3-(4-ethoxyphenyl)-6,7-dihydro-5 H -pyrrolo[1,2- a ]imidazole (EPPI) and 3-(4-chlorophenyl)-6,7-dihydro-5 H -pyrrolo[1,2- a ]imidazole (CPPI) can inhibit the nuclear localization and transcriptional activity of AR and reduce the proliferation of AR-positive but not AR-negative prostate cancer cell lines. EPPI and CPPI did not inhibit nuclear localization of the glucocorticoid receptor or the estrogen receptor, suggesting they selectively target AR. In LNCaP tumor xenografts, CPPI inhibited the proliferation of relapsed LNCaP tumors. These findings suggest that EPPI and CPPI could serve as lead structures for the development of therapeutic agents for CRPC. Mol Cancer Ther; 16(10); 2120-9. ©2017 AACR . ©2017 American Association for Cancer Research.

  19. Epigenetic markers in circulating cell-free DNA as prognostic markers for survival of castration-resistant prostate cancer patients.

    Science.gov (United States)

    Hendriks, Rianne J; Dijkstra, Siebren; Smit, Frank P; Vandersmissen, Johan; Van de Voorde, Hendrik; Mulders, Peter F A; van Oort, Inge M; Van Criekinge, Wim; Schalken, Jack A

    2018-04-01

    Noninvasive biomarkers to guide personalized treatment for castration-resistant prostate cancer (CRPC) are needed. In this study, we analyzed hypermethylation patterns of two genes (GSTP1 and APC) in plasma cell-free DNA (cfDNA) of CRPC patients. The aim of this study was to analyze the cfDNA concentrations and levels of the epigenetic markers and to assess the value of these biomarkers for prognosis. In this prospective study, patients were included before starting new treatment after developing CRPC. The blood samples were collected prior to start of the treatment and at three time points thereafter. cfDNA was extracted from 1.5 mL of plasma and before performing a methylation-specific PCR, bisulfate modification was carried out. The median levels of cfDNA, GSTP1, and APC copies in the baseline samples of CRPC patients (n = 47) were higher than in controls (n = 30). In the survival analysis, the group with baseline marker levels below median had significant less PCa-related deaths (P-values Prostate Published by Wiley Periodicals, Inc.

  20. Nucleoporin 62 and Ca(2+)/calmodulin dependent kinase kinase 2 regulate androgen receptor activity in castrate resistant prostate cancer cells.

    Science.gov (United States)

    Karacosta, Loukia G; Kuroski, Laura A; Hofmann, Wilma A; Azabdaftari, Gissou; Mastri, Michalis; Gocher, Angela M; Dai, Shuhang; Hoste, Allen J; Edelman, Arthur M

    2016-02-15

    Re-activation of the transcriptional activity of the androgen receptor (AR) is an important factor mediating progression from androgen-responsive to castrate-resistant prostate cancer (CRPC). However, the mechanisms regulating AR activity in CRPC remain incompletely understood. Ca(2+) /calmodulin-dependent kinase kinase (CaMKK) 2 was previously shown to regulate AR activity in androgen-responsive prostate cancer cells. Our objective was to further explore the basis of this regulation in CRPC cells. The abundance of CaMKK2 in nuclear fractions of androgen-responsive prostate cancer and CRPC, cells were determined by subcellular fractionation and Western blotting. CaMKK2 association with nuclear pore complexes (NPCs) and nucleoporins (Nups) including Nup62, were imaged by structured illumination and super-resolution fluorescence microscopy and co-immunoprecipitation, respectively. The abundance and subcellular localization of CaMKK2 and Nup62 in human clinical specimens of prostate cancer was visualized by immunohistochemistry. The role of Nups in the growth and viability of CRPC cells was assessed by RNA interference and cell counting. The involvement of CaMKK2 and Nup62 in regulating AR transcriptional activity was addressed by RNA interference, chromatin immunoprecipitation, androgen response element reporter assay, and Western blotting. CaMKK2 was expressed at higher levels in the nuclear fraction of CPRC C4-2 cells, than in that of androgen-responsive LNCaP cells. In C4-2 cells, CaMKK2 associated with NPCs of the nuclear envelope and physically interacted with Nup62. CaMKK2 and Nup62 demonstrated pronounced, and similar increases in both expression and perinuclear/nuclear localization in human clinical specimens of advanced prostate cancer relative to normal prostate. Knockdown of Nup62, but not of Nups, 98 or 88, reduced growth and viability of C4-2 cells. Knockdown of Nup62 produced a greater reduction of the growth and viability of C4-2 cells than of non

  1. ASC-J9 Suppresses Castration-Resistant Prostate Cancer Growth through Degradation of Full-length and Splice Variant Androgen Receptors

    Directory of Open Access Journals (Sweden)

    Shinichi Yamashita

    2012-01-01

    Full Text Available Early studies suggested androgen receptor (AR splice variants might contribute to the progression of prostate cancer (PCa into castration resistance. However, the therapeutic strategy to target these AR splice variants still remains unresolved. Through tissue survey of tumors from the same patients before and after castration resistance, we found that the expression of AR3, a major AR splice variant that lacks the AR ligand-binding domain, was substantially increased after castration resistance development. The currently used antiandrogen, Casodex, showed little growth suppression in CWR22Rv1 cells. Importantly, we found that AR degradation enhancer ASC-J9 could degrade both full-length (fAR and AR3 in CWR22Rv1 cells as well as in C4-2 and C81 cells with addition of AR3. The consequences of such degradation of both fAR and AR3 might then result in the inhibition of AR transcriptional activity and cell growth in vitro. More importantly, suppression of AR3 specifically by short-hairpin AR3 or degradation of AR3 by ASC-J9 resulted in suppression of AR transcriptional activity and cell growth in CWR22Rv1-fARKD (fAR knockdown cells in which DHT failed to induce, suggesting the importance of targeting AR3. Finally, we demonstrated the in vivo therapeutic effects of ASC-J9 by showing the inhibition of PCa growth using the xenografted model of CWR22Rv1 cells orthotopically implanted into castrated nude mice with undetectable serum testosterone. These results suggested that targeting both fAR- and AR3-mediated PCa growth by ASC-J9 may represent the novel therapeutic approach to suppress castration-resistant PCa. Successful clinical trials targeting both fAR and AR3 may help us to battle castration-resistant PCa in the future.

  2. CX4945 suppresses the growth of castration-resistant prostate cancer cells by reducing AR-V7 expression.

    Science.gov (United States)

    Deng, Chuangzhong; Chen, Jieping; Guo, Shengjie; Wang, Yanjun; Zhou, Qianghua; Li, Zaishang; Yang, Xingping; Yu, Xingsu; Zhang, Zhenfeng; Zhou, Fangjian; Han, Hui; Yao, Kai

    2017-08-01

    The aberrant expression of casein kinase 2 (CK2) has been reported to be involved in the tumorigenesis and progression of prostate cancer. The inhibition of CK2 activity represses androgen-dependent prostate cancer cells by attenuating the androgen receptor (AR) signaling pathway. In this study, we examined the effect of CK2 inhibition in castration-resistant prostate cancer (CRPC) cells, in which AR variants (ARVs) play a predominant role. A newly synthetic CK2 selective inhibitor CX4945 was utilized to study the effect of CK2 inhibition in CRPC cells by CCK8 assay and colony formation assay. Protein and mRNA levels of full-length AR (AR-FL) and AR-V7 were determined by qPCR and western blot, respectively. The nuclear translocation of p50 and p65 was assessed to reflect the activity of the NF-κB pathway. CX4945 reduced the proliferation of CRPC cells in a dose-dependent and time-dependent manner. AR-V7 rather than AR-FL was downregulated by CX4945 in both the mRNA and protein level. Furthermore, CX4945 could restore the sensitivity of CRPC cells to bicalutamide. The analysis of possible mechanisms demonstrated that the inhibition of CK2 diminished the phosphorylation of p65 at ser529 and thus attenuated the activity of the NF-κB pathway. The inhibition of CK2 by CX4945 can repress the viability of CRPC cells and restore their sensitivity to anti-androgen therapy by suppressing AR-V7. This finding presents a potential option for the treatment of prostate cancer, especially CRPC.

  3. PSA time to nadir as a prognostic factor of first-line docetaxel treatment in castration-resistant prostate cancer: evidence from patients in Northwestern China.

    Science.gov (United States)

    Wu, Kai-Jie; Pei, Xin-Qi; Tian, Ge; Wu, Da-Peng; Fan, Jin-Hai; Jiang, Yu-Mei; He, Da-Lin

    2018-01-01

    Docetaxel-based chemotherapy remains the first-line treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) in China; however, the prognostic factors associated with effects in these patients are still controversial. In this study, we retrospectively reviewed the data from 71 eligible Chinese patients who received docetaxel chemotherapy from 2009 to 2016 in our hospital and experienced a reduction of prostate-specific antigen (PSA) level ≥50% during the treatment and investigated the potential role of time to nadir (TTN) of PSA. TTN was defined as the time from start of chemotherapy to the nadir of PSA level during the treatment. Multivariable Cox regression models and Kaplan-Meier analysis were used to predict overall survival (OS). In these patients, the median of TTN was 17 weeks. Patients with TTN ≥17 weeks had a longer response time to chemotherapy compared to TTN PSA progression in patients with TTN ≥17 weeks was 11.44 weeks compared to 5.63 weeks when TTN was PSA level at the diagnosis of cancer (HR: 4.337, 95% CI: 1.616-11.645, P = 0.004), duration of initial androgen deprivation therapy (HR: 2.982, 95% CI: 1.104-8.045, P = 0.031), neutrophil-to-lymphocyte ratio (HR: 3.963, 95% CI: 1.380-11.384, P = 0.011), and total PSA response (Class 1 [PSA remains an important prognostic marker in predicting therapeutic outcome in Chinese population who receive chemotherapy for mCRPC and have >50% PSA remission.

  4. Minnelide Inhibits Androgen Dependent, Castration Resistant Prostate Cancer Growth by Decreasing Expression of Androgen Receptor Full Length and Splice Variants.

    Science.gov (United States)

    Isharwal, Sumit; Modi, Shrey; Arora, Nivedita; Uhlrich, Charles; Giri, Bhuwan; Barlass, Usman; Soubra, Ayman; Chugh, Rohit; Dehm, Scott M; Dudeja, Vikas; Saluja, Ashok; Banerjee, Sulagna; Konety, Badrinath

    2017-05-01

    With almost 30,000 deaths per year, prostate cancer is the second-leading cause of cancer-related death in men. Androgen Deprivation Therapy (ADT) has been the corner stone of prostate cancer treatment for decades. However, despite an initial response of prostate cancer to ADT, this eventually fails and the tumors recur, resulting in Castration Resistant Prostate Cancer (CRPC). Triptolide, a diterpene triepoxide, has been tested for its anti-tumor properties in a number of cancers for over a decade. Owing to its poor solubility in aqueous medium, its clinical application had been limited. To circumvent this problem, we have synthesized a water-soluble pro-drug of triptolide, Minnelide, that is currently being evaluated in a Phase 1 clinical trial against gastrointestinal tumors. In the current study, we assessed the therapeutic potential of Minnelide and its active compound triptolide against androgen dependent prostate cancer both in vitro as well as in vivo. Cell viability was measured by a MTT based assay after treating prostate cancer cells with multiple doses of triptolide. Apoptotic cell death was measured using a caspase 3/7 activity. Androgen Receptor (AR) promoter-binding activity was evaluated by using luciferase reporter assay. For evaluating the effect in vivo, 22Rv1 cells were implanted subcutaneously in animals, following which, treatment was started with 0.21 mg/kg Minnelide. Our study showed that treatment with triptolide induced apoptotic cell death in CRPC cells. Triptolide treatment inhibited AR transcriptional activity and decreased the expression of AR and its splice variants both at the mRNA and the protein level. Our studies show that triptolide inhibits nuclear translocation of Sp1, resulting in its decreased transcriptional activity leading to downregulation of AR and its splice variants in prostate cancer cells. In vivo, Minnelide (0.21 mg/kg) regressed subcutaneous tumors derived from CRPC 22RV1 at our study endpoint. Our animal

  5. Shifting paradigms in the estimation of survival for castration-resistant prostate cancer: A tertiary academic center experience.

    Science.gov (United States)

    Afshar, Mehran; Evison, Felicity; James, Nicholas D; Patel, Prashant

    2015-08-01

    Castration-resistant prostate cancer (CRPC) has retained a guarded prognosis, with historical survival estimates of 18 to 24 months. However, the landscape of available therapy has changed, and the emphasis has altered from supportive to active treatment. Few large series from real-world populations exist in the contemporary era with fully mature survival data to confirm the indication based on clinical trials that patients with CRPC are surviving far longer than the historical estimates. We aim to review a large patient cohort with CRPC and provide mature survival data. Using the electronic histopathology database at Queen Elizabeth Hospital, Birmingham, UK, all prostate-specific antigentest results between April 2006 and September 2007 were extracted, and patients satisfying the American Society for Radiation Oncology (ASTRO) definition of hormone failure were identified. Electronic records were reviewed and variables were collected, including survival, treatment, biochemistry, histopathology, and demographics. Probability of survival, and of developing metastasis or CRPC, was determined using the Kaplan-Meier method. Patients were stratified into 3 groups, namely, D0--no metastasis at diagnosis but later appearance, D1--no metastasis at diagnosis or at last follow-up, and D2--metastasis at diagnosis. From 8,062 patient-prostate-specific antigen episodes, we identified 447 patients meeting the criteria. A notes review revealed 147 patients with CRPC. Median overall survival (OS) from diagnosis was 84.7 months (95% CI: 73-89), and 129 deaths had occurred (88%). Median OS from diagnosis for D0, D1, and D2 patients was 100.4, 180.1, and 58.9 months, respectively (Pdata benefit clinicians and patients in understanding prognosis and treatment choices. Importantly, our patients were diagnosed before the current wave of novel therapeutics for CRPC, so survival for men diagnosed today may be more than our findings. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Metastatic prostate cancer in transsexual diagnosed after three decades of estrogen therapy.

    Science.gov (United States)

    Turo, Rafal; Jallad, Samer; Prescott, Stephen; Cross, William Richard

    2013-01-01

    The incidence of prostate cancer in transsexual patients is very low with only few reported cases. Many years before presenting with prostate cancer, these patients receive hormone ablation as a part of their gender therapy. Their disease is already defined as castrate resistant, and the treatment and follow-up of such patients remains a challenge. We report a case of a male-to-female transgender woman who was diagnosed with metastatic prostate cancer, 31 years post-feminization.

  7. Metastatic prostate cancer in transsexual diagnosed after three decades of estrogen therapy

    OpenAIRE

    Turo, Rafal; Jallad, Samer; Prescott, Stephen; Cross, William Richard

    2013-01-01

    The incidence of prostate cancer in transsexual patients is very low with only few reported cases. Many years before presenting with prostate cancer, these patients receive hormone ablation as a part of their gender therapy. Their disease is already defined as castrate resistant, and the treatment and follow-up of such patients remains a challenge. We report a case of a male-to-female transgender woman who was diagnosed with metastatic prostate cancer, 31 years post-feminization.

  8. Automatic classification of EpCAM+, Cytokeratin+ objects versus survival in castration resistant prostate cancer

    NARCIS (Netherlands)

    Ligthart, Sjoerd T.; Coumans, Frank A.W.; Attard, Gert; de Bono, Johann S.; Terstappen, Leon W.M.M.

    2010-01-01

    Introduction: Circulating tumor cells (CTC) in patients with metastatic carcinomas are associated with poor survival and may guide therapy. CTC are morphologically heterogeneous and many research groups apply different morphological definitions. Manual assignment of CTC is therefore subjective. We

  9. Combination treatment with docetaxel and histone deacetylase inhibitors downregulates androgen receptor signaling in castration-resistant prostate cancer.

    Science.gov (United States)

    Park, Sang Eun; Kim, Ha-Gyeong; Kim, Dong Eun; Jung, Yoo Jung; Kim, Yunlim; Jeong, Seong-Yun; Choi, Eun Kyung; Hwang, Jung Jin; Kim, Choung-Soo

    2018-04-01

    Backgrounds Since most patients with castration-resistant prostate cancer (CRPC) develop resistance to its standard therapy docetaxel, many studies have attempted to identify novel combination treatment to meet the large clinical unmet need. In this study, we examined whether histone deacetylase inhibitors (HDACIs) enhanced the effect of docetaxel on AR signaling in CRPC cells harboring AR and its splice variants. Methods HDACIs (vorinostat and CG200745) were tested for their ability to enhance the effects of docetaxel on cell viability and inhibition of AR signaling in CRPC 22Rv1 and VCaP cells by using CellTiter-Glo™ Luminescent cell viability assay, synergy index analysis and Western blotting. The nuclear localization of AR was examined via immunocytochemical staining in 22Rv1 cells and primary tumor cells from a patient with CRPC. Results Combination treatment with HDACIs (vorinostat or CG200745) and docetaxel synergistically inhibited the growth of 22Rv1 and VCaP cells. Consistently, the combination treatment decreased the levels of full-length AR (AR-FL), AR splice variants (AR-Vs), prostate-specific antigen (PSA), and anti-apoptotic Bcl-2 proteins more efficiently compared with docetaxel or vorinostat alone. Moreover, the combination treatment accelerated the acetylation and bundling of tubulin, which significantly inhibited the nuclear accumulation of AR in 22Rv1 cells. The cytoplasmic colocalization of AR-FL and AR-V7 with microtubule bundles increased after combination treatment in primary tumor cells from a patient with CRPC. Conclusions The results suggested that docetaxel, in combination with HDACIs, suppressed the expression and nuclear translocation of AR-FL and AR-Vs and showed synergistic anti-proliferative effect in CRPC cells. This combination therapy may be useful for the treatment of patients with CRPC.

  10. Comparative efficacy, tolerability, and survival outcomes of various radiopharmaceuticals in castration-resistant prostate cancer with bone metastasis: a meta-analysis of randomized controlled trials

    Directory of Open Access Journals (Sweden)

    Tunio M

    2015-09-01

    Full Text Available Mutahir Tunio,1 Mushabbab Al Asiri,1 Abdulrehman Al Hadab,1 Yasser Bayoumi2 1Radiation Oncology, Comprehensive Cancer Center, King Fahad Medical City, Riyadh, Saudi Arabia; 2Radiation Oncology, National Cancer Institute, Cairo University, Cairo, Egypt Background: A meta-analysis was conducted to assess the impact of radiopharmaceuticals (RPs in castration-resistant prostate cancer (CRPC on pain control, symptomatic skeletal events (SSEs, toxicity profile, quality of life (QoL, and overall survival (OS.Materials and methods: The PubMed/MEDLINE, CANCERLIT, EMBASE, Cochrane Library database, and other search engines were searched to identify randomized controlled trials (RCTs comparing RPs with control (placebo or radiation therapy in metastatic CRPC. Data were extracted and assessed for the risk of bias (Cochrane’s risk of bias tool. Pooled data were expressed as odds ratio (OR, with 95% confidence intervals (CIs; Mantel–Haenszel fixed-effects model.Results: Eight RCTs with a total patient population of 1,877 patients were identified. The use of RP was associated with significant reduction in pain intensity and SSE (OR: 0.63, 95% CI: 0.51–0.78, I2=27%, P<0.0001, improved QoL (OR: 0.71, 95% CI: 0.55–0.91, I2=65%, three trials, 1,178 patients, P=0.006, and a minimal improved OS (OR: 0.84, 95% CI: 0.64–1.04, I2=47%, seven trials, 1,845 patients, P=0.11. A subgroup analysis suggested an improved OS with radium-223 (OR: 0.68, 95% CI: 0.51–0.90, one trial, 921 patients and strontium-89 (OR: 0.21, 95% CI: 0.05–0.91, one trial, 49 patients. Strontium-89 (five trials was associated with increased rates of grade 3 and 4 thrombocytopenia (OR: 4.26, 95% CI: 2.22–8.18, P=0.01, leucopenia (OR: 7.98, 95% CI: 1.82–34.95, P=0.02, pain flare (OR: 6.82, 95% CI: 3.42–13.55, P=0.04, and emesis (OR: 3.61, 95% CI: 1.76–7.40, P=0.02.Conclusion: The use of RPs was associated with significant reduction in SSEs and improved QoL, while the radium-223

  11. New therapies for relapsed castration-resistant prostate cancer based on peptide analogs of hypothalamic hormones

    Directory of Open Access Journals (Sweden)

    Andrew V Schally

    2015-01-01

    Full Text Available It is a pleasure to contribute our presentation at the International Prostate Forum of the Annual Meeting of the American Urological Association (AUA to this special issue of the Asian Journal of Andrology.

  12. {sup 177}Lu-PSMA-617 radioligand therapy and outcome in patients with metastasized castration-resistant prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Braeuer, Axel; Grubert, Lena Sophie; Roll, Wolfgang; Schaefers, Michael; Rahbar, Kambiz [University Hospital Muenster, Department of Nuclear Medicine, Muenster (Germany); Schrader, Andres Jan; Boegemann, Martin [University Hospital Muenster, Department of Urology, Muenster (Germany)

    2017-09-15

    Radioligand therapies targeting prostate-specific membrane antigen (PSMA) have been established for the treatment of metastasized castration-resistant prostate cancer (mCRPC) in the last decade and show promising response rates and a favourable toxicity profile. The aim of this study was to evaluate the overall survival (OS) and to identify parameters predicting outcome in mCRPC patients treated with {sup 177}Lu-PSMA-617. Between December 2014 and January 2017, 59 consecutive patients (median age 72 years); interquartile range, (IQR, 66-76 years) with mCRPC, who had been treated with at least one next-generation antihormonal drug as well as chemotherapy, were included in this study. Biochemical response was evaluated using Prostate Cancer Working Group 3 (PCWG3) criteria. Survival was evaluated using Kaplan-Meier estimates and Cox regression proportional hazards model. Toxicity was assessed using Common Toxicity Criteria for Adverse Events (CTCAE). The study was approved by the local ethics committee. The 59 patients were treated with a total of 159 cycles (median 3 cycles, range 1-7) of {sup 177}Lu-PSMA-617 (median dose 6.11 GBq, IQR 5.9-6.3 GBq). The median follow-up was 24 weeks (IQR 15-36 weeks). Follow-up data for at least 12 weeks (PCWG3) were available in 76% (45) of the patients. For outcome results data from all patients treated with at least one cycle were analysed. A decline in prostate-specific antigen (PSA) of ≥50% occurred in 53%, and a decline in PSA of any amount in 91% of patients. The estimated median OS was 32 weeks. An initial alkaline phosphatase (ALP) level <220 U/L and a PSA decline after the first cycle were associated with a longer OS (56 vs. 28 weeks, p < 0.01, and 56 vs. 29 weeks, p = 0.04, respectively). The median estimated PSA progression-free survival (PPFS) was 18 weeks. Only ALP level <220 U/L was significantly associated with a longer PPFS (41 vs. 18 weeks, p < 0.01). A PSA decline after the first cycle of {sup 177}Lu-PSMA-617

  13. Phosphoproteomic Assessment of Therapeutic Kinases for Personalized Therapy in Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2016-10-01

    including bladder cancer and squamous cell carcinoma (22–24). Constitutive activation of the Notch receptors through gene rearrangements or mutations leads to...Babic I, Wei X, Huang J, Witte ON (2011) Invasive prostate carcinoma driven by c-Src and androgen receptor synergy. Cancer Res 71(3):862–872. 20. Dai B...prostate cancer cells. Cancer Res 70(13):5587–5596. 21. Guo Z, et al. (2006) Regulation of androgen receptor activity by tyrosine phosphor- ylation. Cancer

  14. Free Testosterone During Androgen Deprivation Therapy Predicts Castration-Resistant Progression Better Than Total Testosterone.

    Science.gov (United States)

    Regis, Lucas; Planas, Jacques; Carles, Joan; Maldonado, Xavier; Comas, Inma; Ferrer, Roser; Morote, Juan

    2017-01-01

    The optimal degree of testosterone suppression in patients with prostate cancer undergoing androgen deprivation therapy remains in question. Furthermore, serum free testosterone, which is the active form of testosterone, seems to correlate with intraprostatic testosterone. Here we compared free and total serum testosterone as predictors of survival free of castration resistance. Total testosterone (chemiluminescent assay, lower sensitivity 10 ng/dl) and free testosterone (analogue-ligand radioimmunoassay, lower sensitivity 0.05 pg/ml) were determined at 6 months of LHRH agonist treatment in a prospective cohort of 126 patients with prostate cancer. During a mean follow-up of 67 months (9-120), 75 (59.5%) events of castration-resistant progression were identified. Multivariate analysis and survival analysis according to total testosterone cutoffs of 50, 32, and 20 ng/dl, and free testosterone cutoffs of 1.7, 1.1, and 0.7 pg/ml were performed. Metastatic spread was the most powerful predictor of castration resistance, HR: 2.09 (95%CI: 1.18-3.72), P = 0.012. Gleason score, baseline PSA and PSA at 6 months were also independents predictors, but not free and total testosterone. Stratified analysis was conducted on the basis of the status of metastatic diseases and free testosterone was found to be an independent predictor of survival free of castration resistance in the subgroup of patients without metastasis, HR: 2.12 (95%CI: 1.16-3.85), P = 0.014. The lowest threshold of free testosterone which showed significant differences was 1.7 pg/ml, P = 0.003. Free testosterone at 6 months of LHRH agonist treatment seems to be a better surrogate than total testosterone to predict castration resistance in no metastatic prostate cancer patients. Prostate 77:114-120, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  15. Developing Novel Therapeutics Targeting Undifferentiated and Castration-Resistant Prostate Cancer Stem Cells

    Science.gov (United States)

    2016-10-01

    2009;106:268-73. 41. Carver BS, Chapinski C, Wongvipat J, Hieronymus H, Chen Y, Chandarlapaty S, Arora VK, Le C, Koutcher J, Scher H, Scardino PT... Rosen N, Sawyers CL. Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN- deficient prostate cancer. Cancer Cell. 2011;19

  16. Prognostic factors and risk stratification in patients with castration-resistant prostate cancer receiving docetaxel-based chemotherapy.

    Science.gov (United States)

    Yamashita, Shimpei; Kohjimoto, Yasuo; Iguchi, Takashi; Koike, Hiroyuki; Kusumoto, Hiroki; Iba, Akinori; Kikkawa, Kazuro; Kodama, Yoshiki; Matsumura, Nagahide; Hara, Isao

    2016-03-22

    While novel drugs have been developed, docetaxel remains one of the standard initial systemic therapies for castration-resistant prostate cancer (CRPC) patients. Despite the excellent anti-tumor effect of docetaxel, its severe adverse effects sometimes distress patients. Therefore, it would be very helpful to predict the efficacy of docetaxel before treatment. The aims of this study were to evaluate the potential value of patient characteristics in predicting overall survival (OS) and to develop a risk classification for CRPC patients treated with docetaxel-based chemotherapy. This study included 79 patients with CRPC treated with docetaxel. The variables, including patient characteristics at diagnosis and at the start of chemotherapy, were retrospectively collected. Prognostic factors predicting OS were analyzed using the Cox proportional hazard model. Risk stratification for overall survival was determined based on the results of multivariate analysis. PSA response ≥50 % was observed in 55 (69.6 %) of all patients, and the median OS was 22.5 months. The multivariate analysis showed that age, serum PSA level at the start of chemotherapy, and Hb were independent prognostic factors for OS. In addition, ECOG performance status (PS) and the CRP-to-albumin ratio were not significant but were considered possible predictors for OS. Risk stratification according to the number of these risk factors could effectively stratify CRPC patients treated with docetaxel in terms of OS. Age, serum PSA level at the start of chemotherapy, and Hb were identified as independent prognostic factors of OS. ECOG PS and the CRP-to-albumin ratio were not significant, but were considered possible predictors for OS in Japanese CRPC patients treated with docetaxel. Risk stratification based on these factors could be helpful for estimating overall survival.

  17. Epithelial Plasticity in Castration-Resistant Prostate Cancer: Biology of the Lethal Phenotype

    Science.gov (United States)

    2014-07-01

    34·- ... _ ···-·--.. ~ .... _.... ..... , - .... -.==-:; ...... 0(1"𔃻""!:* Figure 6. Analysis of the genomic locus of MYCN ( chromosome 2) by arrayCGH in...uncoupled from mutations and chromosomal anomalies. This metastatic dis- semination leads to pathological fractures, anemia, bone mar- row failure...emergence of active bone lesions over time in the same regions, indicating persistent viable tumor despite the disappearance on scans. We hypothesize

  18. Early Prediction of Therapy Response to Abiraterone Acetate Using PSA Subforms in Patients with Castration Resistant Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Katrin Schlack

    2016-09-01

    Full Text Available The purpose of this study was to evaluate the prognostic ability of early changes of total prostate specific antigen (tPSA, free PSA (fPSA, [−2]proPSA and the Prostate Health Index (PHI following initiation of Abiraterone-therapy in men with castration resistant prostate cancer (mCRPC. In 25 patients, PSA-subforms were analyzed before and at 8–12 weeks under therapy as prognosticators of progression-free-survival (PFS and overall survival (OS. Comparing patients with a PFS < vs. ≥12 months by using Mann–Whitney–Wilcoxon Tests, the relative-median-change of tPSA (−0.1% vs. −86.8%; p = 0.02, fPSA (12.1% vs. −55.3%; p = 0.03 and [−2]proPSA (8.1% vs. −59.3%; p = 0.05 differed significantly. For men with ≤ vs. >15 months of OS there was a non-significant trend for a difference in the relative-median-change of fPSA (17.0% vs. −46.3%; p = 0.06. In Kaplan–Meier analyses, declining fPSA and [−2]proPSA were associated with a longer median PFS (13 months, 95% confidence interval (CI: 9.6–16.4 vs. 10 months, 95% CI: 3.5–16.5; p = 0.11, respectively. Correspondingly, decreasing fPSA and [−2]proPSA values indicated an OS of 32 months (95% CI: not reached (NR compared to 21 months in men with rising values (95% CI: 7.7–34.3; p = 0.14, respectively. We concluded that the addition of fPSA- and [−2]proPSA-changes to tPSA-information might be further studied as potential markers of early Abiraterone response in mCRPC patients.

  19. Understanding and Targeting Tumor Microenvironment in Prostate Cancer to Inhibit Tumor Progression and Castration Resistance

    Science.gov (United States)

    2016-10-01

    cancer-secreted chemokine to attract Cxcr2-expressing MDSCs and, correspondingly, pharmacological inhibition of Cxcr2 impeded tumor progression...impact of pharmacological inhibition of Cxcl5 and Cxcr2 on MDSCs using the transwell migration assay 26 . First, anti-Cxcl5 neutralizing antibody...and MRI . (B) Generation of the CPPSML chimera model. (C) Fluorescence microscopy and H&E image of snap frozen prostate tumor from chimera showing that

  20. Androgen receptor (AR) degradation enhancer ASC-J9® in an FDA-approved formulated solution suppresses castration resistant prostate cancer cell growth.

    Science.gov (United States)

    Cheng, Max A; Chou, Fu-Ju; Wang, Keliang; Yang, Rachel; Ding, Jie; Zhang, Qiaoxia; Li, Gonghui; Yeh, Shuyuan; Xu, Defeng; Chang, Chawnshang

    2018-03-28

    ASC-J9 ® is a recently-developed androgen receptor (AR)-degradation enhancer that effectively suppresses castration resistant prostate cancer (PCa) cell proliferation and invasion. The optimal half maximum inhibitory concentrations (IC 50 ) of ASC-J9 ® at various PCa cell confluences (20%, 50%, and 100%) were assessed via both short-term MTT growth assays and long-term clonogenic proliferation assays. Our results indicate that the IC 50 values for ASC-J9 ® increased with increasing cell confluency. The IC 50 values were significantly decreased in PCa AR-positive cells compared to PCa AR-negative cells or in normal prostate cells. This suggests that ASC-J9 ® may function mainly via targeting the AR-positive PCa cells with limited unwanted side-effects to suppress the surrounding normal prostate cells. Mechanism dissection indicated that ASC-J9 ® might function via altering the apoptosis signals to suppress the PCa AR-negative PC-3 cells. Preclinical studies using multiple in vitro PCa cell lines and an in vivo mouse model with xenografted castration-resistant PCa CWR22Rv1 cells demonstrated that ASC-J9 ® has similar AR degradation effects when dissolved in FDA-approved solvents, including DMSO, PEG-400:Tween-80 (95:5), DMA:Labrasol:Tween-80 (10:45:45), and DMA:Labrasol:Tween-20 (10:45:45). Together, results from preclinical studies suggest a potential new therapy with AR-degradation enhancer ASC-J9 ® may potentially be ready to be used in human clinical trials in order to better suppress PCa at later castration resistant stages. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. The predictive value of ERG protein expression for development of castration-resistant prostate cancer in hormone-naïve advanced prostate cancer treated with primary androgen deprivation therapy

    DEFF Research Database (Denmark)

    Berg, Kasper Drimer; Røder, Martin A; Thomsen, Frederik B

    2015-01-01

    BACKGROUND: Biomarkers predicting response to primary androgen deprivation therapy (ADT) and risk of castration-resistant prostate cancer (CRPC) is lacking. We aimed to analyse the predictive value of ERG expression for development of CRPC. METHODS: In total, 194 patients with advanced and....../or metastatic prostate cancer (PCa) treated with first-line castration-based ADT were included. ERG protein expression was analysed in diagnostic specimens using immunohistochemistry (anti-ERG, EPR3864). Time to CRPC was compared between ERG subgroups using multiple cause-specific Cox regression stratified......-negative group, respectively. Compared to a model omitting ERG-status, the ERG-stratified model showed comparable AUC values 1 year (77.6% vs. 78.0%, P = 0.82), 2 years (71.7% vs. 71.8%, P = 0.85), 5 years (68.5% vs. 69.9%, P = 0.32), and 8 years (67.9% vs. 71.4%, P = 0.21) from ADT initiation. No differences...

  2. Using a Novel Transgenic Mouse Model to Study c-Myc Oncogenic Pathway in Castration Resistance and Chemoresistance of Prostate Cancer

    Science.gov (United States)

    2017-12-01

    AWARD NUMBER: W81XWH-13-1-0162 TITLE: Using a Novel Transgenic Mouse Model to Study c -Myc Oncogenic Pathway in Castration Resistance and...DATES COVERED 15Sept2013 - 14Sept2017 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Using a Novel Transgenic Mouse Model to Study c -Myc Oncogenic...ABSTRACT We previously made a PB-Cre4/Ai-Myc model for Cre-induced and androgen-independent expression of c -Myc and Luc2 in prostate. This is designed

  3. Alpha Particle Therapy in Metastatic Prostate Cancer

    International Nuclear Information System (INIS)

    O’Sullivan, Joe

    2013-01-01

    Metastatic castrate resistant prostate cancer (CRPC) is a leading cause of cancer mortality among men in western countries. Although nearly 85% of patients present with localised disease, up to 40% will eventually develop metastatic disease during the course of illness. Of men dying from prostate cancer, more than 90% have bone metastases many with no other significant metastatic sites. Symptoms related to bone metastases and skeletal related events (SREs) account for the major cause of morbidity in these patients. Bone-seeking radionuclides have been used in the treatment of prostate cancer bone metastases for many years. The first bone seeking radionuclide drug approved by the FDA was Strontium-89. Other agents have also been used including Samarium-153 EDTMP, Rhenium-186 (-188)-HEDP. These radionuclides are all emit shortrange therapeutic beta radiation with bone marrow as the dose limiting toxicity. There is strong clinical trial evidence of benefit for these radionuclides in reducing pain in advanced prostate cancer; however, none of the drugs has been shown to improve survival, albeit none of the clinical trials were powered to detect differences in survival

  4. A low carbohydrate, high protein diet suppresses intratumoral androgen synthesis and slows castration-resistant prostate tumor growth in mice.

    Science.gov (United States)

    Fokidis, H Bobby; Yieng Chin, Mei; Ho, Victor W; Adomat, Hans H; Soma, Kiran K; Fazli, Ladan; Nip, Ka Mun; Cox, Michael; Krystal, Gerald; Zoubeidi, Amina; Tomlinson Guns, Emma S

    2015-06-01

    Dietary factors continue to preside as dominant influences in prostate cancer prevalence and progression-free survival following primary treatment. We investigated the influence of a low carbohydrate diet, compared to a typical Western diet, on prostate cancer (PCa) tumor growth in vivo. LNCaP xenograft tumor growth was studied in both intact and castrated mice, representing a more advanced castration resistant PCa (CRPC). No differences in LNCaP tumor progression (total tumor volume) with diet was observed for intact mice (P = 0.471) however, castrated mice on the Low Carb diet saw a statistically significant reduction in tumor growth rate compared with Western diet fed mice (P = 0.017). No correlation with serum PSA was observed. Steroid profiles, alongside serum cholesterol and cholesteryl ester levels, were significantly altered by both diet and castration. Specifically, DHT concentration with the Low Carb diet was 58% that of the CRPC-bearing mice on the Western diet. Enzymes in the steroidogenesis pathway were directly impacted and tumors isolated from intact mice on the Low Carb diet had higher AKR1C3 protein levels and lower HSD17B2 protein levels than intact mice on the Western diet (ARK1C3: P = 0.074; HSD17B2: P = 0.091, with α = 0.1). In contrast, CRPC tumors from mice on Low Carb diets had higher concentrations of both HSD17B2 (P = 0.016) and SRD5A1 (P = 0.058 with α = 0.1) enzymes. There was no correlation between tumor growth in castrated mice for Low Carb diet versus Western diet and (a) serum insulin (b) GH serum levels (c) insulin receptor (IR) or (d) IGF-1R in tumor tissue. Intact mice fed Western diet had higher serum insulin which was associated with significantly higher blood glucose and tumor tissue IR. We conclude that both diet and castration have a significant impact on the endocrinology of mice bearing LNCaP xenograft tumors. The observed effects of diet on cholesterol and steroid regulation impact tumor tissue DHT specifically and are

  5. Disease Progression/Clinical Outcome Model for Castration-Resistant Prostate Cancer in Patients Treated with Eribulin

    NARCIS (Netherlands)

    Van Hasselt, J. G C; Gupta, A.; Hussein, Z.; Beijnen, J. H.; Schellens, J. H M; Huitema, A. D R

    2015-01-01

    Frameworks that associate cancer dynamic disease progression models with parametric survival models for clinical outcome have recently been proposed to support decision making in early clinical development. Here we developed such a disease progression clinical outcome model for castration-resistant

  6. AR-V7 in circulating tumor cells cluster as a predictive biomarker of abiraterone acetate and enzalutamide treatment in castration-resistant prostate cancer patients.

    Science.gov (United States)

    Okegawa, Takatsugu; Ninomiya, Naoki; Masuda, Kazuki; Nakamura, Yu; Tambo, Mitsuhiro; Nutahara, Kikuo

    2018-06-01

    We examined whether androgen receptor splice variant 7 (AR-V7) in circulating tumor cell(CTC)clusters can be used to predict survival in patients with bone metastatic castration resistant-prostate cancer (mCRPC) treated with abiraterone or enzalutamide. We retrospectively enrolled 98 patients with CRPC on abiraterone or enzalutamide, and investigated the prognostic value of CTC cluster detection (+ v -) and AR-V7 detection (+ v -) using a CTC cluster detection - based AR-V7 mRNA assay. We examined ≤50% prostate-specific antigen (PSA) responses, PSA progression-free survival (PSA-PFS), clinical and radiological progression-free survival (radiologic PSF), and overall survival (OS). We then assessed whether AR-V7 expression in CTC clusters identified after On-chip multi-imaging flow cytometry was related to disease progression and survival after first-line systemic therapy. All abiraterone-treated or enzalutamide-treated patients received prior docetaxel. The median follow-up was 20.7 (range: 3.0-37.0) months in the abiraterone and enzalutamide cohorts, respectively. Forty-nine of the 98 men (50.0%) were CTC cluster (-), 23 of the 98 men (23.5%) were CTC cluster(+)/AR-V7(-), and 26 of the 98 men (26.5%) were CTC cluster(+)/AR-V7(+). CTC cluster(+)/AR-V7(+) patients were more likely to have EOD ≥3 at diagnosis (P = 0.003), pain (P = 0.023), higher alkaline phosphatase levels (P cluster(+), CTC cluster(+)/AR-V7(-), and ALP >UNL were independently associated with a poor PSA-PFS, radiographic PFS, and OS in abiraterone-treated patients and enzalutamide-treated patients. The CTC clusters and AR-V7-positive CTC clusters detected were important for assessing the response to abiraterone or enzalutamide therapy and for predicting disease outcome. © 2018 Wiley Periodicals, Inc.

  7. Improvement of a predictive model of castration-resistant prostate cancer: functional genetic variants in TGFβ1 signaling pathway modulation.

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    Ana L Teixeira

    Full Text Available Prostate cancer (PC is the most frequently diagnosed cancer in men. The acquisition of castration-resistant (CR phenotype is associated with the activation of signaling pathways mediated by growth factors. The TGFβ1 and its receptors have an important role in tumor progression, being the pro-apoptotic function modulated by the expression of TGFBR2. A single nucleotide polymorphism -875 G > A in TGFBR2 gene has been described, which may influence the expression levels of the receptor. Our purpose was to investigate the potential role of TGFBR2-875G>A in PC risk and in the response to androgen deprivation therapy (ADT. TGFBR2-875G>A polymorphism was studied by allelic discrimination using real-time polymerase chain reaction (PCR in 891 patients with PC and 874 controls. A follow-up study was undertaken to evaluate response to ADT. The TGFBR2 and SMAD7 mRNA expression were analyzed by a quantitative real-time PCR. We found that TGFBR2-875GG homozygous patients present lower expression levels of TGFBR2 mRNA (AA/AG: 2(-ΔΔCT =1.5, P=0.016. GG genotype was also associated with higher Gleason grade (OR=1.51, P=0.019 and increased risk of an early relapse after ADT (HR=1.47, P=0.024. The concordance (c index analysis showed that the definition of profiles that contains information regarding tumor characteristics associated with genetic information present an increased capacity to predict the risk for CR development (c-index model 1: 0.683 vs model 2: 0.736 vs model 3: 0.746 vs model 4: 0.759. The TGFBR2-875G>A contribution to an early relapse in ADT patients, due to changes in mRNA expression, supports the involvement of TGFβ1 pathway in CRPC. Furthermore, according to our results, we hypothesize the potential benefits of the association of genetic information in predictive models of CR development.

  8. The AhR Ligand, TCDD, Regulates Androgen Receptor Activity Differently in Androgen-Sensitive versus Castration-Resistant Human Prostate Cancer Cells

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    Maryam Ghotbaddini

    2015-07-01

    Full Text Available The reported biological effects of TCDD include induction of drug metabolizing enzymes, wasting syndrome and tumor promotion. TCDD elicits most of its effects through binding the aryl hydrocarbon receptor (AhR. TCDD induced degradation of AhR has been widely reported and requires ubiquitination of the protein. The rapid depletion of AhR following TCDD activation serves as a mechanism to modulate AhR mediated gene induction. In addition to inducing AhR degradation, TCDD has been reported to induce degradation of hormone receptors. The studies reported here, evaluate the effect of TCDD exposure on androgen receptor (AR expression and activity in androgen-sensitive LNCaP and castration-resistant C4-2 prostate cancer cells. Our results show that TCDD exposure does not induce AhR or AR degradation in C4-2 cells. However, both AhR and AR are degraded in LNCaP cells following TCDD exposure. In addition, TCDD enhances AR phosphorylation and induces expression of AR responsive genes in LNCaP cells. Our data reveals that TCDD effect on AR expression and activity differs in androgen-sensitive and castration-resistant prostate cancer cell models.

  9. Metalloproteinase 11, potential marker and molecular target in advanced and castration-resistant prostate cancer. Culture study of peritumoral fibroblasts.

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    Fernandez-Gomez, J M; Eiro, N; García-Rodríguez, J J; Quintás-Blanco, A; Gonzalez-Ruiz de León, C; Perez de Haro, M L; Vizoso-Piñero, F

    To analyze the expression of metalloprotein 11 (MMP11) in cultured fibroblasts obtained from human prostate tumors with different clinical and pathological characteristics. For this study we analyzed samples of transrectal prostate biopsies from tumors with different characteristics, treated with or whithout androgen deprivation (AD). After optimization of the culture method, fibroblasts were isolated and cultured to perform the study (PCR) of MMP11 mRNA. Finally, 37 cases were studied: 5 samples of benign prostatic hyperplasia, 14 cases with localized neoplasms (7 high-risk according to the D'Amico classification), 5 with metastasic tumors (bone metastases), and 13 treated with AD therapy, of which 6 fulfilled the requirements to be defined as resistant to castration. In tumors without AD therapy, MMP11 expression was significantly higher (P=.001) in fibroblasts of higher grade tumors. A significant (P=.001) correlation was found between PSA and expression of MMP11 in fibroblast s and a significant increase of MMP11 expression in metastatic tumors. In tumors with AD therapy, a significantly greater expression of MMP11 was observed in resistant to castration patients than in those sensitive to castration (P=.003). In advanced prostate tumors or in stages of increased tumor aggressiveness, the production of MMP11 by fibroblasts is significantly greater than in non-metastatic tumors or in AD sensitive tumors. Copyright © 2016 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.

  10. The Stromal Contribution to the Development of Resistance to New-Generation Drugs by Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2015-10-01

    abiraterone treatment by further increasing their expressions of steroidogenic genes and by further increasing their outputs of T and DHT . Finally, we...support (stromal) cells within a bone metastasis have a supportive role in the development of CRPC through their ability to synthesize T and DHT upon Hh...dihydrotestosterone ( DHT ) (3, 9-11). 4 After ADT, recurrence as castration-resistant disease is common (8). For PCa, the most common site for metastasis is bone

  11. Baseline prostate-specific antigen levels following treatment with abiraterone acetate as a prognostic factor in castration-resistant prostate cancer.

    Science.gov (United States)

    Hiroshige, Tasuku; Eguchi, Yoshiro; Yoshizumi, Osamu; Chikui, Katsuaki; Kumagai, Hisaji; Kawaguchi, Yoshihiro; Onishi, Rei; Hayashi, Tokumasa; Watanabe, Kouta; Mitani, Tomotaro; Saito, Koujiro; Igawa, Tsukasa

    2018-05-01

    The aim of the present study was to investigate the prognostic factors associated with progression-free survival (PFS) and overall survival (OS) times in patients with castration-resistant prostate cancer (CRPC) who received treatment with abiraterone acetate (AA) in routine clinical settings. A total of 93 patients treated with AA between September 2014 and February 2017 were selected and their medical records were analyzed retrospectively. The median PFS time of docetaxel (DTX)-naïve patients was 171 days, and that of post-DTX patients was 56 days. The OS time of DTX-naïve patients did not reach the median. The median OS time of post-DTX patients was 761 days. Multivariate analyses identified baseline prostate-specific antigen (PSA) level prior to treatment with AA and the PSA response rate as independent prognostic factors for PFS time, and baseline PSA prior to treatment with AA as the only independent prognostic factor for OS time. The results of the present study indicate that the baseline PSA level prior to treatment with AA is a notable prognostic factor in patients with CRPC.

  12. The Role of PCA 3 as a Prognostic Factor in Patients with Castration-resistant Prostate Cancer (CRPC) Treated with Docetaxel.

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    Bourdoumis, Andreas; Chrisofos, Michael; Stasinou, Theodora; Christopoulos, Panagiotis; Mourmouris, Panagiotis; Kostakopoulos, Athanasios; Deliveliotis, Charalambos

    2015-05-01

    To investigate potential fluctuations in prostate cancer antigen 3 (PCA 3) scores in castration-resistant prostate cancer (CRPC) patients treated with docetaxel and investigate the assay as a potential prognostic factor. This was a prospective observational cohort study. Inclusion criteria included patients on hormonal treatment who were recently diagnosed with CRPC. Exclusion criteria included patients previously having radical treatment (surgery or radiotherapy) and patients who have completed the first cycle of chemotherapy. All urine samples were collected and analyzed using the Progensa® assay. Samples were collected before starting chemotherapy and at 12 months. A prospective database was created including routine blood tests, prostate staging and prostate-specific antigen (PSA) levels throughout the study period. The effects of chemotherapy were also recorded. Between January 2010 and February 2013, 12 patients were included in the study out of an initial cohort of 23 patients with CRPC. Mean follow-up was 14.8 months. Mean age at CRPC diagnosis was 73.8 years (±3.6 SD). Mean Gleason score was 8, with PSA 84.23 ng/ml (±158 SD). Mean duration of androgen deprivation treatment (ADT) was 45.16 months (±34.9 SD). Mean time to castrate-resistant state was 46.58 months (±35.3 SD). All twelve (n=12, 100%) patients had non-assessable PCA 3 scores at baseline and at 12 months follow-up. As a direct consequence, statistical analysis was not performed as the anticipated change in PCA 3 scores was not identified and correlation between measurable differences was not possible. All patients tolerated chemotherapy and completed the scheduled cycles with no serious adverse effects. To our knowledge, this is the first prospective study to demonstrate lack of expression of PCA3 in CRPC, with the result apparently not influenced by chemotherapy. There appears to be a strong association between hormonal treatment and lack of PCA 3 expression. It is still unknown whether

  13. Targeting Hsp27/eIF4E interaction with phenazine compound: a promising alternative for castration-resistant prostate cancer treatment.

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    Hajer, Ziouziou; Claudia, Andrieu; Erik, Laurini; Sara, Karaki; Maurizio, Fermeglia; Ridha, Oueslati; David, Taieb; Michel, Camplo; Olivier, Siri; Sabrina, Pricl; Maria, Katsogiannou; Palma, Rocchi

    2017-09-29

    The actual strategy to improve current therapies in advanced prostate cancer involves targeting genes activated by androgen withdrawal, either to delay or prevent the emergence of the castration-refractory phenotype. However, these genes are often implicated in several physiological processes, and long-term inhibition of survival proteins might be accompanied with cytotoxic effects. To avoid this problem, an alternative therapeutic strategy relies on the identification and use of compounds that disrupt specific protein-protein interactions involved in androgen withdrawal. Specifically, the interaction of the chaperone protein Hsp27 with the initiation factor eIF4E leads to the protection of protein synthesis initiation process and enhances cell survival during cell stress induced by castration or chemotherapy. Thus, in this work we aimed at i) identifying the interaction site of the Hsp27/eIF4E complex and ii) interfere with the relevant protein/protein association mechanism involved in castration-resistant progression of prostate cancer. By a combination of experimental and modeling techniques, we proved that eIF4E interacts with the C-terminal part of Hsp27, preferentially when Hsp27 is phosphorylated. We also observed that the loss of this interaction increased cell chemo-and hormone-sensitivity. In order to find a potential inhibitor of Hsp27/eIF4E interaction, BRET assays in combination with molecular simulations identified the phenazine derivative 14 as the compound able to efficiently interfere with this protein/protein interaction, thereby inhibiting cell viability and increasing cell death in chemo- and castration-resistant prostate cancer models in vitro and in vivo .

  14. Prostate-specific antigen kinetics and outcomes in patients with bone metastases from castration-resistant prostate cancer treated with or without zoledronic acid.

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    Saad, Fred; Segal, Scott; Eastham, James

    2014-01-01

    Zoledronic acid (ZOL) is a standard therapy for the prevention of skeletal-related events (SREs) in patients with castration-resistant prostate cancer (CRPC). Although prostate-specific antigen (PSA) is an established marker for monitoring prostate cancer patients, correlations between PSA and disease outcomes during ZOL therapy are unclear. To evaluate the relationships among PSA kinetics, bone-directed therapy with ZOL, and clinical outcomes in men with bone metastases from CRPC using a ZOL phase 3 trial database. Exploratory analyses from a phase 3 trial in men with bone metastases from CRPC (n=643) randomized to ZOL or placebo every 3 wk. PSA levels during the first 3 mo of the study were evaluated in linear and logarithmic (log) models stratified using prognostic factors established in a ZOL phase 3 trial and a CRPC nomogram. Relative risks of SREs, bone disease progression (BDP), and death were calculated per 1 log (nanograms per milliliter) PSA increase. Baseline PSA models used the study median (PSA: 77.3 ng/ml) as the high/low cut-off point. A total of 202 placebo- and 434 ZOL-treated patients were assessable. In both groups, PSA increases correlated with significantly increased risks of death, BDP, and first SRE. In the placebo and ZOL groups, associated increases in risk per 1 log (nanograms per milliliter) PSA increase were 29% (p<0.0001) and 10% (p<0.0074), respectively, for BDP, and 24% (p=0.0010) and 13% (p=0.0079), respectively, for first SRE. Limitations include the retrospective nature of these analyses and the potential confounding effects of concurrent antineoplastic therapies. PSA is an important prognostic tool for survival in patients with bone metastases from CRPC, and these analyses show that PSA is also prognostic for BDP and SREs regardless of bone-targeted therapy. Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.

  15. Silencing CAPN2 Expression Inhibited Castration-Resistant Prostate Cancer Cells Proliferation and Invasion via AKT/mTOR Signal Pathway

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    Pu Li

    2017-01-01

    Full Text Available The mRNA expression of CAPN2 was upregulated in CRPC cells (DU145 and PC3 than that in non-CRPC cells. Silencing CAPN2 expression could inhibit DU145 and PC3 cells proliferation by cell cycle arrest at G1 phase. Knockdown of CPAN2 level suppressed the migration and invasion capacity of CRPC cells by reducing matrix metalloproteinase-2 (MMP-2 and MMP-9 activation, as well as repressing the phosphorylation protein expression of AKT and mTOR. In addition, we found that the expression of CAPN2 was elevated in Pca tissues than that in normal control tissues. Therefore, we showed the important roles of CAPN2 in the development and progression in CRPC cells, suggesting a new therapeutic intervention for treating castration-resistant prostate cancer patients.

  16. Inhibition of glycogen synthase kinase-3β counteracts ligand-independent activity of the androgen receptor in castration resistant prostate cancer.

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    Stefanie V Schütz

    Full Text Available In order to generate genomic signals, the androgen receptor (AR has to be transported into the nucleus upon androgenic stimuli. However, there is evidence from in vitro experiments that in castration-resistant prostate cancer (CRPC cells the AR is able to translocate into the nucleus in a ligand-independent manner. The recent finding that inhibition of the glycogen-synthase-kinase 3β (GSK-3β induces a rapid nuclear export of the AR in androgen-stimulated prostate cancer cells prompted us to analyze the effects of a GSK-3β inhibition in the castration-resistant LNCaP sublines C4-2 and LNCaP-SSR. Both cell lines exhibit high levels of nuclear AR in the absence of androgenic stimuli. Exposure of these cells to the maleimide SB216763, a potent GSK-3β inhibitor, resulted in a rapid nuclear export of the AR even under androgen-deprived conditions. Moreover, the ability of C4-2 and LNCaP-SSR cells to grow in the absence of androgens was diminished after pharmacological inhibition of GSK-3β in vitro. The ability of SB216763 to modulate AR signalling and function in CRPC in vivo was additionally demonstrated in a modified chick chorioallantoic membrane xenograft assay after systemic delivery of SB216763. Our data suggest that inhibition of GSK-3β helps target the AR for export from the nucleus thereby diminishing the effects of mislocated AR in CRPC cells. Therefore, inhibition of GSK-3β could be an interesting new strategy for the treatment of CRPC.

  17. The DHEA-sulfate depot following P450c17 inhibition supports the case for AKR1C3 inhibition in high risk localized and advanced castration resistant prostate cancer.

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    Tamae, Daniel; Mostaghel, Elahe; Montgomery, Bruce; Nelson, Peter S; Balk, Steven P; Kantoff, Philip W; Taplin, Mary-Ellen; Penning, Trevor M

    2015-06-05

    Prostate cancer is the second leading cause of cancer death in the United States. Treatment of localized high-risk disease and de novo metastatic disease frequently leads to relapse. These metastatic castration resistant prostate cancers (mCRPC) claim a high mortality rate, despite the extended survival afforded by the growing armamentarium of androgen deprivation, radiation and immunotherapies. Here, we review two studies of neoadjuvant treatment of high-risk localized prostate cancer prior to prostatectomy, the total androgen pathway suppression (TAPS) trial and the neoadjuvant abiraterone acetate (AA) trial. These two trials assessed the efficacy of the non-specific P450c17 inhibitor, ketoconazole and the specific P450c17 inhibitor, AA, to inhibit tissue and serum androgen levels. Furthermore, a novel and validated stable isotope dilution liquid chromatography electrospray ionization selected reaction monitoring mass spectrometry assay was used to accurately quantify adrenal and gonadal androgens in circulation during the course of these trials. The adrenal androgens, Δ(4)-androstene-3,17-dione, dehydroepiandrosterone and dehydroepiandrosterone sulfate were significantly reduced in the patients receiving ketoconazole or AA compared to those who did not. However, in both trials, a significant amount of DHEA-S (∼20 μg/dL) persists and thus may serve as a depot for intratumoral conversion to the potent androgen receptor ligands, testosterone (T) and 5α-dihydrotestosterone (DHT). The final step in conversion of Δ(4)-androstene-3,17-dione and 5α-androstanedione to T and DHT, respectively, is catalyzed by AKR1C3. We therefore present the case that in the context of the DHEA-S depot, P450c17 and AKR1C3 inhibition may be an effective combinatorial treatment strategy. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  18. Denosumab and Bone Metastasis–Free Survival in Men With Nonmetastatic Castration-Resistant Prostate Cancer: Exploratory Analyses by Baseline Prostate-Specific Antigen Doubling Time

    Science.gov (United States)

    Smith, Matthew R.; Saad, Fred; Oudard, Stephane; Shore, Neal; Fizazi, Karim; Sieber, Paul; Tombal, Bertrand; Damiao, Ronaldo; Marx, Gavin; Miller, Kurt; Van Veldhuizen, Peter; Morote, Juan; Ye, Zhishen; Dansey, Roger; Goessl, Carsten

    2013-01-01

    Purpose Denosumab, an anti–RANK ligand monoclonal antibody, significantly increases bone metastasis–free survival (BMFS; hazard ratio [HR], 0.85; P = .028) and delays time to first bone metastasis in men with nonmetastatic castration-resistant prostate cancer (CRPC) and baseline prostate-specific antigen (PSA) ≥ 8.0 ng/mL and/or PSA doubling time (PSADT) ≤ 10.0 months. To identify men at greatest risk for bone metastasis or death, we evaluated relationships between PSA and PSADT with BMFS in the placebo group and the efficacy and safety of denosumab in men with PSADT ≤ 10, ≤ 6, and ≤ 4 months. Patients and Methods A total of 1,432 men with nonmetastatic CRPC were randomly assigned 1:1 to monthly subcutaneous denosumab 120 mg or placebo. Enrollment began February 2006; primary analysis cutoff was July 2010, when approximately 660 men were anticipated to have developed bone metastases or died. Results In the placebo group, shorter BMFS was observed as PSADT decreased below 8 months. In analyses by shorter baseline PSADT, denosumab consistently increased BMFS by a median of 6.0, 7.2, and 7.5 months among men with PSADT ≤ 10 (HR, 0.84; P = .042), ≤ 6 (HR, 0.77; P = .006), and ≤ 4 months (HR, 0.71; P = .004), respectively. Denosumab also consistently increased time to bone metastasis by PSADT subset. No difference in survival was observed between treatment groups for the overall study population or PSADT subsets. Conclusion Patients with shorter PSADT are at greater risk for bone metastasis or death. Denosumab consistently improves BMFS in men with shorter PSADT and seems to have the greatest treatment effects in men at high risk for progression. PMID:24043751

  19. Denosumab and bone metastasis-free survival in men with nonmetastatic castration-resistant prostate cancer: exploratory analyses by baseline prostate-specific antigen doubling time.

    Science.gov (United States)

    Smith, Matthew R; Saad, Fred; Oudard, Stephane; Shore, Neal; Fizazi, Karim; Sieber, Paul; Tombal, Bertrand; Damiao, Ronaldo; Marx, Gavin; Miller, Kurt; Van Veldhuizen, Peter; Morote, Juan; Ye, Zhishen; Dansey, Roger; Goessl, Carsten

    2013-10-20

    Denosumab, an anti-RANK ligand monoclonal antibody, significantly increases bone metastasis-free survival (BMFS; hazard ratio [HR], 0.85; P = .028) and delays time to first bone metastasis in men with nonmetastatic castration-resistant prostate cancer (CRPC) and baseline prostate-specific antigen (PSA) ≥ 8.0 ng/mL and/or PSA doubling time (PSADT) ≤ 10.0 months. To identify men at greatest risk for bone metastasis or death, we evaluated relationships between PSA and PSADT with BMFS in the placebo group and the efficacy and safety of denosumab in men with PSADT ≤ 10, ≤ 6, and ≤ 4 months. A total of 1,432 men with nonmetastatic CRPC were randomly assigned 1:1 to monthly subcutaneous denosumab 120 mg or placebo. Enrollment began February 2006; primary analysis cutoff was July 2010, when approximately 660 men were anticipated to have developed bone metastases or died. In the placebo group, shorter BMFS was observed as PSADT decreased below 8 months. In analyses by shorter baseline PSADT, denosumab consistently increased BMFS by a median of 6.0, 7.2, and 7.5 months among men with PSADT ≤ 10 (HR, 0.84; P = .042), ≤ 6 (HR, 0.77; P = .006), and ≤ 4 months (HR, 0.71; P = .004), respectively. Denosumab also consistently increased time to bone metastasis by PSADT subset. No difference in survival was observed between treatment groups for the overall study population or PSADT subsets. Patients with shorter PSADT are at greater risk for bone metastasis or death. Denosumab consistently improves BMFS in men with shorter PSADT and seems to have the greatest treatment effects in men at high risk for progression.

  20. Fluorine-18-fluorocholine PET/CT parameters predictive for hematological toxicity to radium-223 therapy in castrate-resistant prostate cancer patients with bone metastases: a pilot study.

    Science.gov (United States)

    Vija Racaru, Lavinia; Sinigaglia, Mathieu; Kanoun, Salim; Ben Bouallègue, Fayçal; Tal, Ilan; Brillouet, Sévérine; Bauriaud-Mallet, Mathilde; Zerdoud, Slimane; Dierickx, Lawrence; Vallot, Delphine; Caselles, Olivier; Gabiache, Erwan; Pascal, Pierre; Courbon, Frederic

    2018-05-21

    This study aims to predict hematological toxicity induced by Ra therapy. We investigated the value of metabolically active bone tumor volume (MBTV) and total bone lesion activity (TLA) calculated on pretreatment fluorine-18-fluorocholine (F-FCH) PET/CT in castrate-resistant prostate cancer (CRPC) patients with bone metastases treated with Ra radionuclide therapy. F-FCH PET/CT imaging was performed in 15 patients with CRPC before treatment with Ra. Bone metastatic disease was quantified on the basis of the maximum standardized uptake value (SUV), total lesion activity (TLA=MBTV×SUVmean), or MBTV/height (MBTV/H) and TLA/H. F-FCH PET/CT bone tumor burden and activity were analyzed to identify which parameters could predict hematological toxicity [on hemoglobin (Hb), platelets (PLTs), and lymphocytes] while on Ra therapy. Pearson's correlation was used to identify the correlations between age, prostate-specific antigen, and F-FCH PET parameters. MBTV ranged from 75 to 1259 cm (median: 392 cm). TLA ranged from 342 to 7198 cm (median: 1853 cm). Patients benefited from two to six cycles of Ra (n=56 cycles in total). At the end of Ra therapy, five of the 15 (33%) patients presented grade 2/3 toxicity on Hb and lymphocytes, whereas three of the 15 (20%) patients presented grade 2/3 PLT toxicity.Age was correlated negatively with both MBTV (r=-0.612, P=0.015) and TLA (r=-0.596, P=0.018). TLA, TLA/H, and MBTV/H predicted hematological toxicity on Hb, whereas TLA/H and MBTV/H predicted toxicity on PLTs at the end of Ra cycles. Receiver operating characteristic curve analysis allowed to define the cutoffs for MBTV (915 cm) and TLA (4198 cm) predictive for PLT toxicity, with an accuracy of 0.92 and 0.99. Tumor bone burden calculation is feasible with F-FCH PET/CT with freely available open-source software. In this pilot study, baseline F-FCH PET/CT markers (TLA, MBTV) have shown abilities to predict Hb and PLT toxicity after Ra therapy and could be explored for

  1. Transcript Levels of Androgen Receptor Variant 7 and Ubiquitin-Conjugating Enzyme 2C in Hormone Sensitive Prostate Cancer and Castration-Resistant Prostate Cancer.

    Science.gov (United States)

    Lee, Chan Ho; Ku, Ja Yoon; Ha, Jung Min; Bae, Sun Sik; Lee, Jeong Zoo; Kim, Choung-Soo; Ha, Hong Koo

    2017-01-01

    This study is designed to identify the androgen receptor variant 7 (AR-V7) status, clinical significance of AR-V7 in hormone sensitive prostate cancer (HSPC). Then, we evaluated AR-V7 and changes of its target gene, ubiquitin-conjugating enzyme E2C (UBE2C) which is an anaphase-promoting complex/cyclosome (APC/C)-specific ubiquitin-conjugating enzyme, in castration-resistant prostate cancer (CRPC) in serial tumor biopsies from patients receiving androgen deprivation therapy. We used RT-PCR and Q-PCR assay to evaluate AR-V7, androgen receptor full length (AR-FL), and UBE2C in tumor biopsies from patients with HSPC and CRPC. We examined associations between mRNA expression of AR-V7 and clinicopathologic factors. Furthermore, to identify other potential genes involved in the development of CRPC, RNA sequencing was conducted, using paired prostate cancer (PCa) tissues obtained immediately prior to treatment and at the time of therapeutic resistance. A total of 13 HSPC patients and three CRPC patients were enrolled. Neither a high Gleason score (score of 8 and 9) nor a high risk of PCa (a high risk of locally advanced PCa according to NCCN guidelines) was correlated with mRNA expression of AR-V7 in HSPC (P = 0.153 and P = 0.215). The mRNA expression of AR-FL, but not AR-V7, was significantly associated with the mRNA expression of UBE2C level in HSPC (P = 0.007). However, increased expression of AR-V7, not AR-FL, paralleled increased expression of UBE2C in the CRPC specimens (P = 0.03). AR-V7 expression status before ADT was likely related to shorter CRPC development in patients treating ADT. The result of the RNA-sequencing analysis using serial samples from the same patient before and after castration demonstrated an increased level of the PI3K regulatory subunit 1 (P = 0.018). Our study revealed the role of UBE2C as a marker of the androgen signaling pathway in PCa. Differential gene expression analysis using serial samples from the same patient

  2. Detection of AR-V7 mRNA in whole blood may not predict the effectiveness of novel endocrine drugs for castration-resistant prostate cancer.

    Science.gov (United States)

    Takeuchi, Takumi; Okuno, Yumiko; Hattori-Kato, Mami; Zaitsu, Masayoshi; Mikami, Koji

    2016-01-01

    A splice variant of androgen receptor (AR), AR-V7, lacks in androgen-binding portion and leads to aggressive cancer characteristics. Reverse transcription-polymerase chain reactions (PCRs) and subsequent nested PCRs for the amplification of AR-V7 and prostate-specific antigen (PSA) transcripts were done for whole blood of patients with prostate cancer and male controls. With primary reverse transcription PCRs, AR-V7 and PSA were detected in 4.5% and 4.7% of prostate cancer, respectively. With nested PCRs, AR-V7 messenger RNA (mRNA) was positive in 43.8% of castration-sensitive prostate cancer and 48.1% of castration-resistant prostate cancer (CRPC), while PSA mRNA was positive in 6.3% of castration-sensitive prostate cancer and 18.5% of CRPC. Whole-blood samples of controls showed AR-V7 mRNA expression by nested PCR. Based on multivariate analysis, expression of AR-V7 mRNA in whole blood was not significantly correlated with clinical parameters and PSA mRNA in blood, while univariate analysis showed a correlation between AR-V7 mRNA and metastasis at initial diagnosis. Detection of AR-V7 mRNA did not predict the reduction of serum PSA in patients with CRPC following abiraterone and enzalutamide administration. In conclusion, AR-V7 mRNA expression in normal hematopoietic cells may have annihilated the manifestation of aggressiveness of prostate cancer and the prediction of the effectiveness of abiraterone and enzalutamide by the assessment of AR-V7 mRNA in blood.

  3. Tumour cell lysate-loaded dendritic cell vaccine induces biochemical and memory immune response in castration-resistant prostate cancer patients.

    Science.gov (United States)

    Reyes, D; Salazar, L; Espinoza, E; Pereda, C; Castellón, E; Valdevenito, R; Huidobro, C; Inés Becker, M; Lladser, A; López, M N; Salazar-Onfray, F

    2013-09-17

    Recently, we produced a tumour antigen-presenting cells (TAPCells) vaccine using a melanoma cell lysate, called TRIMEL, as an antigen source and an activation factor. Tumour antigen-presenting cells induced immunological responses and increased melanoma patient survival. Herein, we investigated the effect of TAPCells loaded with prostate cancer cell lysates (PCCL) as an antigen source, and TRIMEL as a dendritic cell (DC) activation factor; which were co-injected with the Concholepas concholepas haemocyanin (CCH) as an adjuvant on castration-resistant prostate cancer (CRPC) patients. The lysate mix capacity, for inducing T-cell activation, was analysed by flow cytometry and Elispot. Delayed-type hypersensitivity (DTH) reaction against PCCL, frequency of CD8(+) memory T cells (Tm) in blood and prostate-specific antigen (PSA) levels in serum were measured in treated patients. The lysate mix induced functional mature DCs that were capable of activating PCCL-specific T cells. No relevant adverse reactions were observed. Six out of 14 patients showed a significant decrease in levels of PSA. DTH(+) patients showed a prolonged PSA doubling-time after treatment. Expansion of functional central and effector CD8(+) Tm were detected. Treatment of CRPC patients with lysate-loaded TAPCells and CCH as an adjuvant is safe: generating biochemical and memory immune responses. However, the limited number of cases requires confirmation in a phase II clinical trial.

  4. Suppression of LIM and SH3 Domain Protein 1 (LASP1) Negatively Regulated by Androgen Receptor Delays Castration Resistant Prostate Cancer Progression.

    Science.gov (United States)

    Dejima, Takashi; Imada, Kenjiro; Takeuchi, Ario; Shiota, Masaki; Leong, Jeffrey; Tombe, Tabitha; Tam, Kevin; Fazli, Ladan; Naito, Seiji; Gleave, Martin E; Ong, Christopher J

    2017-02-01

    LIM and SH3 domain protein 1 (LASP1) has been implicated in several human malignancies and has been shown to predict PSA recurrence in prostate cancer. However, the anti-tumor effect of LASP1 knockdown and the association between LASP1 and the androgen receptor (AR) remains unclear. The aim of this study is to clarify the significance of LASP1 as a target for prostate cancer, and to test the effect of silencing LASP1 in vivo using antisense oligonucleotides (ASO). A tissue microarray (TMA) was performed to characterize the differences in LASP1 expression in prostate cancer treated after hormone deprivation therapy. Flow cytometry was used to analyze cell cycle. We designed LASP1 ASO for knockdown of LASP1 in vivo studies. The expression of LASP1 in TMA was increased after androgen ablation and persisted in castration resistant prostate cancer (CRPC). Also in TMA, compared with LNCaP cell, LASP1 expression is elevated in CRPC cell lines (C4-2 and VehA cells). Interestingly, suppression of AR elevated LASP1 expression conversely, AR activation decreased LASP1 expression. Silencing of LASP1 reduced cell growth through G1 arrest which was accompanied by a decrease of cyclin D1. Forced overexpression of LASP1 promoted cell cycle and induced cell growth which was accompanied by an increase of cyclin D1. Systemic administration of LASP1 ASO with athymic mice significantly inhibited tumor growth in CRPC xenografts. These results indicate that LASP1 is negatively regulated by AR at the transcriptional level and promotes tumor growth through induction of cell cycle, ultimately suggesting that LASP1 may be a potential target in prostate cancer treatment. Prostate 77:309-320, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  5. The retinamide VNLG-152 inhibits f-AR/AR-V7 and MNK-eIF4E signaling pathways to suppress EMT and castration-resistant prostate cancer xenograft growth.

    Science.gov (United States)

    Ramamurthy, Vidya P; Ramalingam, Senthilmurugan; Gediya, Lalji K; Njar, Vincent C O

    2018-03-01

    VNLG-152 is a novel retinamide (NR) shown to suppress growth and progression of genetically diverse prostate cancer cells via inhibition of androgen receptor signaling and eukaryotic initiation factor 4E (eIF4E) translational machinery. Herein, we report therapeutic effects of VNLG-152 on castration-resistant prostate cancer (CRPC) growth and metastatic phenotype in a CRPC tumor xenograft model. Administration of VNLG-152 significantly and dose-dependently suppressed the growth of aggressive CWR22Rv1 tumors by 63.4% and 76.3% at 10 and 20 mg·kg -1 bw, respectively (P AR)/androgen receptor splice variant-7 (AR-V7), mitogen-activated protein kinase-interacting kinases 1 and 2 (MNK1/2), phosphorylated eIF4E and their associated target proteins, including prostate-specific antigen, cyclin D1 and Bcl-2, were strongly decreased in VNLG-152-treated tumors signifying inhibition of f-AR/AR-V7 and MNK-eIF4E signaling in VNLG-152-treated CWR22Rv1 tumors as observed in vitro. VNLG-152 also suppressed the epithelial to mesenchymal transition in CWR22Rv1 tumors as evidenced by repression of N-cadherin, β-catenin, claudin, Slug, Snail, Twist, vimentin and matrix metalloproteinases (MMP-2 and MMP-9) with upsurge in E-cadherin. These results highlight the promising use of VNLG-152 in CRPC therapy and justify its further development towards clinical trials. © 2018 Federation of European Biochemical Societies.

  6. Lu-177-PSMA-617 Prostate-Specific Membrane Antigen Inhibitor Therapy in Patients with Castration-Resistant Prostate Cancer: Stability, Bio-distribution and Dosimetry

    Directory of Open Access Journals (Sweden)

    Levent Kabasakal

    2017-06-01

    Full Text Available Objective: The aim of the study was to estimate the radiation-absorbed doses and to study the in vivo and in vitro stability as well as pharmacokinetic characteristics of lutetium-177 (Lu-177 prostate-specific membrane antigen (PSMA-617. Methods: For this purpose, 7 patients who underwent Lu-177-PSMA therapy were included into the study. The injected Lu-177-PSMA-617 activity ranged from 3.6 to 7.4 GBq with a mean of 5.2±1.8 GBq. The stability of radiotracer in saline was calculated up to 48 h. The stability was also calculated in blood and urine samples. Post-therapeutic dosimetry was performed based on whole body and single photon emission computed tomography/computed tomography (SPECT/CT scans on dual-headed SPECT/CT system. Results: The radiochemical yield of Lu-177-PSMA-617 was >99%. It remained stable in saline up to 48 h. Analyses of the blood and urine samples showed a single radioactivity peak even at 24 hours after injection. Half-life of the distribution and elimination phases were calculated to be 0.16±0.09 and 10.8±2.5 hours, respectively. The mean excretion rate was 56.5±8.8% ranging from 41.5% to 65.4% at 24 h. Highest radiation estimated doses were calculated for parotid glands and kidneys (1.90±1.19 and 0.82±0.25 Gy/GBq respectively. Radiation dose given to the bone marrow was significantly lower than those of kidney and parotid glands (p<0.05 (0.030±0.008 Gy/GBq. Conclusion: Lu-177-PSMA-617 is a highly stable compound both in vitro and in vivo. Lu-177-PSMA-617 therapy seems to be a safe method for the treatment of castration-resistant prostate cancer patients. The fractionation regime that enables the longest duration of tumor control and/or survival will have to be developed in further studies.

  7. Development and Implementation of a High-Throughput High-Content Screening Assay to Identify Inhibitors of Androgen Receptor Nuclear Localization in Castration-Resistant Prostate Cancer Cells

    Science.gov (United States)

    Nguyen, Minh M.; Dar, Javid A.; Ai, Junkui; Wang, Yujuan; Masoodi, Khalid Z.; Shun, Tongying; Shinde, Sunita; Camarco, Daniel P.; Hua, Yun; Huryn, Donna M.; Wilson, Gabriela Mustata; Lazo, John S.; Nelson, Joel B.; Wipf, Peter

    2016-01-01

    Abstract Patients with castration-resistant prostate cancer (CRPC) can be treated with abiraterone, a potent inhibitor of androgen synthesis, or enzalutamide, a second-generation androgen receptor (AR) antagonist, both targeting AR signaling. However, most patients relapse after several months of therapy and a majority of patients with relapsed CRPC tumors express the AR target gene prostate-specific antigen (PSA), suggesting that AR signaling is reactivated and can be targeted again to inhibit the relapsed tumors. Novel small molecules capable of inhibiting AR function may lead to urgently needed therapies for patients resistant to abiraterone, enzalutamide, and/or other previously approved antiandrogen therapies. Here, we describe a high-throughput high-content screening (HCS) campaign to identify small-molecule inhibitors of AR nuclear localization in the C4-2 CRPC cell line stably transfected with GFP-AR-GFP (2GFP-AR). The implementation of this HCS assay to screen a National Institutes of Health library of 219,055 compounds led to the discovery of 3 small molecules capable of inhibiting AR nuclear localization and function in C4-2 cells, demonstrating the feasibility of using this cell-based phenotypic assay to identify small molecules targeting the subcellular localization of AR. Furthermore, the three hit compounds provide opportunities to develop novel AR drugs with potential for therapeutic intervention in CRPC patients who have relapsed after treatment with antiandrogens, such as abiraterone and/or enzalutamide. PMID:27187604

  8. Vitamin K2, a menaquinone present in dairy products targets castration-resistant prostate cancer cell-line by activating apoptosis signaling.

    Science.gov (United States)

    Dasari, Subramanyam; Samy, Angela Lincy Prem Antony; Kajdacsy-Balla, Andre; Bosland, Maarten C; Munirathinam, Gnanasekar

    2018-05-01

    The aim of this study was to evaluate the therapeutic effects of vitamin K2 (VK2) on castration-resistant prostate cancer (CRPC) and its anti-cancer mechanisms in a pre-clinical study using a VCaP cell line (ATCC ® CRL-2876™) which was established from a vertebral bone metastasis from a patient with hormone refractory prostate cancer. Our data showed that VK2 significantly inhibited CRPC VCaP cell proliferation in a dose-dependent manner at 48 h treatment in vitro. In addition, VK2 reduced the migration potential of VCaP cells and inhibited anchorage-independent growth of these cells. Our results also showed that VK2 induces apoptosis in VCaP cells. Furthermore, VK2 enforced growth arrest in VCaP cells by activating cellular senescence. Notably, VK2 treatment elevated the levels of reactive oxygen species in VCaP cells. Western blot analysis revealed that VK2 downregulated the expression of androgen receptor, BiP, survivin, while activating caspase-3 and -7, PARP-1 cleavage, p21 and DNA damage response marker, phospho-H2AX in VCaP cells. In conclusion, our study suggests that VK2 might be a potential anti-cancer agent for CRPC by specifically targeting key anti-apoptotic, cell cycle progression and metastasis-promoting signaling molecules. Copyright © 2018 Elsevier Ltd. All rights reserved.

  9. Lycopene Enhances Docetaxel's Effect in Castration-Resistant Prostate Cancer Associated with Insulin-like Growth Factor I Receptor Levels1

    Science.gov (United States)

    Tang, Yaxiong; Parmakhtiar, Basmina; Simoneau, Anne R; Xie, Jun; Fruehauf, John; Lilly, Michael; Zi, Xiaolin

    2011-01-01

    Docetaxel is currently the most effective drug for the treatment of castration-resistant prostate cancer (CRPC), but it only extends life by an average of 2 months. Lycopene, an antioxidant phytochemical, has antitumor activity against prostate cancer (PCa) in several models and is generally safe. We present data on the interaction between docetaxel and lycopene in CRPC models. The growth-inhibitory effect of lycopene on PCa cell lines was positively associated with insulin-like growth factor I receptor (IGF-IR) levels. In addition, lycopene treatment enhanced the growth-inhibitory effect of docetaxel more effectively on DU145 cells with IGF-IR high expression than on those PCa cell lines with IGF-IR low expression. In a DU145 xenograft tumor model, docetaxel plus lycopene caused tumor regression, with a 38% increase in antitumor efficacy (P = .047) when compared with docetaxel alone. Lycopene inhibited IGF-IR activation through inhibiting IGF-I stimulation and by increasing the expression and secretion of IGF-BP3. Downstream effects include inhibition of AKT kinase activity and survivin expression, followed by apoptosis. Together, the enhancement of docetaxel's antitumor efficacy by lycopene supplementation justifies further clinical investigation of lycopene and docetaxel combination for CRPC patients. CRPC patients with IGF-IR-overexpressing tumors may be most likely to benefit from this combination. PMID:21403837

  10. Methylated Glutathione S-transferase 1 (mGSTP1) is a potential plasma free DNA epigenetic marker of prognosis and response to chemotherapy in castrate-resistant prostate cancer

    OpenAIRE

    Mahon, K L; Qu, W; Devaney, J; Paul, C; Castillo, L; Wykes, R J; Chatfield, M D; Boyer, M J; Stockler, M R; Marx, G; Gurney, H; Mallesara, G; Molloy, P L; Horvath, L G; Clark, S J

    2014-01-01

    Background: Glutathione S-transferase 1 (GSTP1) inactivation is associated with CpG island promoter hypermethylation in the majority of prostate cancers (PCs). This study assessed whether the level of circulating methylated GSTP1 (mGSTP1) in plasma DNA is associated with chemotherapy response and overall survival (OS). Methods: Plasma samples were collected prospectively from a Phase I exploratory cohort of 75 men with castrate-resistant PC (CRPC) and a Phase II independent validation cohort ...

  11. Patient-derived Hormone-naive Prostate Cancer Xenograft Models Reveal Growth Factor Receptor Bound Protein 10 as an Androgen Receptor-repressed Gene Driving the Development of Castration-resistant Prostate Cancer.

    Science.gov (United States)

    Hao, Jun; Ci, Xinpei; Xue, Hui; Wu, Rebecca; Dong, Xin; Choi, Stephen Yiu Chuen; He, Haiqing; Wang, Yu; Zhang, Fang; Qu, Sifeng; Zhang, Fan; Haegert, Anne M; Gout, Peter W; Zoubeidi, Amina; Collins, Colin; Gleave, Martin E; Lin, Dong; Wang, Yuzhuo

    2018-06-01

    Although androgen deprivation therapy is initially effective in controlling growth of hormone-naive prostate cancers (HNPCs) in patients, currently incurable castration-resistant prostate cancer (CRPC) inevitably develops. To identify CRPC driver genes that may provide new targets to enhance CRPC therapy. Patient-derived xenografts (PDXs) of HNPCs that develop CRPC following host castration were examined for changes in expression of genes at various time points after castration using transcriptome profiling analysis; particular attention was given to pre-CRPC changes in expression indicative of genes acting as potential CRPC drivers. The functionality of a potential CRPC driver was validated via its knockdown in cultured prostate cancer cells; its clinical relevance was established using data from prostate cancer patient databases. Eighty genes were found to be significantly upregulated at the CRPC stage, while seven of them also showed elevated expression prior to CRPC development. Among the latter, growth factor receptor bound protein 10 (GRB10) was the most significantly and consistently upregulated gene. Moreover, elevated GRB10 expression in clinical prostate cancer samples correlated with more aggressive tumor types and poorer patient treatment outcome. GRB10 knockdown markedly reduced prostate cancer cell proliferation and activity of AKT, a well-established CRPC mediator. A positive correlation between AKT activity and GRB10 expression was also found in clinical cohorts. GRB10 acts as a driver of CRPC and sensitizes androgen receptor pathway inhibitors, and hence GRB10 targeting provides a novel therapeutic strategy for the disease. Development of castration-resistant prostate cancer (CRPC) is a major problem in the management of the disease. Using state-of-the-art patient-derived hormone-naive prostate cancer xenograft models, we found and validated the growth factor receptor bound protein 10 gene as a driver of CRPC, indicating that it may be used as a

  12. Downregulation of androgen receptors by NaAsO2 via inhibition of AKT-NF-κB and HSP90 in castration resistant prostate cancer.

    Science.gov (United States)

    Kim, Yunlim; Park, Sang Eun; Moon, Jeong-Weon; Kim, Bong-Min; Kim, Ha-Gyeong; Jeong, In Gab; Yoo, Sangjun; Ahn, Jae Beom; You, Dalsan; Pak, Jhang Ho; Kim, Sujong; Hwang, Jung Jin; Kim, Choung-Soo

    2017-07-01

    Androgen and androgen receptor (AR) play essential roles in the development and maintenance of prostate cancer. The recently identified AR splice variants (AR-Vs) have been considered as a plausible mechanism for the primary resistance against androgen deprivation therapy (ADT) in castration-resistant prostate cancer (CRPC). Sodium meta-arsenite (NaAsO 2 ; KML001; Kominox), a trivalent arsenical, is an orally bioavailable and water soluble, which is currently in phase I/II clinical trials for the treatment of prostate cancer. It has a potent anti-cancer effect on prostate cancer cells and xenografts. The aim of this study was to examine the effect of NaAsO 2 on AR signaling in LNCaP and 22Rv1 CRPC cells. We used hormone-sensitive LNCaP cells, hormone-insensitive 22Rv1 cells, and CRPC patient-derived primary cells. We analyzed anti-cancer effect of NaAsO 2 using real-time quantitative reverse transcription-PCR, Western blotting, immunofluorescence staining and CellTiter Glo® luminescent assay. Statistical evaluation of the results was performed by one-way ANOVA. NaAsO 2 significantly reduced the translocation of AR and AR-Vs to the nucleus as well as their level in LNCaP and 22Rv1 cells. Besides, the level of the prostate-specific antigen (PSA), downstream target gene of AR, was also decreased. This compound was also an effective modulator of AKT-dependent NF-κB activation which regulates AR. NaAsO 2 significantly inhibited phosphorylation of AKT and expression and nuclear translocation of NF-κB. We then investigated the effect of NaAsO 2 on AR stabilization. NaAsO 2 promoted HSP90 acetylation by down-regulating HDAC6, which reduces the stability of AR in prostate cancer cells. Here, we show that NaAsO 2 disrupts AR signaling at multiple levels by affecting AR expression, stability, and degradation in primary tumor cell cultures from prostate cancer patients as well as CRPC cell lines. These results suggest that NaAsO 2 could be a novel therapeutics for prostate

  13. Phase I dose-escalation and pharmacokinetic study (TED 11576) of cabazitaxel in Japanese patients with castration-resistant prostate cancer.

    Science.gov (United States)

    Mukai, Hirofumi; Takahashi, Shunji; Nozawa, Masahiro; Onozawa, Yusuke; Miyazaki, Jun; Ohno, Keiji; Suzuki, Kazuhiro

    2014-04-01

    The purpose of the study is to analyze the pharmacokinetic (PK) profile of cabazitaxel and evaluate its safety and tolerability as a 1-h IV infusion every 3 weeks in Japanese patients with castration-resistant prostate cancer (CRPC). Seventeen patients were treated with cabazitaxel at doses of 20 and 25 mg/m(2) for PK analyses. Dose escalation was performed only in the absence of dose-limiting toxicity (DLT). The maximum tolerated dose (MTD) was the highest dose at which less than 33 % of the patients developed DLT. Cabazitaxel exhibited a triphasic elimination profile with a long terminal half-life of 116 ± 29.0 or 113 ± 28.0 h after IV infusion of 20 or 25 mg/m(2) cabazitaxel, respectively. The major differences in the PK parameters of cabazitaxel and docetaxel were cabazitaxel's fairly high clearance rate, representing approximately half the hepatic flow, and its large volume of distribution at steady-state conditions. No DLT was observed during Cycle 1. Mild-to-moderate hematological adverse events (AEs), including neutropenia, and other AEs typically associated with taxanes were observed; all AEs were manageable. Cabazitaxel at 25 mg/m(2) every 3 weeks was selected as the MTD in Japanese patients. The PK parameters of cabazitaxel in Japanese CRPC patients were comparable with those previously determined in Caucasian subjects. The safety and tolerability of cabazitaxel were also comparable in both ethnic populations.

  14. PTEN loss promotes intratumoral androgen synthesis and tumor microenvironment remodeling via aberrant activation of RUNX2 in castration-resistant prostate cancer

    Science.gov (United States)

    Yang, Yinhui; Bai, Yang; He, Yundong; Zhao, Yu; Chen, Jiaxiang; Ma, Linlin; Pan, Yunqian; Hinten, Michael; Zhang, Jun; Karnes, R. Jeffrey; Kohli, Manish; Westendorf, Jennifer J.; Li, Benyi; Zhu, Runzhi; Huang, Haojie; Xu, Wanhai

    2018-01-01

    Purpose Intratumoral androgen synthesis (IAS) is a key mechanism promoting androgen receptor (AR)reactivation and anti-androgen resistance in castration-resistant prostate cancer (CRPC). However, signaling pathways driving aberrant IAS remain poorly understood. Experimental Design The effect of components of the AKT-RUNX2-osteocalcin (OCN)-GPRC6A-CREB signaling axis on expression of steroidogenesis genes CYP11A1 and CYP17A1 and testosterone level were examined in PTEN-null human PCa cell lines. Pten knockout mice were employed to examine the effect of Runx2 heterozygous deletion or abiraterone acetate (ABA), a prodrug of the CYP17A1 inhibitor abiraterone on Cyp11a1 and Cyp17a1 expression, testosterone level and tumor microenvironment (TME) remodeling in vivo. Results We uncovered that activation of the AKT-RUNX2-OCN-GPRC6A-CREB signaling axis induced expression of CYP11A1 and CYP17A1 and testosterone production in PTEN-null PCa cell lines in culture. Deletion of Runx2 in Pten homozygous knockout prostate tumors decreased Cyp11a1 and Cyp17a1 expression, testosterone level and tumor growth in castrated mice. ABA treatment also inhibited testosterone synthesis and alleviated Pten loss-induced tumorigenesis in vivo. Pten deletion induced TME remodeling, but Runx2 heterozygous deletion or ABA treatment reversed the effect of Pten loss by decreasing expression of the collagenase Mmp9. Conclusions Abnormal RUNX2 activation plays a pivotal role in PTEN loss-induced IAS and TME remodeling, suggesting that the identified signaling cascade represents a viable target for effective treatment of PTEN-null PCa including CRPC. PMID:29167276

  15. PET/CT With 68Ga-DOTA-TATE for Diagnosis of Neuroendocrine: Differentiation in Patients With Castrate-Resistant Prostate Cancer.

    Science.gov (United States)

    Gofrit, Ofer Nathan; Frank, Stephen; Meirovitz, Amichay; Nechushtan, Hovav; Orevi, Marina

    2017-01-01

    Castrate-resistant prostate cancer (CRPC) often shows histological evidence of neuroendocrine differentiation (NED). To evaluate the extent of NED in patients with CRPC, we used PET/CT with Ga-[DOTA-Tyr]-octreotate (Ga-DOTA-TATE), a somatostatin analog that binds somatostatin receptor 2 with high affinity. This radiotracer is used in imaging of neuroendocrine tumors. Twelve patients (mean age, 65 [SD, 12] years) with CRPC were studied. Their mean prostate-specific antigen level at scanning was 85.6 (SD, 144.6) ng/mL. PET/CT images were obtained after the injection of 120 to 200 MBq of Ga-DOTA-TATE. All participants had at least 1 blastic metastasis demonstrating uptake of Ga-DOTA-TATE (mean SUVmax of 5.3 [SD, 2.3]). In 6 patients, moderately high to high uptakes (SUVmax, >5) were seen. Patients with multiple bone metastases had a significantly higher SUVmax compared with patients with few metastases (mean of 5.8 vs 3.8, P = 0.05). In 4 patients, lytic bone lesions or lymph node metastases also showed uptake of the tracer (mean SUVmax of 7.2 [SD, 3.2]). Uptake of the radiotracer was also observed in bones showing normal architecture in CT, suggesting that NED cells appear early during metastases development. Uptake of Ga-DOTA-TATE is a common finding in metastases of CRPC patients, suggesting that NED is frequent in these patients. In half of the patients, widespread uptake of Ga-DOTA-TATE was observed. This suggests that the possibility of treating selected CRCP patients with anti-neuroendocrine tumor therapies should be explored and that Ga-DOTA-TATE scanning could have a role in predicting the efficacy of these treatments.

  16. Solitary recurrence of castration-resistant prostate cancer with low or undetectable levels of prostate specific antigen salvaged with local ablative radiation therapy: A case report.

    Science.gov (United States)

    Wang, Chiachien Jake; Ying, James; Kapur, Payal; Wohlfeld, Bryan; Roehrborn, Claus; Kim, Dong W Nathan

    2016-01-01

    Prostate cancer recurrences are usually first detected by increased levels of prostate specific antigen (PSA), and systemic therapy is often initiated if distant metastasis is confirmed. However, low or nearly undetectable levels of PSA in the modern era of ultrasensitive PSA assay may be difficult to interpret in patients with a history of prostate cancer. Deciding whether to initiate additional systemic therapy in limited indolent metastatic disease while balancing the quality of life of the patient and ensuring the oncologic control of the disease may be challenging. In the present study, the case of a biopsy-confirmed solitary spine recurrence of prostate cancer with nearly undetectable but persistent levels of PSA (0.05 ng/ml) is reported. Treatment of the recurrence with local ablative radiotherapy improved the pain experienced by the patient, and reduced his levels of PSA to undetectable limits (<0.05 ng/ml). Repeated imaging analysis, PSA assay and clinical assessment demonstrated durable control of the disease without the requirement for additional systemic treatments. The present case highlighted the importance of initiating appropriate work-up according to the clinical scenario. Local treatment for solitary or oligometastatic recurrence of prostate cancer may enhance the effectiveness of current therapeutic strategies and benefit certain patients.

  17. Glyphosate Vedotin for Treatment of Bone Metastatic Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2015-07-01

    Louisiana, New Orleans, LA, USA; 5Department of Orthopaedic Surgery, Tu- lane University, New Orleans, LA, USA; 6Tulane Center for Stem Cell Research and...expression or any change upon MAA treatment for B-cell CLL /lymphoma 2 (BCL2), BCL2-associated X protein (BAX), BCL2- like 1 (BCL2L1), BCL2-associated...2 family proteins in germ cell apoptosis during testicular devel- opment in the rat and pro-survival effect of stem cell factor on germ cells in

  18. Radium-223 therapy of advanced metastatic castration-resistant prostate cancer

    DEFF Research Database (Denmark)

    Fosbøl, Marie Øbro; Petersen, Peter Meidahl; Kjaer, Andreas

    2018-01-01

    ) can serve as a prognostic biomarker of overall survival (OS) and hematological toxicity, as well as a tool for response assessment in patients with mCRPC treated with223RaCl2Methods:Retrospective study of the Danish cohort of mCRPC patients who received223RaCl2therapy between March 2014 and October...... ratio 2.65 [95% CI: 1.5-4.71];P= 0.001). Likewise, baseline BSI was prognostic for occurrence of hematological toxicity and patients with BSI > 5 had an odds ratio of 3.02 (95% CI: 1.2-7.8;P= 0.02) for toxicity. BSI declined during therapy in 44% of patients who completed three cycles of223RaCl2(n= 52......) and in 84% of patients after EOT (n= 32). There was no significant association between change in BSI during therapy and OS.Conclusion:BSI is a promising biomarker for late-stage mCRPC patients receiving223RaCl2for prognostication of OS and hematological toxicity. Further prospective studies are needed...

  19. PRM113 - Timed Automata Modeling of The Personalized Treatment Decisions In Metastatic Castration Resistant Prostate Cancer

    NARCIS (Netherlands)

    Schivo, Stefano; Degeling, K.; Degeling, Koen; Koffijberg, Hendrik; IJzerman, Maarten Joost; Langerak, Romanus

    2015-01-01

    Objectives The Timed Automata modeling paradigm has emerged from Computer Science as a mature tool for the functional analysis and performance evaluation of timed distributed systems. This study is a first exploration of the suitability of Timed Automata for health economic modeling, using a case

  20. Immunotherapy and Immune Evasion in Prostate Cancer

    International Nuclear Information System (INIS)

    Thakur, Archana; Vaishampayan, Ulka; Lum, Lawrence G.

    2013-01-01

    Metastatic prostate cancer remains to this day a terminal disease. Prostatectomy and radiotherapy are effective for organ-confined diseases, but treatment for locally advanced and metastatic cancer remains challenging. Although advanced prostate cancers treated with androgen deprivation therapy achieves debulking of disease, responses are transient with subsequent development of castration-resistant and metastatic disease. Since prostate cancer is typically a slowly progressing disease, use of immune-based therapies offers an advantage to target advanced tumors and to induce antitumor immunity. This review will discuss the clinical merits of various vaccines and immunotherapies in castrate resistant prostate cancer and challenges to this evolving field of immune-based therapies

  1. Immunotherapy and Immune Evasion in Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Thakur, Archana, E-mail: thakur@karmanos.org; Vaishampayan, Ulka [Department of Oncology, Wayne State University, Detroit, MI 48201 (United States); Lum, Lawrence G., E-mail: thakur@karmanos.org [Department of Oncology, Wayne State University, Detroit, MI 48201 (United States); Department of Medicine, Wayne State University, Detroit, MI 48201 (United States); Department of Immunology and Microbiology, Wayne State University, Detroit, MI 48201 (United States)

    2013-05-24

    Metastatic prostate cancer remains to this day a terminal disease. Prostatectomy and radiotherapy are effective for organ-confined diseases, but treatment for locally advanced and metastatic cancer remains challenging. Although advanced prostate cancers treated with androgen deprivation therapy achieves debulking of disease, responses are transient with subsequent development of castration-resistant and metastatic disease. Since prostate cancer is typically a slowly progressing disease, use of immune-based therapies offers an advantage to target advanced tumors and to induce antitumor immunity. This review will discuss the clinical merits of various vaccines and immunotherapies in castrate resistant prostate cancer and challenges to this evolving field of immune-based therapies.

  2. "1"7"7Lu-PSMA-617 radioligand therapy and outcome in patients with metastasized castration-resistant prostate cancer

    International Nuclear Information System (INIS)

    Braeuer, Axel; Grubert, Lena Sophie; Roll, Wolfgang; Schaefers, Michael; Rahbar, Kambiz; Schrader, Andres Jan; Boegemann, Martin

    2017-01-01

    Radioligand therapies targeting prostate-specific membrane antigen (PSMA) have been established for the treatment of metastasized castration-resistant prostate cancer (mCRPC) in the last decade and show promising response rates and a favourable toxicity profile. The aim of this study was to evaluate the overall survival (OS) and to identify parameters predicting outcome in mCRPC patients treated with "1"7"7Lu-PSMA-617. Between December 2014 and January 2017, 59 consecutive patients (median age 72 years); interquartile range, (IQR, 66-76 years) with mCRPC, who had been treated with at least one next-generation antihormonal drug as well as chemotherapy, were included in this study. Biochemical response was evaluated using Prostate Cancer Working Group 3 (PCWG3) criteria. Survival was evaluated using Kaplan-Meier estimates and Cox regression proportional hazards model. Toxicity was assessed using Common Toxicity Criteria for Adverse Events (CTCAE). The study was approved by the local ethics committee. The 59 patients were treated with a total of 159 cycles (median 3 cycles, range 1-7) of "1"7"7Lu-PSMA-617 (median dose 6.11 GBq, IQR 5.9-6.3 GBq). The median follow-up was 24 weeks (IQR 15-36 weeks). Follow-up data for at least 12 weeks (PCWG3) were available in 76% (45) of the patients. For outcome results data from all patients treated with at least one cycle were analysed. A decline in prostate-specific antigen (PSA) of ≥50% occurred in 53%, and a decline in PSA of any amount in 91% of patients. The estimated median OS was 32 weeks. An initial alkaline phosphatase (ALP) level <220 U/L and a PSA decline after the first cycle were associated with a longer OS (56 vs. 28 weeks, p < 0.01, and 56 vs. 29 weeks, p = 0.04, respectively). The median estimated PSA progression-free survival (PPFS) was 18 weeks. Only ALP level <220 U/L was significantly associated with a longer PPFS (41 vs. 18 weeks, p < 0.01). A PSA decline after the first cycle of "1"7"7Lu-PSMA-617 and an

  3. Prostate radiation in non-metastatic castrate refractory prostate cancer provides an interesting insight into biology of prostate cancer

    Directory of Open Access Journals (Sweden)

    Pascoe Abigail C

    2012-03-01

    Full Text Available Abstract Background The natural history of non-metastatic castrate refractory prostate cancer is unknown and treatment options are limited. We present a retrospective review of 13 patients with locally advanced or high risk prostate cancer, initially treated with hormone monotherapy and then treated with prostate radiation after becoming castration refractory. Findings Median PSA response following prostate radiation was 67.4%. Median time to biochemical progression following radiotherapy was 15 months and to detection of metastatic disease was 18.5 months. Median survival from castration resistance (to date of death or November 2011 was 60 months, with median survival from RT 42 months. Conclusion Prostate radiation appears to be beneficial even in patients with potential micrometastatic disease, which supports the hypothesis that the primary tumour is important in the progression of prostate cancer. These results are an interesting addition to the literature on the biology of prostate cancer especially as this data is unlikely to be available in the future due to combined prostate radiation and androgen deprivation therapy now being the standard of care.

  4. Differences in treatment patterns among patients with castration-resistant prostate cancer treated by oncologists versus urologists in a US managed care population

    International Nuclear Information System (INIS)

    Engel-Nitz, Nicole M; Alemayehu, Berhanu; Parry, David; Nathan, Faith

    2011-01-01

    Differences in treatment patterns, health care resource utilization, and costs between patients with castration-resistant prostate cancer (CRPC) treated by oncologists and those treated by urologists were examined. Patients aged ≥40 with CRPC were identified using claims from a large US managed health care plan between July 2001 and December 2007. A 6-month baseline period was used to assess patient characteristics. Patients with visits to an urologist, without visits to an oncologist, were assigned to the urology cohort, and patients with visits to an oncologist, with or without visits to an urologist, were assigned to the oncology cohort. Treatment patterns, health care resource utilization, and costs during a variable follow-up period were compared between cohorts using descriptive statistics and Lin’s regression. The urology cohort had fewer comorbid illnesses (P < 0.001) and patients were less likely to have other cancers during baseline (P < 0.001) or to die during follow-up (P = 0.004) compared with the oncology cohort. The oncology cohort patients were significantly more likely to have a claim for hormones (74.5% vs 61.1%; P < 0.001), chemotherapy (46.9% vs 10.2%, P < 0.001), and radiation (22.3% vs 3.7%, P < 0.0001) over follow-up. Mean unadjusted health care costs were higher in the oncology vs the urology cohort (US$31,896 vs US$15,318, respectively; P < 0.001). At 6 years follow-up, cumulative adjusted CRPC-specific costs were significantly higher among patients treated by oncologists with chemotherapy than among patients treated by urologists. CRPC patients treated by oncologists had greater use of hormones, chemotherapy, and radiation; higher percentages of patients with inpatient stays, emergency room, and ambulatory visits; and higher health care costs, than patients treated by urologists

  5. The Stromal Contribution to the Development of Resistance to New Generation Drugs by Castrate Resistant Prostate Cancers

    Science.gov (United States)

    2016-05-01

    and by further increasing their outputs of T and DHT . Finally, in Aim 3, I will attempt to demonstrate in cell co-culture models that Sonic Hh produced...of CRPC through their ability to synthesize T and DHT upon Hh stimulation from metastatic PCa cells, and whether this adaptation can increase...backdoor pathway, which bypasses testosterone (T) as an intermediate for dihydrotestosterone ( DHT ) (3, 9-11). 4 After ADT, recurrence as castration

  6. Small Molecule Antagonists of the Nuclear Androgen Receptor for the Treatment of Castration-Resistant Prostate Cancer.

    Science.gov (United States)

    Johnson, James K; Skoda, Erin M; Zhou, Jianhua; Parrinello, Erica; Wang, Dan; O'Malley, Katherine; Eyer, Benjamin R; Kazancioglu, Mustafa; Eisermann, Kurtis; Johnston, Paul A; Nelson, Joel B; Wang, Zhou; Wipf, Peter

    2016-08-11

    After a high-throughput screening campaign identified thioether 1 as an antagonist of the nuclear androgen receptor, a zone model was developed for structure-activity relationship (SAR) purposes and analogues were synthesized and evaluated in a cell-based luciferase assay. A novel thioether isostere, cyclopropane (1S,2R)-27, showed the desired increased potency and structural properties (stereospecific SAR response, absence of a readily oxidized sulfur atom, low molecular weight, reduced number of flexible bonds and polar surface area, and drug-likeness score) in the prostate-specific antigen luciferase assay in C4-2-PSA-rl cells to qualify as a new lead structure for prostate cancer drug development.

  7. Lactate dehydrogenase predicts combined progression-free survival after sequential therapy with abiraterone and enzalutamide for patients with castration-resistant prostate cancer.

    Science.gov (United States)

    Mori, Keiichiro; Kimura, Takahiro; Onuma, Hajime; Kimura, Shoji; Yamamoto, Toshihiro; Sasaki, Hiroshi; Miki, Jun; Miki, Kenta; Egawa, Shin

    2017-07-01

    An array of clinical issues remains to be resolved for castration-resistant prostate cancer (CRPC), including the sequence of drug use and drug cross-resistance. At present, no clear guidelines are available for the optimal sequence of use of novel agents like androgen-receptor axis-targeted (ARAT) agents, particularly enzalutamide, and abiraterone. This study retrospectively analyzed a total of 69 patients with CRPC treated with sequential therapy using enzalutamide followed by abiraterone or vice versa. The primary outcome measure was the comparative combined progression-free survival (PFS) comprising symptomatic and/or radiographic PFS. Patients were also compared for total prostate-specific antigen (PSA)-PFS, overall survival (OS), and PSA response. The predictors of combined PFS and OS were analyzed with a backward-stepwise multivariate Cox model. Of the 69 patients, 46 received enzalutamide first, followed by abiraterone (E-A group), and 23 received abiraterone, followed by enzalutamide (A-E group). The two groups were not significantly different with regard to basic data, except for hemoglobin values. In a comparison with the E-A group, the A-E group was shown to be associated with better combined PFS in Kaplan-Meier analysis (P = 0.043). Similar results were obtained for total PSA-PFS (P = 0.049), while OS did not differ between groups (P = 0.62). Multivariate analysis demonstrated that pretreatment lactate dehydrogenase (LDH) values and age were significant predictors of longer combined PFS (P < 0.05). Likewise, multivariate analysis demonstrated that pretreatment hemoglobin values and performance status were significant predictors of longer OS (P < 0.05). The results of this study suggested the A-E sequence had longer combined PSA and total PSA-PFS compared to the E-A sequence in patients with CRPC. LDH values in sequential therapy may serve as a predictor of longer combined PFS. © 2017 Wiley Periodicals, Inc.

  8. [14C]Fluciclovine (alias anti-[14C]FACBC) uptake and ASCT2 expression in castration-resistant prostate cancer cells

    International Nuclear Information System (INIS)

    Ono, Masahiro; Oka, Shuntaro; Okudaira, Hiroyuki; Nakanishi, Takeo; Mizokami, Atsushi; Kobayashi, Masato; Schuster, David M.; Goodman, Mark M.; Shirakami, Yoshifumi; Kawai, Keiichi

    2015-01-01

    Introduction: trans-1-Amino-3-[ 18 F]fluorocyclobutanecarboxylic acid ([ 18 F]fluciclovine, also known as anti-[ 18 F]FACBC), is a tracer for positron emission tomography (PET) imaging for detection of tumors such as prostate cancer (PCa). Our previous study showed that ASCT2 (Na + -dependent amino acid transporter (AAT)) mediates fluciclovine uptake in androgen-dependent PCa cells; its expression is influenced by androgen, a key hormone in the progression of primary PCa and castration-resistant prostate cancer (CRPC). In this study, we investigated the uptake mechanisms and feasibility of [ 18 F]fluciclovine for CRPC in the androgen-dependent PCa cell line LNCaP and LNCaP-derivatives LNCaP-SF and LN-REC4. Methods: LNCaP-SF was established after long-term cultivation of LNCaP in steroid-free conditions, and LN-Pre and LN-REC4 were established from LNCaP inoculated in intact and castrated severe combined immunodeficient mice, respectively. Uptake and competitive inhibition experiments were performed with trans-1-amino-3-fluoro[1- 14 C]cyclobutanecarboxylic acid ([ 14 C]fluciclovine) to characterize the involvement of AATs in androgen-dependent PCa (LNCaP and LN-Pre) and CRPC-like (LNCaP-SF and LN-REC4) cell lines. AAT expression was analyzed by Western blotting, and [ 14 C]fluciclovine uptake in androgen-dependent PCa and CRPC-like cell lines were investigated in the presence or absence of dihydrotestosterone (DHT). Results: The contribution of Na + -dependent AATs to [ 14 C]fluciclovine uptake in all cell lines was 88−98%, and [ 14 C]fluciclovine uptake was strongly inhibited by L-glutamine and L-serine, the substrates for Na + -dependent alanine-serine-cysteine (system ASC) AATs, in the presence of Na + . DHT enhanced ASCT2 expression in LNCaP, LN-Pre, and LN-REC4, but not in LNCaP-SF, and the responses of ASCT2 expression to DHT correlated with [ 14 C]fluciclovine uptake. Conclusions: System ASC, especially ASCT2, could play a major role in [ 14 C

  9. Targeting the interleukin-11 receptor α in metastatic prostate cancer: A first-in-man study.

    Science.gov (United States)

    Pasqualini, Renata; Millikan, Randall E; Christianson, Dawn R; Cardó-Vila, Marina; Driessen, Wouter H P; Giordano, Ricardo J; Hajitou, Amin; Hoang, Anh G; Wen, Sijin; Barnhart, Kirstin F; Baze, Wallace B; Marcott, Valerie D; Hawke, David H; Do, Kim-Anh; Navone, Nora M; Efstathiou, Eleni; Troncoso, Patricia; Lobb, Roy R; Logothetis, Christopher J; Arap, Wadih

    2015-07-15

    Receptors in tumor blood vessels are attractive targets for ligand-directed drug discovery and development. The authors have worked systematically to map human endothelial receptors ("vascular zip codes") within tumors through direct peptide library selection in cancer patients. Previously, they selected a ligand-binding motif to the interleukin-11 receptor alpha (IL-11Rα) in the human vasculature. The authors generated a ligand-directed, peptidomimetic drug (bone metastasis-targeting peptidomimetic-11 [BMTP-11]) for IL-11Rα-based human tumor vascular targeting. Preclinical studies (efficacy/toxicity) included evaluating BMTP-11 in prostate cancer xenograft models, drug localization, targeted apoptotic effects, pharmacokinetic/pharmacodynamic analyses, and dose-range determination, including formal (good laboratory practice) toxicity across rodent and nonhuman primate species. The initial BMTP-11 clinical development also is reported based on a single-institution, open-label, first-in-class, first-in-man trial (National Clinical Trials number NCT00872157) in patients with metastatic, castrate-resistant prostate cancer. BMTP-11 was preclinically promising and, thus, was chosen for clinical development in patients. Limited numbers of patients who had castrate-resistant prostate cancer with osteoblastic bone metastases were enrolled into a phase 0 trial with biology-driven endpoints. The authors demonstrated biopsy-verified localization of BMTP-11 to tumors in the bone marrow and drug-induced apoptosis in all patients. Moreover, the maximum tolerated dose was identified on a weekly schedule (20-30 mg/m(2) ). Finally, a renal dose-limiting toxicity was determined, namely, dose-dependent, reversible nephrotoxicity with proteinuria and casts involving increased serum creatinine. These biologic endpoints establish BMTP-11 as a targeted drug candidate in metastatic, castrate-resistant prostate cancer. Within a larger discovery context, the current findings indicate that

  10. The {sup 68}Ga/{sup 177}Lu theragnostic concept in PSMA targeting of castration-resistant prostate cancer: correlation of SUV{sub max} values and absorbed dose estimates

    Energy Technology Data Exchange (ETDEWEB)

    Scarpa, Lorenza; Buxbaum, Sabine; Kendler, Dorota; Decristoforo, Clemens; Uprimny, Christian; Virgolini, Irene [Medical University Innsbruck, Department of Nuclear Medicine, Innsbruck (Austria); Fink, Katharina [Medical University Innsbruck, Department of Nuclear Medicine, Innsbruck (Austria); Medical University of Innsbruck, Department of Radiotherapy / Radiation Oncology, Innsbruck (Austria); Bektic, Jasmin; Horninger, Wolfgang [Medical University of Innsbruck, Department of Urology, Innsbruck (Austria); Gruber, Leonhard [Medical University of Innsbruck, Department of Radiology, Innsbruck (Austria); Lukas, Peter [Medical University of Innsbruck, Department of Radiotherapy / Radiation Oncology, Innsbruck (Austria)

    2017-05-15

    A targeted theragnostic approach based on increased expression of prostate-specific membrane antigen (PSMA) on PC cells is an attractive treatment option for patients with metastatic castration-resistant prostate cancer (mCRPC). Ten consecutive mCRPC patients were selected for {sup 177}Lu-PSMA617 therapy on the basis of PSMA-targeted {sup 68}Ga-PSMA-HBED-CC PET/CT diagnosis showing extensive and progressive tumour load. Following dosimetry along with the first therapy cycle restaging ({sup 68}Ga-PSMA-HBED-CC and {sup 18}F-NaF PET/CT) was performed after 2 and 3 therapy cycles (each 6.1 ± 0.3 GBq, range 5.4-6.5 GBq) given intravenously over 30 minutes, 9 ± 1 weeks apart. PET/CT scans were compared to {sup 177}Lu-PSMA617 24-hour whole-body scans and contrast-enhanced dual-phase CT. Detailed comparison of SUVmax values and absorbed tumour doses was performed. {sup 177}Lu-PSMA617 dosimetry indicated high tumour doses for skeletal (3.4 ± 1.9 Gy/GBq; range 1.1-7.2 Gy/GBq), lymph node (2.6 ± 0.4 Gy/GBq; range 2.3-2.9 Gy/GBq) as well as liver (2.4 ± 0.8 Gy/GBq; range 1.7-3.3 Gy/GBq) metastases whereas the dose for tissues/organs was acceptable in all patients for an intention-to-treat activity of 18 ± 0.3 GBq. Three patients showed partial remission, three mixed response, one stable and three progressive disease. Decreased {sup 177}Lu-PSMA617 and {sup 68}Ga-PSMA-HBED-CC uptake (mean SUVmax values 20.2 before and 15.0 after 2 cycles and 11.5 after 3 cycles, p < 0.05) was found in 41/54 skeletal lesions, 12/13 lymph node metastases, 3/5 visceral metastases and 4/4 primary PC lesions. Due to substantial individual variance, dosimetry is mandatory for a patient-specific approach following {sup 177}Lu-PSMA617 therapy. Higher activities and/or shorter treatment intervals should be applied in a larger prospective study. (orig.)

  11. Restoration of the cellular secretory milieu overrides androgen dependence of in vivo generated castration resistant prostate cancer cells overexpressing the androgen receptor.

    Science.gov (United States)

    Patki, Mugdha; Huang, Yanfang; Ratnam, Manohar

    2016-07-22

    It is believed that growth of castration resistant prostate cancer (CRPC) cells is enabled by sensitization to minimal residual post-castrate androgen due to overexpression of the androgen receptor (AR). Evidence is derived from androgen-induced colony formation in the absence of cell-secreted factors or from studies involving forced AR overexpression in hormone-dependent cells. On the other hand, standard cell line models established from CRPC patient tumors (e.g., LNCaP and VCaP) are hormone-dependent and require selection pressure in castrated mice to re-emerge as CRPC cells and the resulting tumors then tend to be insensitive to the androgen antagonist enzalutamide. Therefore, we examined established CRPC model cells produced by castration of mice bearing hormone-dependent cell line xenografts including CRPC cells overexpressing full-length AR (C4-2) or co-expressing wtAR and splice-variant AR-V7 that is incapable of ligand binding (22Rv1). In standard colony formation assays, C4-2 cells were shown to be androgen-dependent and sensitive to enzalutamide whereas 22Rv1 cells were incapable of colony formation under identical conditions. However, both C4-2 and 22Rv1 cells formed colonies in conditioned media derived from the same cells or from HEK293 fibroblasts that were proven to lack androgenic activity. This effect was (i) not enhanced by androgen, (ii) insensitive to enzalutamide, (iii) dependent on AR (in C4-2) and on AR-V7 and wtAR (in 22Rv1) and (iv) sensitive to inhibitors of several signaling pathways, similar to androgen-stimulation. Therefore, during progression to CRPC in vivo, coordinate cellular changes accompanying overexpression of AR may enable cooperation between hormone-independent activity of AR and actions of cellular secretory factors to completely override androgen-dependence and sensitivity to drugs targeting hormonal factors. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Comprehensive Profiling of the Androgen Receptor in Liquid Biopsies from Castration-resistant Prostate Cancer Reveals Novel Intra-AR Structural Variation and Splice Variant Expression Patterns.

    Science.gov (United States)

    De Laere, Bram; van Dam, Pieter-Jan; Whitington, Tom; Mayrhofer, Markus; Diaz, Emanuela Henao; Van den Eynden, Gert; Vandebroek, Jean; Del-Favero, Jurgen; Van Laere, Steven; Dirix, Luc; Grönberg, Henrik; Lindberg, Johan

    2017-08-01

    Expression of the androgen receptor splice variant 7 (AR-V7) is associated with poor response to second-line endocrine therapy in castration-resistant prostate cancer (CRPC). However, a large fraction of nonresponding patients are AR-V7-negative. To investigate if a comprehensive liquid biopsy-based AR profile may improve patient stratification in the context of second-line endocrine therapy. Peripheral blood was collected from patients with CRPC (n=30) before initiation of a new line of systemic therapy. We performed profiling of circulating tumour DNA via low-pass whole-genome sequencing and targeted sequencing of the entire AR gene, including introns. Targeted RNA sequencing was performed on enriched circulating tumour cell fractions to assess the expression levels of seven AR splice variants (ARVs). Somatic AR variations, including copy-number alterations, structural variations, and point mutations, were combined with ARV expression patterns and correlated to clinicopathologic parameters. Collectively, any AR perturbation, including ARV, was detected in 25/30 patients. Surprisingly, intra-AR structural variation was present in 15/30 patients, of whom 14 expressed ARVs. The majority of ARV-positive patients expressed multiple ARVs, with AR-V3 the most abundantly expressed. The presence of any ARV was associated with progression-free survival after second-line endocrine treatment (hazard ratio 4.53, 95% confidence interval 1.424-14.41; p=0.0105). Six out of 17 poor responders were AR-V7-negative, but four carried other AR perturbations. Comprehensive AR profiling, which is feasible using liquid biopsies, is necessary to increase our understanding of the mechanisms underpinning resistance to endocrine treatment. Alterations in the androgen receptor are associated with endocrine treatment outcomes. This study demonstrates that it is possible to identify different types of alterations via simple blood draws. Follow-up studies are needed to determine the effect of

  13. Treatment of Bone Metastases with Radium-223 in Patients with Castration Resistant Prostate Cancer (CRPC): Alternative or Complementary to Innovative Molecular Therapies?

    International Nuclear Information System (INIS)

    Bombardieri, Emilio

    2013-01-01

    The skeletal metastatic disease is a real clinical problem. Approximately 70% of patients with prostate or breast cancer and 35% of those with advanced lung, thyroid, and kidney cancers will develop skeletal metastases, which cause considerable morbidity. Several options are available for treatment, to be used either alone or in various combinations: hormones in case of hormone-sensitive tumours, chemotherapy, biphosphonates, external beam radiation therapy, surgery (in pathologic or impending fracture), bone-seeking radiopharmceuticals, and also molecular therapies. Focusing our attention to patients with prostate cancer, 50% of patients with bone metastases develop skeletal related events (SREs) such as: severe pain, pathologic fractures, spinal compression syndrome, malignant hypercalcemia, bone marrow suppression. All these SREs require adequate therapy since generally determine several functional impairments and worsen the prognosis. It is well known that skeletal complications reduce the quality of life affecting different aspects, physical, functional end emotional. SREs are associated also with lower survival

  14. Inhibition of Androgen Receptor Function and Level in Castration-Resistant Prostate Cancer Cells by 2-[(isoxazol-4-ylmethyl)thio]-1-(4-phenylpiperazin-1-yl)ethanone.

    Science.gov (United States)

    Masoodi, Khalid Z; Eisermann, Kurtis; Yang, Zhenyu; Dar, Javid A; Pascal, Laura E; Nguyen, Minh; O'Malley, Katherine; Parrinello, Erica; Feturi, Firuz G; Kenefake, Alex N; Nelson, Joel B; Johnston, Paul A; Wipf, Peter; Wang, Zhou

    2017-10-01

    The androgen receptor (AR) plays a critical role in the development of castration-resistant prostate cancer (CRPC) as well as in the resistance to the second-generation AR antagonist enzalutamide and the selective inhibitor of cytochrome P450 17A1 (CYP17A1) abiraterone. Novel agents targeting AR may inhibit the growth of prostate cancer cells resistant to enzalutamide and/or abiraterone. Through a high-throughput/high-content screening of a 220,000-member small molecule library, we have previously identified 2-[(isoxazol-4-ylmethyl)thio]-1-(4-phenylpiperazin-1-yl)ethanone (IMTPPE) (SID 3712502) as a novel small molecule capable of inhibiting AR transcriptional activity and protein level in C4-2 prostate cancer cells. In this study, we show that IMTPPE inhibits AR-target gene expression using real-time polymerase chain reaction, Western blot, and luciferase assays. IMTPPE inhibited proliferation of AR-positive, but not AR-negative, prostate cancer cells in culture. IMTPPE inhibited the transcriptional activity of a mutant AR lacking the ligand-binding domain (LBD), indicating that IMTPPE inhibition of AR is independent of the LBD. Furthermore, animal studies showed that IMTPPE inhibited the growth of 22Rv1 xenograft tumor, a model for enzalutamide-resistant prostate cancer. These findings suggest that IMTPPE is a potential lead compound for developing clinical candidates for the treatment of CRPC, including those resistant to enzalutamide. Copyright © 2017 Endocrine Society.

  15. Beyond the androgen receptor II: New approaches to understanding and treating metastatic prostate cancer; Report from the 2017 Coffey-Holden Prostate Cancer Academy Meeting.

    Science.gov (United States)

    Miyahira, Andrea K; Cheng, Heather H; Abida, Wassim; Ellis, Leigh; Harshman, Lauren C; Spratt, Daniel E; Simons, Jonathan W; Pienta, Kenneth J; Soule, Howard R

    2017-11-01

    The 2017 Coffey-Holden Prostate Cancer Academy (CHPCA) Meeting, "Beyond the Androgen Receptor II: New Approaches to Understanding and Treating Metastatic Prostate Cancer," was held in Carlsbad, California from June 14-17, 2017. The CHPCA is an annual scientific conference hosted by the Prostate Cancer Foundation (PCF) that is uniquely designed to produce extensive and constructive discussions on the most urgent and impactful topics concerning research into the biology and treatment of metastatic prostate cancer. The 2017 CHPCA Meeting was the 5th meeting in this annual series and was attended by 71 investigators focused on prostate cancer and a variety of other fields including breast and ovarian cancer. The discussions at the meeting were concentrated on topics areas including: mechanisms and therapeutic approaches for molecular subclasses of castrate resistant prostate cancer (CRPC), the epigenetic landscape of prostate cancer, the role of DNA repair gene mutations, advancing the use of germline genetics in clinical practice, radionuclides for imaging and therapy, advances in molecular imaging, and therapeutic strategies for successful use of immunotherapy in advanced prostate cancer. This article reviews the presentations and discussions from the 2017 CHPCA Meeting in order to disseminate this knowledge and accelerate new biological understandings and advances in the treatment of patients with metastatic prostate cancer. © 2017 Wiley Periodicals, Inc.

  16. Melatonin Inhibits Androgen Receptor Splice Variant-7 (AR-V7-Induced Nuclear Factor-Kappa B (NF-κB Activation and NF-κB Activator-Induced AR-V7 Expression in Prostate Cancer Cells: Potential Implications for the Use of Melatonin in Castration-Resistant Prostate Cancer (CRPC Therapy

    Directory of Open Access Journals (Sweden)

    Vincent Wing Sun Liu

    2017-05-01

    Full Text Available A major current challenge in the treatment of advanced prostate cancer, which can be initially controlled by medical or surgical castration, is the development of effective, safe, and affordable therapies against progression of the disease to the stage of castration resistance. Here, we showed that in LNCaP and 22Rv1 prostate cancer cells transiently overexpressing androgen receptor splice variant-7 (AR-V7, nuclear factor-kappa B (NF-κB was activated and could result in up-regulated interleukin (IL-6 gene expression, indicating a positive interaction between AR-V7 expression and activated NF-κB/IL-6 signaling in castration-resistant prostate cancer (CRPC pathogenesis. Importantly, both AR-V7-induced NF-κB activation and IL-6 gene transcription in LNCaP and 22Rv1 cells could be inhibited by melatonin. Furthermore, stimulation of AR-V7 mRNA expression in LNCaP cells by betulinic acid, a pharmacological NF-κB activator, was reduced by melatonin treatment. Our data support the presence of bi-directional positive interactions between AR-V7 expression and NF-κB activation in CRPC pathogenesis. Of note, melatonin, by inhibiting NF-κB activation via the previously-reported MT1 receptor-mediated antiproliferative pathway, can disrupt these bi-directional positive interactions between AR-V7 and NF-κB and thereby delay the development of castration resistance in advanced prostate cancer. Apparently, this therapeutic potential of melatonin in advanced prostate cancer/CRPC management is worth translation in the clinic via combined androgen depletion and melatonin repletion.

  17. Melatonin Inhibits Androgen Receptor Splice Variant-7 (AR-V7)-Induced Nuclear Factor-Kappa B (NF-κB) Activation and NF-κB Activator-Induced AR-V7 Expression in Prostate Cancer Cells: Potential Implications for the Use of Melatonin in Castration-Resistant Prostate Cancer (CRPC) Therapy.

    Science.gov (United States)

    Liu, Vincent Wing Sun; Yau, Wing Lung; Tam, Chun Wai; Yao, Kwok-Ming; Shiu, Stephen Yuen Wing

    2017-05-31

    A major current challenge in the treatment of advanced prostate cancer, which can be initially controlled by medical or surgical castration, is the development of effective, safe, and affordable therapies against progression of the disease to the stage of castration resistance. Here, we showed that in LNCaP and 22Rv1 prostate cancer cells transiently overexpressing androgen receptor splice variant-7 (AR-V7), nuclear factor-kappa B (NF-κB) was activated and could result in up-regulated interleukin ( IL ) -6 gene expression, indicating a positive interaction between AR-V7 expression and activated NF-κB/IL-6 signaling in castration-resistant prostate cancer (CRPC) pathogenesis. Importantly, both AR-V7-induced NF-κB activation and IL-6 gene transcription in LNCaP and 22Rv1 cells could be inhibited by melatonin. Furthermore, stimulation of AR-V7 mRNA expression in LNCaP cells by betulinic acid, a pharmacological NF-κB activator, was reduced by melatonin treatment. Our data support the presence of bi-directional positive interactions between AR-V7 expression and NF-κB activation in CRPC pathogenesis. Of note, melatonin, by inhibiting NF-κB activation via the previously-reported MT₁ receptor-mediated antiproliferative pathway, can disrupt these bi-directional positive interactions between AR-V7 and NF-κB and thereby delay the development of castration resistance in advanced prostate cancer. Apparently, this therapeutic potential of melatonin in advanced prostate cancer/CRPC management is worth translation in the clinic via combined androgen depletion and melatonin repletion.

  18. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer.

    Science.gov (United States)

    Fizazi, Karim; Tran, NamPhuong; Fein, Luis; Matsubara, Nobuaki; Rodriguez-Antolin, Alfredo; Alekseev, Boris Y; Özgüroğlu, Mustafa; Ye, Dingwei; Feyerabend, Susan; Protheroe, Andrew; De Porre, Peter; Kheoh, Thian; Park, Youn C; Todd, Mary B; Chi, Kim N

    2017-07-27

    Abiraterone acetate, a drug that blocks endogenous androgen synthesis, plus prednisone is indicated for metastatic castration-resistant prostate cancer. We evaluated the clinical benefit of abiraterone acetate plus prednisone with androgen-deprivation therapy in patients with newly diagnosed, metastatic, castration-sensitive prostate cancer. In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 1199 patients to receive either androgen-deprivation therapy plus abiraterone acetate (1000 mg daily, given once daily as four 250-mg tablets) plus prednisone (5 mg daily) (the abiraterone group) or androgen-deprivation therapy plus dual placebos (the placebo group). The two primary end points were overall survival and radiographic progression-free survival. After a median follow-up of 30.4 months at a planned interim analysis (after 406 patients had died), the median overall survival was significantly longer in the abiraterone group than in the placebo group (not reached vs. 34.7 months) (hazard ratio for death, 0.62; 95% confidence interval [CI], 0.51 to 0.76; P<0.001). The median length of radiographic progression-free survival was 33.0 months in the abiraterone group and 14.8 months in the placebo group (hazard ratio for disease progression or death, 0.47; 95% CI, 0.39 to 0.55; P<0.001). Significantly better outcomes in all secondary end points were observed in the abiraterone group, including the time until pain progression, next subsequent therapy for prostate cancer, initiation of chemotherapy, and prostate-specific antigen progression (P<0.001 for all comparisons), along with next symptomatic skeletal events (P=0.009). These findings led to the unanimous recommendation by the independent data and safety monitoring committee that the trial be unblinded and crossover be allowed for patients in the placebo group to receive abiraterone. Rates of grade 3 hypertension and hypokalemia were higher in the abiraterone group. The addition of abiraterone

  19. Locoregional symptoms in patients with de novo metastatic prostate cancer: Morbidity, management, and disease outcome.

    Science.gov (United States)

    Patrikidou, Anna; Brureau, Laurent; Casenave, Julien; Albiges, Laurence; Di Palma, Mario; Patard, Jean-Jacques; Baumert, Hervé; Blanchard, Pierre; Bossi, Alberto; Kitikidou, Kyriaki; Massard, Christophe; Fizazi, Karim; Blanchet, Pascal; Loriot, Yohann

    2015-05-01

    The paradigm change observed over the last few years in several solid tumors emphasizes the value of locoregional treatment in the presence of metastatic disease, currently ignored in de novo prostate cancer (CaP). We investigated the effect of the primary tumor that is left untreated on prostate cancer-specific morbidity and mortality, time to castration resistance, and overall survival (OS). We performed a bicentric cohort study. The overall population included de novo metastatic CaP managed at the Genito-Urinary Oncology Unit of the Gustave Roussy Institute and the Urology Clinic of the University Hospital of Pointe-à-Pitre, France. Descriptive statistical and outcome analyses were performed in the overall cohort and also separately in the N+M0 and M+subgroups. The overall cohort included 263 patients. Approximately two-thirds of patients (64%) presented with locoregional symptoms at diagnosis, and 78% throughout the disease. Of the symptomatic patients, 59% required a locoregional procedure. Median OS of patients with locoregional symptoms at diagnosis was shorter than in those who were asymptomatic (47 vs. 86 mo, P = 0.0007); this difference was maintained in the N+M0 and M+subgroups. Median OS and time to castration resistance showed a nonsignificant trend in favor of patients undergoing a locoregional treatment at diagnosis. The presence of symptoms due to locoregional disease in de novo metastatic CaP entails significant morbidity and even mortality and requires active management. Randomized prospective trials are needed to evaluate the role of initial definite locoregional treatment in these patients. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. Narrative medicine in metastatic prostate cancer reveals ways to improve patient awareness & quality of care.

    Science.gov (United States)

    Vincentis, Giuseppe De; Monari, Fabio; Baldari, Sergio; Salgarello, Matteo; Frantellizzi, Viviana; Salvi, Elisabetta; Reale, Luigi; Napolitano, Silvia; Conti, Giario; Cortesi, Enrico

    2018-06-15

    To describe the journey of patients with metastatic castration-resistant prostate cancer (mCRPC) in treatment with radium-223. A multiperspective analysis was performed using narrative medicine in four Italian centers. The substantial impact of mCRPC on quality of life through all phases of the disease was described. After an initial lack of awareness of the disease or denial of its effects, symptoms of pain, fatigue and side effects often led to sadness, fear and loneliness. The majority underwent radium-223 therapy positively, restoring their quality of life and routine activities. Using narrative medicine, the importance of a patient-centered approach in the pathway of care for patients with mCRPC through all the stages of the disease was highlighted.

  1. Methylated Glutathione S-transferase 1 (mGSTP1) is a potential plasma free DNA epigenetic marker of prognosis and response to chemotherapy in castrate-resistant prostate cancer.

    Science.gov (United States)

    Mahon, K L; Qu, W; Devaney, J; Paul, C; Castillo, L; Wykes, R J; Chatfield, M D; Boyer, M J; Stockler, M R; Marx, G; Gurney, H; Mallesara, G; Molloy, P L; Horvath, L G; Clark, S J

    2014-10-28

    Glutathione S-transferase 1 (GSTP1) inactivation is associated with CpG island promoter hypermethylation in the majority of prostate cancers (PCs). This study assessed whether the level of circulating methylated GSTP1 (mGSTP1) in plasma DNA is associated with chemotherapy response and overall survival (OS). Plasma samples were collected prospectively from a Phase I exploratory cohort of 75 men with castrate-resistant PC (CRPC) and a Phase II independent validation cohort (n=51). mGSTP1 levels in free DNA were measured using a sensitive methylation-specific PCR assay. The Phase I cohort identified that detectable baseline mGSTP1 DNA was associated with poorer OS (HR, 4.2 95% CI 2.1-8.2; P<0.0001). A decrease in mGSTP1 DNA levels after cycle 1 was associated with a PSA response (P=0.008). In the Phase II cohort, baseline mGSTP1 DNA was a stronger predictor of OS than PSA change after 3 months (P=0.02). Undetectable plasma mGSTP1 after one cycle of chemotherapy was associated with PSA response (P=0.007). We identified plasma mGSTP1 DNA as a potential prognostic marker in men with CRPC as well as a potential surrogate therapeutic efficacy marker for chemotherapy and corroborated these findings in an independent Phase II cohort. Prospective Phase III assessment of mGSTP1 levels in plasma DNA is now warranted.

  2. Low-dose prednisolone in first-line docetaxel for patients with metastatic castration-resistant prostate cancer

    DEFF Research Database (Denmark)

    Kongsted, Per; Svane, Inge Marie; Lindberg, Henriette

    2015-01-01

    incidence of peripheral edema (32% vs. 15%, Pneutropenia in this group (25% vs. 10%, P...% CI: 0.76-1.26, P = 0.89, Cox proportional hazard regression model). CONCLUSIONS: Coadministration of low-dose P reduced the incidence of peripheral edema, grade 3 nonhematological toxicity, and the risk of being admitted owing to febrile neutropenia during treatment with D. Adjusted survival analysis...

  3. Cabazitaxel Versus Docetaxel As First-Line Therapy for Patients With Metastatic Castration-Resistant Prostate Cancer

    DEFF Research Database (Denmark)

    Oudard, Stéphane; Fizazi, Karim; Sengeløv, Lisa

    2017-01-01

    of grade 3 or 4 treatment-emergent adverse events were 41.2%, 60.1%, and 46.0% for C20, C25, and D75, respectively. Febrile neutropenia, diarrhea, and hematuria were more frequent with C25; peripheral neuropathy, peripheral edema, alopecia, and nail disorders were more frequent with D75. Conclusion C20...

  4. Does the Androgen Receptor (AR)-Regulated Map Kinase Phosphatase 1 (MKP-1) Enhance Castration-Resistant Prostate Cancer Survival under Therapeutic Stress?

    Science.gov (United States)

    2016-03-01

    in breast cancer models, and is inversely associated with apoptosis in preclinical prostate cancer models. Androgen and glucocorticoid signaling can...with apoptosis in preclinical prostate cancer models. Androgen and glucocorticoid signaling can induce MKP-1 expression; as mCRPC remains driven by

  5. Weekly, low-dose docetaxel combined with estramustine for Japanese castration-resistant prostate cancer: its efficacy and safety profile compared with tri-weekly standard-dose treatment.

    Science.gov (United States)

    Nakai, Yasutomo; Nishimura, Kazuo; Nakayama, Masashi; Uemura, Motohide; Takayama, Hitoshi; Nonomura, Norio; Tsujimura, Akira

    2014-02-01

    We retrospectively investigated the efficacy and safety profile of weekly low-dose docetaxel (DTX) with estramustine in comparison with triweekly standard-dose DTX treatment for Japanese patients with castration-resistant prostate cancer (CRPC). Between April 2002 and January 2011, 75 CRPC patients were treated with triweekly DTX (60-75 mg/m(2) every 3 weeks) (standard-dose group), and 76 CRPC patients were treated with weekly low-dose DTX (20-30 mg/m(2) on days 2 and 9 with estramustine 560 mg on days 1-3 and 8-10) every 3 weeks (low-dose group). Prostate-specific antigen (PSA) response and progression-free and overall survival were analyzed in each group. Median serum PSA level of the standard-dose group and low-dose group was 25.0 and 35.5 ng/ml, respectively. In the standard-dose and low-dose groups, 57.8 and 65.2 % of patients, respectively, achieved a PSA decline ≥ 50 %. There was no significant difference in either median time to progression between the standard-dose group (10.0 months) and low-dose group (7.1 months) or in median duration of survival between the standard-dose group (24.2 months) and low-dose group (30.6 months). Multivariate analysis with a Cox proportional hazards regression model showed that DTX treatment protocol did not influence the risk of death. Incidences of grade 3-4 neutropenia, febrile neutropenia, and thrombocytopenia were significantly higher in the standard-dose versus low-dose group (58.7 vs. 7.9 %, 16.0 vs. 3.9 %, and 8.0 vs. 0 %, respectively). For Japanese CRPC patients, weekly low-dose DTX combined with estramustine has similar efficacy to standard-dose DTX but with fewer adverse events.

  6. Treatment strategy for metastatic prostate cancer with extremely high PSA level: reconsidering the value of vintage therapy.

    Science.gov (United States)

    Yamada, Yasutaka; Sakamoto, Shinichi; Amiya, Yoshiyasu; Sasaki, Makoto; Shima, Takayuki; Komiya, Akira; Suzuki, Noriyuki; Akakura, Koichiro; Ichikawa, Tomohiko; Nakatsu, Hiroomi

    2018-05-04

    The prognostic significance of initial prostate-specific antigen (PSA) level for metastatic prostate cancer remains uncertain. We investigated the differences in prognosis and response to hormonal therapies of metastatic prostate cancer patients according to initial PSA levels. We analyzed 184 patients diagnosed with metastatic prostate cancer and divided them into three PSA level groups as follows: low (PSA progression-free survival (PFS) for first-line ADT and overall survival (OS) within each of the three groups. Furthermore, we analyzed response to antiandrogen withdrawal (AW) and alternative antiandrogen (AA) therapies after development of castration-resistant prostate cancer (CRPC). No significant differences in OS were observed among the three groups (P = 0.654). Patients with high PSA levels had significantly short PFS for first-line ADT (P = 0.037). Conversely, patients in the high PSA level group had significantly longer PFS when treated with AW than those in the low PSA level group (P = 0.047). Furthermore, patients with high PSA levels had significantly longer PFS when provided with AA therapy (P = 0.049). PSA responders to AW and AA therapies had significantly longer survival after CRPC development than nonresponders (P = 0.011 and P PSA level predicted favorable response to vintage sequential ADT and AW. The current data suggest a novel aspect of extremely high PSA value as a favorable prognostic marker after development of CRPC.

  7. BET inhibitors in metastatic prostate cancer: therapeutic implications and rational drug combinations.

    Science.gov (United States)

    Markowski, Mark C; De Marzo, Angelo M; Antonarakis, Emmanuel S

    2017-12-01

    The bromodomain and extra-terminal (BET) family of proteins are epigenetic readers of acetylated histones regulating a vast network of protein expression across many different cancers. Therapeutic targeting of BET is an attractive area of clinical development for metastatic castration-resistant prostate cancer (mCRPC), particularly due to its putative effect on c-MYC expression and its interaction with the androgen receptor (AR). Areas covered: We speculate that a combination approach using inhibitors of BET proteins (BETi) with other targeted therapies may be required to improve the therapeutic index of BET inhibition in the management of prostate cancer. Preclinical data has identified several molecular targets that may enhance the effect of BET inhibition in the clinic. This review will summarize the known preclinical data implicating BET as an important therapeutic target in advanced prostate cancer, highlight the ongoing clinical trials targeting this protein family, and speculate on rationale combination strategies using BETi together with other agents in prostate cancer. A literature search using Pubmed was performed for this review. Expert opinion: Use of BETi in the treatment of mCRPC patients may require the addition of a second novel agent.

  8. Multimodal actions of the phytochemical sulforaphane suppress both AR and AR-V7 in 22Rv1 cells: Advocating a potent pharmaceutical combination against castration-resistant prostate cancer.

    Science.gov (United States)

    Khurana, Namrata; Kim, Hogyoung; Chandra, Partha K; Talwar, Sudha; Sharma, Pankaj; Abdel-Mageed, Asim B; Sikka, Suresh C; Mondal, Debasis

    2017-11-01

    Prostate cancer (PCa) cells expressing full-length androgen receptor (AR-FL) are susceptible to androgen deprivation therapy (ADT). However, outgrowth of castration-resistant prostate cancer (CRPC) can occur due to the expression of constitutively active (ligand-independent) AR splice variants, particularly AR-V7. We previously demonstrated that sulforaphane (SFN), an isothiocyanate phytochemical, can decrease AR-FL levels in the PCa cell lines, LNCaP and C4-2B. Here, we examined the efficacy of SFN in targeting both AR-FL and AR-V7 in the CRPC cell line, CWR22Rv1 (22Rv1). MTT cell viability, wound-heal assay, and colony forming unit (CFU) measurements revealed that 22Rv1 cells are resistant to the anti-androgen, enzalutamide (ENZ). However, co-exposure to SFN sensitized these cells to the potent anticancer effects of ENZ (PAR-FL and AR-V7 levels, and immunofluorescence microscopy (IFM) depicted decreased AR in both cytoplasm and nucleus with SFN treatment. SFN increased both ubiquitination and proteasomal activity in 22Rv1 cells. Studies using a protein synthesis inhibitor (cycloheximide) or a proteasomal inhibitor (MG132) indicated that SFN increases both ubiquitin-mediated aggregation and subsequent proteasomal-degradation of AR proteins. Previous studies reported that SFN inhibits the chaperone activity of heat-shock protein 90 (Hsp90) and induces the nuclear factor erythroid-2-like 2 (Nrf2) transcription factor. Therefore, we investigated whether the Hsp90 inhibitor, ganetespib (G) or the Nrf2 activator, bardoxolone methyl (BM) can similarly suppress AR levels in 22Rv1 cells. Low doses of G and BM, alone or in combination, decreased both AR-FL and AR-V7 levels, and combined exposure to G+BM sensitized 22Rv1 cells to ENZ. Therefore, adjunct treatment with the phytochemical SFN or a safe pharmaceutical combination of G+BM may be effective against CRPC cells, especially those expressing AR-V7.

  9. Bone stroma-derived cells change coregulators recruitment to androgen receptor and decrease cell proliferation in androgen-sensitive and castration-resistant prostate cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Villagran, Marcelo A.; Gutierrez-Castro, Francisco A.; Pantoja, Diego F.; Alarcon, Jose C.; Fariña, Macarena A.; Amigo, Romina F.; Muñoz-Godoy, Natalia A. [Molecular Endocrinology and Oncology Laboratory, University of Concepcion, Concepcion (Chile); Pinilla, Mabel G. [Department of Medical Specialties, School of Medicine, University of Concepcion, Concepcion (Chile); Peña, Eduardo A.; Gonzalez-Chavarria, Ivan; Toledo, Jorge R.; Rivas, Coralia I.; Vera, Juan C. [Department of Physiopathology, School of Biological Sciences, University of Concepcion, Concepcion (Chile); McNerney, Eileen M. [Molecular Endocrinology and Oncology Laboratory, University of Concepcion, Concepcion (Chile); Onate, Sergio A., E-mail: sergio.onate@udec.cl [Molecular Endocrinology and Oncology Laboratory, University of Concepcion, Concepcion (Chile); Department of Medical Specialties, School of Medicine, University of Concepcion, Concepcion (Chile); Department of Urology, State University of New York at Buffalo, NY (United States)

    2015-11-27

    Prostate cancer (CaP) bone metastasis is an early event that remains inactive until later-stage progression. Reduced levels of circulating androgens, due to andropause or androgen deprivation therapies, alter androgen receptor (AR) coactivator expression. Coactivators shift the balance towards enhanced AR-mediated gene transcription that promotes progression to androgen-resistance. Disruptions in coregulators may represent a molecular switch that reactivates latent bone metastasis. Changes in AR-mediated transcription in androgen-sensitive LNCaP and androgen-resistant C4-2 cells were analyzed for AR coregulator recruitment in co-culture with Saos-2 and THP-1. The Saos-2 cell line derived from human osteosarcoma and THP-1 cell line representing human monocytes were used to display osteoblast and osteoclast activity. Increased AR activity in androgen-resistant C4-2 was due to increased AR expression and SRC1/TIF2 recruitment and decreased SMRT/NCoR expression. AR activity in both cell types was decreased over 90% when co-cultured with Saos-2 or THP-1 due to dissociation of AR from the SRC1/TIF2 and SMRT/NCoR coregulators complex, in a ligand-dependent and cell-type specific manner. In the absence of androgens, Saos-2 decreased while THP-1 increased proliferation of LNCaP cells. In contrast, both Saos-2 and THP-1 decreased proliferation of C4-2 in absence and presence of androgens. Global changes in gene expression from both CaP cell lines identified potential cell cycle and androgen regulated genes as mechanisms for changes in cell proliferation and AR-mediated transactivation in the context of bone marrow stroma cells. - Highlights: • Decreased corepressor expression change AR in androgen-resistance prostate cancer. • Bone stroma-derived cells change AR coregulator recruitment in prostate cancer. • Bone stroma cells change cell proliferation in androgen-resistant cancer cells. • Global gene expression in CaP cells is modified by bone stroma cells in co

  10. Bone stroma-derived cells change coregulators recruitment to androgen receptor and decrease cell proliferation in androgen-sensitive and castration-resistant prostate cancer cells

    International Nuclear Information System (INIS)

    Villagran, Marcelo A.; Gutierrez-Castro, Francisco A.; Pantoja, Diego F.; Alarcon, Jose C.; Fariña, Macarena A.; Amigo, Romina F.; Muñoz-Godoy, Natalia A.; Pinilla, Mabel G.; Peña, Eduardo A.; Gonzalez-Chavarria, Ivan; Toledo, Jorge R.; Rivas, Coralia I.; Vera, Juan C.; McNerney, Eileen M.; Onate, Sergio A.

    2015-01-01

    Prostate cancer (CaP) bone metastasis is an early event that remains inactive until later-stage progression. Reduced levels of circulating androgens, due to andropause or androgen deprivation therapies, alter androgen receptor (AR) coactivator expression. Coactivators shift the balance towards enhanced AR-mediated gene transcription that promotes progression to androgen-resistance. Disruptions in coregulators may represent a molecular switch that reactivates latent bone metastasis. Changes in AR-mediated transcription in androgen-sensitive LNCaP and androgen-resistant C4-2 cells were analyzed for AR coregulator recruitment in co-culture with Saos-2 and THP-1. The Saos-2 cell line derived from human osteosarcoma and THP-1 cell line representing human monocytes were used to display osteoblast and osteoclast activity. Increased AR activity in androgen-resistant C4-2 was due to increased AR expression and SRC1/TIF2 recruitment and decreased SMRT/NCoR expression. AR activity in both cell types was decreased over 90% when co-cultured with Saos-2 or THP-1 due to dissociation of AR from the SRC1/TIF2 and SMRT/NCoR coregulators complex, in a ligand-dependent and cell-type specific manner. In the absence of androgens, Saos-2 decreased while THP-1 increased proliferation of LNCaP cells. In contrast, both Saos-2 and THP-1 decreased proliferation of C4-2 in absence and presence of androgens. Global changes in gene expression from both CaP cell lines identified potential cell cycle and androgen regulated genes as mechanisms for changes in cell proliferation and AR-mediated transactivation in the context of bone marrow stroma cells. - Highlights: • Decreased corepressor expression change AR in androgen-resistance prostate cancer. • Bone stroma-derived cells change AR coregulator recruitment in prostate cancer. • Bone stroma cells change cell proliferation in androgen-resistant cancer cells. • Global gene expression in CaP cells is modified by bone stroma cells in co

  11. Light of DNA-alkylating agents in castration-resistant prostate cancer cells: a novel mixed EGFR/DNA targeting combi-molecule.

    Science.gov (United States)

    Liang, Guan-Can; Zheng, Hao-Feng; Chen, Yan-Xiong; Li, Teng-Cheng; Liu, Wei; Fang, You-Qiang

    2017-01-01

    The mechanism underlying the therapeutic effects of combi-molecule JDF12 on prostate cancer (PCa) DU145 cells remains still unclear. This study aimed to investigate the proteomic profile after JDF12 treatment in DU145 cells by comparing with that in Iressa treated cells and untreated cells. MTT was used to evaluate drug cytotoxicity, DAPI staining was done to assess apoptosis of cells, and flow cytometry was used to analyze cell cycle. iTRAQ and qPCR were employed to obtain the proteomic profiles of JDF12 treated, Iressa treated, and untreated DU145 cells, and validate the expression of selected differentially expressed proteins, respectively. JDF12 could significantly inhibit the proliferation and increase the apoptosis of DU145 cells when compared with Iressa or blank group. In total, 5071 proteins were obtained, out of which, 42, including 21 up-regulated and 21 down-regulated proteins, were differentially expressed in JDF12 group when compared with Iressa and blank groups. The up-regulated proteins were mainly involved in DNA damage/repair and energy metabolism; while the down-regulated proteins were mainly associated with cell apoptosis. qPCR confirmed the expression of several biologically important proteins in DU145 cells after JDF12 treatment. The molecular mechanisms of DNA alkylating agents on PCa therapy that with the assistant of EGFR-blocker were revealed on proteomic level, which may increase the possible applications of DNA alkylating agents and JDF12 on PCa therapy.

  12. Management Options in Advanced Prostate Cancer: What is the Role for Sipuleucel-T?

    OpenAIRE

    Bitting, Rhonda L.; Armstrong, Andrew J.; George, Daniel J.

    2011-01-01

    Most prostate cancer-related deaths occur in patients with castration-resistant prostate cancer (CRPC). Until recently, only therapy with docetaxel and prednisone has been shown to prolong survival in men with metastatic CRPC. With the United States Food and Drug Administration (US FDA) approvals of sipuleucel-T, cabazitaxel, and abiraterone acetate, all based on improvement in overall survival, the landscape for management of men with metastatic CRPC has dramatically changed. In this review ...

  13. Advantages and Disadvantages of Bone Protective Agents in Metastatic Prostate Cancer: Lessons Learned

    Directory of Open Access Journals (Sweden)

    Christian Thomas

    2016-08-01

    Full Text Available Nine out of ten metastatic prostate cancer (PCa patients will develop osseous metastases. Of these, every second will suffer from skeletal-related events (SRE. SRE are associated with an increased risk for death, which is markedly increased in the presence of pathological fracture. Moreover, health insurance costs nearly double in the presence of SRE. Zoledronic acid and denosumab are both approved drugs for the prevention or delay of SRE in castration-resistant prostate cancer (CRPC patients with osseous metastases. However, long-term treatment with one of these two drugs is associated with the development of medication-related osteonecrosis of the jaw (MRONJ. Routine inspections of the oral cavity before and during treatment are mandatory in these patients. Regarding imaging techniques, bone scintigraphy seems to be a promising tool to detect early stage MRONJ. Zoledronic acid does not reduce the incidence of SRE in hormone-sensitive PCa. First data shows 3-monthly application of zoledronic acid to be equi-effective to monthly application.

  14. TRAF4 and Castration Resistant Prostate Cancer

    Science.gov (United States)

    2016-10-01

    Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202...was abolished 3 Fig. 2: TRAF4 regulated AR target gene played a role in CRPC growth (A-B) TRAF4 overexpression in LNCaP cell upregulated non...Identification of TRAF4 substrate ubiquitination sites We previously found that deletion of the ligand binding domain (LBD) of AR abolished TRAF4-mediated AR

  15. Association of body composition with outcome of docetaxel chemotherapy in metastatic prostate cancer: a retrospective review.

    Science.gov (United States)

    Wu, Weixin; Liu, Xiandong; Chaftari, Patrick; Cruz Carreras, Maria Teresa; Gonzalez, Carmen; Viets-Upchurch, Jayne; Merriman, Kelly; Tu, Shi-Ming; Dalal, Shalini; Yeung, Sai-Ching J

    2015-01-01

    Docetaxel, a lipophilic drug, is indicated for castration-resistant metastatic prostate cancer. Most men with such disease would have had androgen-deprivation therapy, which decreases muscle and increases body fat. Obesity and body composition changes may influence the outcomes of docetaxel therapy. We conducted a retrospective review of 333 patients with metastatic prostate cancer treated with docetaxel at a comprehensive cancer center between October 7, 2004 and December 31, 2012. Body composition parameters were measured based on the areas of muscle and adipose tissues in the visceral and subcutaneous compartments on CT images at L3-4 levels. Dose calculations, toxicity and adverse reaction profiles, and overall survival were analyzed. Obese patients were younger at the diagnosis of prostate cancer and had a shorter duration from diagnosis to docetaxel therapy. Analysis of body composition found that a high visceral fat-to-subcutaneous fat area ratio (VSR) was associated with poor prognosis but a high visceral fat-to-muscle area ratio (VMR) and high body mass index were associated with increased duration from starting docetaxel to death, allowing such men to catch up with patients with normal body mass index in overall survival from cancer diagnosis to death. Cox proportional hazard regression showed that age ≥65 years, high VSR, abnormal serum alkaline phosphatase, and >10% reduction of initial dosage were significant predictors of shorter time between starting docetaxel and death, and that high VMR, obesity, and weekly regimens were significant predictors of longer survival after docetaxel. Obese and overweight patients may benefit more from weekly docetaxel regimens using the reference dosage of 35 mg/m2 without empirical dosage reduction.

  16. Multiple urinary bladder masses from metastatic prostate adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Richard Choo

    2010-12-01

    Full Text Available We present an unusual case of metastatic prostate adenocarcinoma that manifested with multiple exophytic intravesical masses, mimicking a multifocal primary bladder tumor. Biopsy with immunohistochemical analysis confirmed metastatic prostate adenocarcinoma. The patient was treated palliatively with external beam radiotherapy to prevent possible symptoms from local tumor progression. This case illustrates that when a patient with known prostate cancer presents with multifocal bladder tumors, the possibility of metastatic prostate cancer should be considered.

  17. Combination immunotherapy with prostate GVAX and ipilimumab: safety and toxicity.

    Science.gov (United States)

    Karan, Dev; Van Veldhuizen, Peter

    2012-06-01

    Evaluation of: van den Eertwegh AJ, Versluis J, van den Berg HP et al. Combined immunotherapy with granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castration-resistant prostate cancer: a Phase 1 dose-escalation trial. Lancet Oncol. 13(5), 509 – 517 (2012). A significant interest in the development of therapeutic cancer vaccines over the last decade has led to an improvement in overall survival of cancer patients in several clinical trials. As a result, two active immunotherapy agents, sipuleucel-T and ipilimumab, have been approved by the US FDA for the treatment of prostate cancer and melanoma, respectively. GVAX(®) cellular vaccine (Cell Genesysis, Inc., CA, USA) is another active immunotherapy agent targeting prostate cancer and it has been well studied in various clinical trials. The current publication, by van den Eertwegh et al., demonstrated a combination of two active immunotherapy approaches, using GVAX and ipilimumab for the treatment of metastatic castration-resistant prostate cancer. While GVAX is designed to amplify the antitumor response specific to prostate cancer cells, ipilimumab contributes to T-cell activation. Thus, the authors presented the possibility of augmenting antitumor T-cell activity in two different ways. They successfully demonstrated a tolerable dose and safety profile of ipilimumab in combination with GVAX for patients with metastatic castration-resistant prostate cancer. However, further studies of such immunotherapy combinations and detailed analysis of their immunological effects are needed to observe clinical benefit.

  18. Immunotherapy in metastatic prostate cancer

    Directory of Open Access Journals (Sweden)

    Susan F Slovin

    2016-01-01

    Full Text Available Introduction: Prostate cancer remains a challenge as a target for immunological approaches. The approval of the first cell-based immune therapy, Sipuleucel-T for prostate cancer introduced prostate cancer as a solid tumor with the potential to be influenced by the immune system. Methods: We reviewed articles on immunological management of prostate cancer and challenges that lie ahead for such strategies. Results: Treatments have focused on the identification of novel cell surface antigens thought to be unique to prostate cancer. These include vaccines against carbohydrate and blood group antigens, xenogeneic and naked DNA vaccines, and pox viruses used as prime-boost or checkpoint inhibitors. No single vaccine construct to date has resulted in a dramatic antitumor effect. The checkpoint inhibitor, anti-CTLA-4 has resulted in several long-term remissions, but phase III trials have not demonstrated an antitumor effect or survival benefit. Conclusions: Multiple clinical trials suggest that prostate cancer may not be optimally treated by single agent immune therapies and that combination with biologic agents, chemotherapies, or radiation may offer some enhancement of benefit.

  19. Treatments for Metastatic Prostate Cancer (mPC): A Review of Costing Evidence.

    Science.gov (United States)

    Norum, Jan; Nieder, Carsten

    2017-12-01

    Prostate cancer (PC) is the most common cancer in Western countries. More than one third of PC patients develop metastatic disease, and the 5-year expected survival in distant disease is about 35%. During the last few years, new treatments have been launched for metastatic castrate-resistant prostate cancer (mCRPC). We aimed to review the current literature on health economic analysis on the treatment of metastatic prostate cancer (mPC), compare the studies, summarize the findings and make the results available to administrators and decision makers. A systematic literature search was done for economic evaluations (cost-minimization, cost-effectiveness, cost-utility, cost-of-illness, cost-of-drug, and cost-benefit analyses). We employed the PubMed ® search engine and searched for publications published between 2012 and 2016. The terms used were "prostate cancer", "metastatic" and "cost". An initial screening of all headlines was performed, selected abstracts were analysed, and finally the full papers investigated. Study characteristics, treatment and comparator, country, type of evaluation, perspective, year of value, time horizon, efficacy data, discount rate, total costs and sensitivity analysis were analysed. The quality was assessed using the Quality of Health Economic Studies (QHES) instrument. A total of 227 publications were detected and screened, 58 selected for full-text assessment and 31 included in the final analyses. Despite the significant international literature on the treatment of mCRPC, there were only 15 studies focusing on cost-effectiveness analysis (CEA). Medical treatment constituted two thirds of the selected studies. Significant costs in the treatment of mCRPC were disclosed. In the pre-docetaxel setting, both abiraterone acetate (AA) and enzalutamide were concluded beyond accepted cost/quality-adjusted life year limits. In the docetaxel refractory setting, most studies concluded that enzalutamide was cost-effective and superior to AA. In

  20. Prostate Specific Membrane Antigen (PSMA) Targeted Bio-orthogonal Therapy for Metastatic Prostate Cancer

    Science.gov (United States)

    2017-10-01

    AWARD NUMBER: W81XWH-16-1-0595 TITLE: Prostate-Specific Membrane Antigen (PSMA) Targeted Bio -orthogonal Therapy for Metastatic Prostate Cancer...Sep 2016 - 14 Sep 2017 4. TITLE AND SUBTITLE Prostate-Specific Membrane Antigen (PSMA) Targeted Bio -orthogonal Therapy for Metastatic Prostate

  1. Whole-Genome Sequence of the Metastatic PC3 and LNCaP Human Prostate Cancer Cell Lines

    Directory of Open Access Journals (Sweden)

    Inge Seim

    2017-06-01

    Full Text Available The bone metastasis-derived PC3 and the lymph node metastasis-derived LNCaP prostate cancer cell lines are widely studied, having been described in thousands of publications over the last four decades. Here, we report short-read whole-genome sequencing (WGS and de novo assembly of PC3 (ATCC CRL-1435 and LNCaP (clone FGC; ATCC CRL-1740 at ∼70 × coverage. A known homozygous mutation in TP53 and homozygous loss of PTEN were robustly identified in the PC3 cell line, whereas the LNCaP cell line exhibited a larger number of putative inactivating somatic point and indel mutations (and in particular a loss of stop codon events. This study also provides preliminary evidence that loss of one or both copies of the tumor suppressor Capicua (CIC contributes to primary tumor relapse and metastatic progression, potentially offering a treatment target for castration-resistant prostate cancer (CRPC. Our work provides a resource for genetic, genomic, and biological studies employing two commonly-used prostate cancer cell lines.

  2. Whole-Genome Sequence of the Metastatic PC3 and LNCaP Human Prostate Cancer Cell Lines.

    Science.gov (United States)

    Seim, Inge; Jeffery, Penny L; Thomas, Patrick B; Nelson, Colleen C; Chopin, Lisa K

    2017-06-07

    The bone metastasis-derived PC3 and the lymph node metastasis-derived LNCaP prostate cancer cell lines are widely studied, having been described in thousands of publications over the last four decades. Here, we report short-read whole-genome sequencing (WGS) and de novo assembly of PC3 (ATCC CRL-1435) and LNCaP (clone FGC; ATCC CRL-1740) at ∼70 × coverage. A known homozygous mutation in TP53 and homozygous loss of PTEN were robustly identified in the PC3 cell line, whereas the LNCaP cell line exhibited a larger number of putative inactivating somatic point and indel mutations (and in particular a loss of stop codon events). This study also provides preliminary evidence that loss of one or both copies of the tumor suppressor Capicua ( CIC ) contributes to primary tumor relapse and metastatic progression, potentially offering a treatment target for castration-resistant prostate cancer (CRPC). Our work provides a resource for genetic, genomic, and biological studies employing two commonly-used prostate cancer cell lines. Copyright © 2017 Seim et al.

  3. Metastatic prostate adenocarcinoma penis: Case report

    Directory of Open Access Journals (Sweden)

    Pablo Santiago Caicedo

    2014-08-01

    Full Text Available Objective: Describe a case report of a patient with prostatic adenocarcinoma metastatic to penis due to shortage reports of similar cases to perform a literature review. Methods: We identified a case of a patient with prostatic adenocarcinoma, who during de the course of a cystoscopy at Hospital Universitario San Jose (Third-level Public Hospital in Popayan, Colombia a suspicious nodule of malignancy was observed in the penis. We described the clinical case in order to proceed to a literature search for the discussion. Results: 72-year-old patient diagnosed with prostatic adenocarcinoma Gleason Score 4+5=9, treated with bilateral orchiectomy and a suspicious nodule of malignancy incidentally observed in the penis, currently undergoing palliative care with Karnofsky score of 30 points. Conclusion: cutaneous metastases are rare; indicate longstanding disease and poor prognosis.

  4. Characterizing the Hypermutated Subtype of Advanced Prostate Cancer as a Predictive Biomarker for Precision Medicine

    Science.gov (United States)

    2017-10-01

    was a think tank of leading prostate cancer researchers focused on the question of oligo- metastatic disease. I was part of the program organizing...Wilke, J., Wilder-Romans, K., Dhanireddy, S., Engelke, C., et al. (2014). Therapeutic targeting of BET bromodomain proteins in castration-resistant...begun to make a positive difference in the lives of men with advanced prostate cancer. Attention to how we might similarly adjust the way we think

  5. MOLECULAR MARKERS FOR METASTATIC PROSTATE ADENOCARCINOMA

    Directory of Open Access Journals (Sweden)

    I. S. Kunin

    2012-01-01

    Full Text Available The search of molecular markers of metastasing and prognosis in prostate cancer remains an urgent task. In this study, we investigated the relationship of gene expression heparanase-1 (HPSE1 and D-glucuronil C5-epimerase (GLCE with early disease relapse and metastasis of a 2,5−3 years after diagnosis. It was shown that the ratio of the expression levels of genes HPSE1/GLCE > 1 may serve as a prognostic relapse marker and trends of the tumour to metastasis. The data obtained suggest to use this option as a molecular marker for the diagnostics of metastatic process and the disease prognosis.

  6. Prostate specific antigen (PSA) kinetic as a prognostic factor in metastatic prostate cancer receiving androgen deprivation therapy: systematic review and meta-analysis.

    Science.gov (United States)

    Afriansyah, Andika; Hamid, Agus Rizal Ardy Hariandy; Mochtar, Chaidir Arif; Umbas, Rainy

    2018-01-01

    Aim: Metastatic prostate cancer (mPCa) has a poor outcome with median survival of two to five years. The use of androgen deprivation therapy (ADT) is a gold standard in management of this stage.  Aim of this study is to analyze the prognostic value of PSA kinetics of patient treated with hormonal therapy related to survival from several published studies Method: Systematic review and meta-analysis was performed using literature searching in the electronic databases of MEDLINE, Science Direct, and Cochrane Library. Inclusion criteria were mPCa receiving ADT, a study analyzing Progression Free Survival (PFS), Overall Survival (OS), or Cancer Specific Survival (CSS) and prognostic factor of survival related to PSA kinetics (initial PSA, PSA nadir, and time to achieve nadir (TTN)). The exclusion criteria were metastatic castration resistant of prostate cancer (mCRPC) and non-metastatic disease. Generic inverse variance method was used to combine hazard ratio (HR) within the studies. Meta-analysis was performed using Review Manager 5.2 and a p-value PSA and PFS. In addition, there was no association between initial PSA and CSS/ OS. We found association of reduced PFS (HR 2.22; 95% CI 1.82 to 2.70) and OS/ CSS (HR 3.31; 95% CI 2.01-5.43) of patient with high PSA nadir. Shorter TTN was correlated with poor result of survival either PFS (HR 2.41; 95% CI 1.19 - 4.86) or CSS/ OS (HR 1.80; 95%CI  1.42 - 2.30) Conclusion: Initial PSA before starting ADT do not associated with survival in mPCa.  There is association of PSA nadir and TTN with survival.

  7. Pre-therapeutic dosimetry of normal organs and tissues of {sup 177}Lu-PSMA-617 prostate-specific membrane antigen (PSMA) inhibitor in patients with castration-resistant prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Kabasakal, Levent; AbuQbeitah, Mohammad; Ayguen, Aslan; Yeyin, Nami [Istanbul University, Department of Nuclear Medicine, Cerrahpasa Medical Faculty, Istanbul (Turkey); Ocak, Meltem [Istanbul University, Department of Pharmaceutical Technology, Pharmacy Faculty, Istanbul (Turkey); Demirci, Emre [Sisli Etfal Training and Research Hospital, Department of Nuclear Medicine, Istanbul (Turkey); Toklu, Turkay [Yeditepe University Medical Faculty, Department of Nuclear Medicine, Istanbul (Turkey)

    2015-12-15

    {sup 177}Lu-617-prostate-specific membrane antigen (PSMA) ligand seems to be a promising tracer for radionuclide therapy of progressive prostate cancer. However, there are no published data regarding the radiation dose given to the normal tissues. The aim of the present study was to estimate the pretreatment radiation doses in patients who will undergo radiometabolic therapy using a tracer amount of {sup 177}Lu-labeled PSMA ligand. The study included seven patients with progressive prostate cancer with a mean age of 63.9 ± 3.9 years. All patients had prior PSMA positron emission tomography (PET) imaging and had intense tracer uptake at the lesions. The injected {sup 177}Lu-PSMA-617 activity ranged from 185 to 210 MBq with a mean of 192.6 ± 11.0 MBq. To evaluate bone marrow absorbed dose 2-cc blood samples were withdrawn in short variable times (3, 15, 30, 60, and 180 min and 24, 48, and 120 h) after injection. Whole-body images were obtained at 4, 24, 48, and 120 h post-injection (p.i.). The geometric mean of anterior and posterior counts was determined through region of interest (ROI) analysis. Attenuation correction was applied using PSMA PET/CT images. The OLINDA/EXM dosimetry program was used for curve fitting, residence time calculation, and absorbed dose calculations. The calculated radiation-absorbed doses for each organ showed substantial variation. The highest radiation estimated doses were calculated for parotid glands and kidneys. Calculated radiation-absorbed doses per megabecquerel were 1.17 ± 0.31 mGy for parotid glands and 0.88 ± 0.40 mGy for kidneys. The radiation dose given to the bone marrow was significantly lower than those of kidney and parotid glands (p < 0.05). The calculated radiation dose to bone marrow was 0.03 ± 0.01 mGy/MBq. Our first results suggested that {sup 177}Lu-PSMA-617 therapy seems to be a safe method. The dose-limiting organ seems to be the parotid glands rather than kidneys and bone marrow. The lesion radiation doses are

  8. The HGF/c-MET Axis as a Critical Driver of Resistance to Androgen Suppression in Metastatic Castrate-Resistant Prostate Cancer

    Science.gov (United States)

    2016-10-01

    signaling inhibition in AR-positive CRPC models increased MET expression and resulted in susceptibility to ligand (HGF) activation. Likewise, our work...positive CRPC models , as detailed in the initial proposal, we found that combined MET inhibition and enzalutamide (AR antagonist) treatment was more...wide analyses, we will be able to better test the study hypothesis with increased patient accrual. Figure: Waterfall plots showing association

  9. Weekly low-dose docetaxel is an effective treatment with fewer adverse events for metastatic castration-resistant prostate cancer in Taiwanese patients

    Directory of Open Access Journals (Sweden)

    Cheng-Li Kao

    2015-12-01

    Conclusion: For Taiwanese mCRPC patients, weekly DTX 30 mg/m2 is an efficient regimen for disease control with relatively low Grade 3 or 4 hematological adverse effects. The proper treatment duration of DTX therapy for mCRPC in Taiwanese patients is still uncertain, so further research is needed.

  10. Automated Bone Scan Index as a quantitative imaging biomarker in metastatic castration-resistant prostate cancer patients being treated with enzalutamide

    DEFF Research Database (Denmark)

    Anand, Aseem; Morris, Michael J.; Larson, Steven M

    2016-01-01

    alone (C-index 0.73), p = 0.041. Conclusions: The upgraded and analytically validated automated BSI was found to be a strong predictor of OS in mCRPC patients. Additionally, the change in automated BSI demonstrated an additive clinical value to the change in PSA in mCRPC patients being treated...

  11. Abiraterone Acetate for the Treatment of Chemotherapy-Naive Metastatic Castration-Resistant Prostate Cancer : An Evidence Review Group Perspective of an NICE Single Technology Appraisal

    NARCIS (Netherlands)

    Ramaekers, Bram L. T.; Riemsma, Rob; Tomini, Florian; van Asselt, Thea; Deshpande, Sohan; Duffy, Steven; Armstrong, Nigel; Severens, Johan L.; Kleijnen, Jos; Joore, Manuela A.

    The National Institute for Health and Care Excellence (NICE) invited Janssen, the company manufacturing abiraterone acetate (AA; tradename Zytiga(A (R))), to submit evidence for the clinical and cost effectiveness of AA in combination with prednisone/prednisolone (AAP) compared with watchful waiting

  12. Pleuropulmonary and Lymph Node Progression after Docetaxel - Benefits from Treatment with Cabazitaxel in Metastatic Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Angel Segura Huerta

    2013-07-01

    Full Text Available Introduction: To date, there are no guidelines for a rational and more favourable sequence of treatment after docetaxel. Two drugs (cabazitaxel and abiraterone have recently been approved as second-line treatment after docetaxel failure in metastatic castration-resistant prostate cancer (mCRPC, but there are no studies comparing abiraterone versus cabazitaxel. The most suitable drug is chosen based on the physician's opinion and the patient's characteristics. In patients with a good performance status who are able to receive either treatment, it would be convenient to begin with cabazitaxel and to reserve abiraterone in case there is a worsening of the general status, in consideration of abiraterone's more favourable toxicity profile. Case Report: We describe the case of a 74-year-old male with mCRPC who presented with an interesting and uncommon tumour dissemination (pleuropulmonary occurring after the first standard treatment with docetaxel. Intravenous treatment with cabazitaxel 25 mg/m2 and oral prednisone 10 mg continuously was initiated. The patient received a total of 8 cycles of chemotherapy. A reduction of mediastinal adenopathies and infrarenal para-aortic stable bone involvement and an absence of pleural effusion were observed. No relevant toxicity was noted. Since February 2012, a progressive PSA increase without clinical deterioration has been noted. Conclusions: The selection criteria for second- and third-line systemic treatment and the excellent response obtained with cabazitaxel in an unusual disease setting are described. The results confirm the long duration and quality of response of cabazitaxel treatment. Further therapeutic options in this group of patients are suggested.

  13. Molecular Subgroup of Primary Prostate Cancer Presenting with Metastatic Biology.

    Science.gov (United States)

    Walker, Steven M; Knight, Laura A; McCavigan, Andrena M; Logan, Gemma E; Berge, Viktor; Sherif, Amir; Pandha, Hardev; Warren, Anne Y; Davidson, Catherine; Uprichard, Adam; Blayney, Jaine K; Price, Bethanie; Jellema, Gera L; Steele, Christopher J; Svindland, Aud; McDade, Simon S; Eden, Christopher G; Foster, Chris; Mills, Ian G; Neal, David E; Mason, Malcolm D; Kay, Elaine W; Waugh, David J; Harkin, D Paul; Watson, R William; Clarke, Noel W; Kennedy, Richard D

    2017-10-01

    Approximately 4-25% of patients with early prostate cancer develop disease recurrence following radical prostatectomy. To identify a molecular subgroup of prostate cancers with metastatic potential at presentation resulting in a high risk of recurrence following radical prostatectomy. Unsupervised hierarchical clustering was performed using gene expression data from 70 primary resections, 31 metastatic lymph nodes, and 25 normal prostate samples. Independent assay validation was performed using 322 radical prostatectomy samples from four sites with a mean follow-up of 50.3 months. Molecular subgroups were identified using unsupervised hierarchical clustering. A partial least squares approach was used to generate a gene expression assay. Relationships with outcome (time to biochemical and metastatic recurrence) were analysed using multivariable Cox regression and log-rank analysis. A molecular subgroup of primary prostate cancer with biology similar to metastatic disease was identified. A 70-transcript signature (metastatic assay) was developed and independently validated in the radical prostatectomy samples. Metastatic assay positive patients had increased risk of biochemical recurrence (multivariable hazard ratio [HR] 1.62 [1.13-2.33]; p=0.0092) and metastatic recurrence (multivariable HR=3.20 [1.76-5.80]; p=0.0001). A combined model with Cancer of the Prostate Risk Assessment post surgical (CAPRA-S) identified patients at an increased risk of biochemical and metastatic recurrence superior to either model alone (HR=2.67 [1.90-3.75]; pmolecular subgroup of primary prostate cancers with metastatic potential. The metastatic assay may improve the ability to detect patients at risk of metastatic recurrence following radical prostatectomy. The impact of adjuvant therapies should be assessed in this higher-risk population. Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

  14. Commentary on: "Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): A multicentre, randomised, double-blind, phase 3 trial." Kwon ED, Drake CG, Scher HI, Fizazi K, Bossi A, van den Eertwegh AJ, Krainer M, Houede N, Santos R, Mahammedi H, Ng S, Maio M, Franke FA, Sundar S, Agarwal N, Bergman AM, Ciuleanu TE, Korbenfeld E, Sengeløv L, Hansen S, Logothetis C, Beer TM, McHenry MB, Gagnier P, Liu D, Gerritsen WR, CA184-043 Investigators. Departments of Urology and Immunology and Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Rochester, MN, USA, Electronic address: kwon.eugene@mayo.edu; Johns Hopkins Sidney Kimmel Comprehensive Cancer Center and Brady Urological Institute, Baltimore, MD, USA; Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA; Institut Gustave Roussy, University of Paris-Sud, Villejuif, France; Institut Gustave Roussy, Villejuif, France; VU University Medical Centre, Amsterdam, Netherlands; Vienna General Hospital, Medical University Vienna, Vienna, Austria; Institut Bergonié, Bordeaux, France; CHU Caremeau, Nimes, France; Centro Médico Austral, Buenos Aires, Argentina; Centre Jean Perrin, Clermont-Ferrand, France; St John of God Hospital, Subiaco, WA, Australia; University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy; Hospital de Caridade de Ijuí, Ijuí, Brazil; Nottingham University Hospital, Nottingham, UK; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA; Netherlands Cancer Institute and Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands; Institute of Oncology Ion Chiricuta and University of Medicine and Pharmacy Iuliu Hatieganu, Cluj-Napoca, Romania; Hospital Británico de Buenos Aires, Buenos Aires, Argentina; Herlev Hospital, Herlev, Denmark; Odense University Hospital, Odense, Denmark; University of Texas MD Anderson Cancer Center, Houston,

    Science.gov (United States)

    Trump, Donald

    2016-05-01

    Ipilimumab is a fully human monoclonal antibody that binds cytotoxic T-lymphocyte antigen 4 to enhance antitumour immunity. Our aim was to assess the use of ipilimumab after radiotherapy in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel chemotherapy. We did a multicentre, randomised, double-blind, phase 3 trial in which men with at least one bone metastasis from castration-resistant prostate cancer that had progressed after docetaxel treatment were randomly assigned in a 1:1 ratio to receive bone-directed radiotherapy (8Gy in one fraction) followed by either ipilimumab 10mg/kg or placebo every 3 weeks for up to four doses. Non-progressing patients could continue to receive ipilimumab at 10mg/kg or placebo as maintenance therapy every 3 months until disease progression, unacceptable toxic effect, or death. Patients were randomly assigned to either treatment group via a minimisation algorithm, and stratified by Eastern Cooperative Oncology Group performance status, alkaline phosphatase concentration, haemoglobin concentration, and investigator site. Patients and investigators were masked to treatment allocation. The primary endpoint was overall survival, assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00861614. From May 26, 2009, to Feb 15, 2012, 799 patients were randomly assigned (399 to ipilimumab and 400 to placebo), all of whom were included in the intention-to-treat analysis. Median overall survival was 11.2 months (95% CI: 9.5-12.7) with ipilimumab and 10.0 months (8.3-11.0) with placebo (hazard ratio [HR] = 0.85, 0.72-1.00; P = 0.053). However, the assessment of the proportional hazards assumption showed that it was violated (P = 0.0031). A piecewise hazard model showed that the HR changed over time: the HR for 0-5 months was 1.46 (95% CI: 1.10-1.95), for 5-12 months was 0.65 (0.50-0.85), and beyond 12 months was 0.60 (0.43-0.86). The most common grade 3

  15. Cytoreductive surgery for men with metastatic prostate cancer

    Directory of Open Access Journals (Sweden)

    Nikolas Katelaris

    2016-09-01

    Conclusions: This data supports recent findings demonstrating that radical prostatectomy for metastatic prostate cancer is feasible. Further studies are needed to explore the role of cytoreductive surgery with regards to the potential oncological benefit.

  16. Metastatic Prostate Adenocarcinoma Presenting Central Diabetes Insipidus

    Directory of Open Access Journals (Sweden)

    Hakkı Yılmaz

    2012-01-01

    Full Text Available The pituitary gland and infundibulum can be involved in a variety of medical conditions, including infiltrative diseases, fungal infections, tuberculosis, and primary and metastatic tumors. Metastases to the pituitary gland are absolutely rare, and they are generally secondary to pulmonary carcinoma in men and breast carcinoma in women. Pituitary metastases more commonly affect the posterior lobe and the infundibulum than the anterior lobe. The posterior lobe involvement may explain why patients with pituitary metastases frequently present with diabetes insipidus. We are presenting a case report of a 78-year-old male patient who had metastatic prostate with sudden onset of polyuria and persistent thirst. He had no electrolyte imbalance except mild hypernatremia. The MRI scan of the brain yielded a suspicious area in pituitary gland. A pituitary stalk metastasis was found on magnetic resonance imaging (MRI of pituitary. Water deprivation test was compatible with DI. A clinical response to nasal vasopressin was achieved and laboratory results revealed central diabetes insipidus. As a result, the intrasellar and suprasellar masses decreased in size, and urinary output accordingly decreased.

  17. Precision medicine for advanced prostate cancer.

    Science.gov (United States)

    Mullane, Stephanie A; Van Allen, Eliezer M

    2016-05-01

    Precision cancer medicine, the use of genomic profiling of patient tumors at the point-of-care to inform treatment decisions, is rapidly changing treatment strategies across cancer types. Precision medicine for advanced prostate cancer may identify new treatment strategies and change clinical practice. In this review, we discuss the potential and challenges of precision medicine in advanced prostate cancer. Although primary prostate cancers do not harbor highly recurrent targetable genomic alterations, recent reports on the genomics of metastatic castration-resistant prostate cancer has shown multiple targetable alterations in castration-resistant prostate cancer metastatic biopsies. Therapeutic implications include targeting prevalent DNA repair pathway alterations with PARP-1 inhibition in genomically defined subsets of patients, among other genomically stratified targets. In addition, multiple recent efforts have demonstrated the promise of liquid tumor profiling (e.g., profiling circulating tumor cells or cell-free tumor DNA) and highlighted the necessary steps to scale these approaches in prostate cancer. Although still in the initial phase of precision medicine for prostate cancer, there is extraordinary potential for clinical impact. Efforts to overcome current scientific and clinical barriers will enable widespread use of precision medicine approaches for advanced prostate cancer patients.

  18. Association of Gleason Risk Groups with Metastatic Sites in Prostate ...

    African Journals Online (AJOL)

    Prostate cancer is the second most common non cutaneous male malignancy worldwide. Gleason composite score is used for risk classification. The most common site of metastasis in prostate cancer is the bone among others. The site and number of metastasis affect overall survival. The ability to predict the metastatic site ...

  19. Phenotypic and genetic heterogeneity of tumor tissue and circulating tumor cells in patients with metastatic castrationresistant prostate cancer: a report from the PETRUS prospective study

    Science.gov (United States)

    Massard, Christophe; Oulhen, Marianne; Le Moulec, Sylvestre; Auger, Nathalie; Foulon, Stéphanie; Abou-Lovergne, Aurélie; Billiot, Fanny; Valent, Alexander; Marty, Virginie; Loriot, Yohann; Fizazi, Karim; Vielh, Philippe; Farace, Francoise

    2016-01-01

    Molecular characterization of cancer samples is hampered by tumor tissue availability in metastatic castration-resistant prostate cancer (mCRPC) patients. We reported the results of prospective PETRUS study of biomarker assessment in paired primary prostatic tumors, metastatic biopsies and circulating tumor cells (CTCs). Among 54 mCRPC patients enrolled, 38 (70%) had biopsies containing more than 50% tumour cells. 28 (52%) patients were analyzed for both tissue samples and CTCs. FISH for AR-amplification and TMPRSS2-ERG translocation were successful in 54% and 32% in metastatic biopsies and primary tumors, respectively. By comparing CellSearch and filtration (ISET)-enrichment combined to four color immunofluorescent staining, we showed that CellSearch and ISET isolated distinct subpopulations of CTCs: CTCs undergoing epithelial-to-mesenchymal transition, CTC clusters and large CTCs with cytomorphological characteristics but no detectable markers were isolated using ISET. Epithelial CTCs detected by the CellSearch were mostly lost during the ISET-filtration. AR-amplification was detected in CellSearch-captured CTCs, but not in ISET-enriched CTCs which harbor exclusively AR gain of copies. Eighty-eight percent concordance for ERG-rearrangement was observed between metastatic biopsies and CTCs even if additional ERG-alteration patterns were detected in ISET-enriched CTCs indicating a higher heterogeneity in CTCs. Molecular screening of metastatic biopsies is achievable in a multicenter context. Our data indicate that CTCs detected by the CellSearch and the ISET-filtration systems are not only phenotypically but also genetically different. Close attention must be paid to CTC characterization since neither approach tested here fully reflects the tremendous phenotypic and genetic heterogeneity present in CTCs from mCRPC patients. PMID:27391263

  20. Adipose Stem Cell-Based Therapeutic Targeting of Residual Androgens in African Americans with Bone-Metastatic Prostate Cancer

    Science.gov (United States)

    2015-11-01

    Figure 2: PC cell soluble factors confer transcriptional upregulation of DHT converting enzymes by patient derived ADMSCs (pASCs...associated exosomes. Stem Cells, 2014. 32(4): p. 983-97. 30. Mathur, A., et al., Subverting ER-stress towards apoptosis by nelfinavir and curcumin coexposure...and curcumin coexposure augments docetaxel efficacy in castration resistant prostate cancer cells. PLoS One, 2014. 9(8): p. e103109. 29. Datta, A., et

  1. Whole body MRI (WB-MRI) assessment of metastatic spread in prostate cancer: Therapeutic perspectives on targeted management of oligometastatic disease.

    Science.gov (United States)

    Larbi, Ahmed; Dallaudière, Benjamin; Pasoglou, Vasiliki; Padhani, Anwar; Michoux, Nicolas; Vande Berg, Bruno C; Tombal, Bertrand; Lecouvet, Frédéric E

    2016-08-01

    To determine the proportion of prostate cancer (PCa) patients with oligometastatic disease (≤3 synchronous lesions) using whole body magnetic resonance imaging with diffusion-weighted imaging (WB-MRI/DWI). To determine the proportion of patients with nodal disease confined within currently accepted target areas for extended lymph node dissection (eLND) and pelvic external beam radiation therapy (EBRT). Two radiologists reviewed WB-MRI/DWI studies in 96 consecutive newly diagnosed metastatic PCa patients; 46 patients with newly diagnosed castration naive PCa (mHNPC) and 50 patients with first appearance of metastasis during monitoring for non-metastatic castration resistant PCa (M0 to mCRPC). The distribution of metastatic deposits was assessed and the proportions of patients with oligometastatic disease and with LN metastases located within eLND and EBRT targets were determined. Twenty-eight percent of mHNPC and 50% of mCPRC entered the metastatic disease with ≤3 sites. Bone metastases (BM) were identified in 68.8% patients; 71.7% of mHNPC and 66% mCRPC patients. Most commonly involved areas were iliac bones and lumbar spine. Enlarged lymph nodes (LN) were detected in 68.7% of patients; 69.6% of mHNPC and 68.0% of mCRPC. Most commonly involved areas were para-aortic, inter-aortico-cava, and external iliac areas. BM and LN were detected concomitantly in 41% of mHNPC and 34% of mCRPC. Visceral metastases were detected in 6.7%. Metastatic disease was confined to LN located within the accepted boundaries of eLND or pelvic EBRT target areas in only ≤25% and ≤30% of patients, respectively. Non-invasive mapping of metastatic landing sites in PCa using WB-MRI/DWI shows that 28% of the mHNPC patients, and 52% of the mCRPC can be classified as oligometastatic, thus challenging the concept of metastatic targeted therapy. More than two thirds of metastatic patients have LN located outside the usually recommended targets of eLND and pelvic EBRT. Prophylactic or salvage

  2. MO-AB-BRA-05: [18F]NaF PET/CT Imaging Biomarkers in Metastatic Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Harmon, S; Perk, T; Lin, C; Eickhoff, J; Perlman, S; Liu, G; Jeraj, R [University of Wisconsin Madison, Madison, WI (United States); Choyke, P; Dahut, W; Apolo, A [National Cancer Institute at the National Institutes of Health, Bethesda, MD (United States); Humm, J; Larson, S; Morris, MJ [Memorial Sloan-Kettering Cancer Center, New York, NY (United States)

    2016-06-15

    Purpose: Clinical use of {sup 18}F-Sodium Fluoride (NaF) PET/CT in metastatic settings often lacks technology to quantitatively measure full disease dynamics due to high tumor burden. This study assesses radiomics-based extraction of NaF PET/CT measures, including global metrics of overall burden and local metrics of disease heterogeneity, in metastatic prostate cancer for correlation to clinical outcomes. Methods: Fifty-six metastatic Castrate-Resistant Prostate Cancer (mCRPC) patients had NaF PET/CT scans performed at baseline and three cycles into chemotherapy (N=16) or androgen-receptor (AR) inhibitors (N=39). A novel technology, Quantitative Total Bone Imaging (QTBI), was used for analysis. Employing hybrid PET/CT segmentation and articulated skeletal-registration, QTBI allows for response assessment of individual lesions. Various SUV metrics were extracted from each lesion (iSUV). Global metrics were extracted from composite lesion-level statistics for each patient (pSUV). Proportion of detected lesions and those with significant response (%-increase or %-decrease) was calculated for each patient based on test-retest limits for iSUV metrics. Cox proportional hazard regression analyses were conducted between imaging metrics and progression-free survival (PFS). Results: Functional burden (pSUV{sub total}) assessed mid-treatment was the strongest univariate predictor of PFS (HR=2.03; p<0.0001). Various global metrics outperformed baseline clinical markers, including fraction of skeletal burden, mean uptake (pSUV{sub mean}), and heterogeneity of average lesion uptake (pSUV{sub hetero}). Of 43 patients with paired baseline/mid-treatment imaging, 40 showed heterogeneity in lesion-level response, containing populations of lesions with both increasing/decreasing metrics. Proportion of lesions with significantly increasing iSUV{sub mean} was highly predictive of clinical PFS (HR=2.0; p=0.0002). Patients exhibiting higher proportion of lesions with decreasing i

  3. Repeated PSMA-targeting radioligand therapy of metastatic prostate cancer with {sup 131}I-MIP-1095

    Energy Technology Data Exchange (ETDEWEB)

    Afshar-Oromieh, Ali; Haberkorn, Uwe [Heidelberg University Hospital, Department of Nuclear Medicine, Heidelberg (Germany); German Cancer Research Center, Clinical Cooperation Unit Nuclear Medicine, Heidelberg (Germany); Zechmann, Christian; Mier, Walter; Spohn, Fabian; Debus, Nils; Kratochwil, Clemens [Heidelberg University Hospital, Department of Nuclear Medicine, Heidelberg (Germany); Armor, Thomas [Progenics Pharmaceuticals, Inc., New York, NY (United States); Holland-Letz, Tim [German Cancer Research Center, Department of Biostatistics, Heidelberg (Germany); Babich, John [Weill Cornell Medicine, Division of Radiopharmaceutical Sciences, Department of Radiology, New York, NY (United States); Weill Cornell Medicine, Citigroup Biomedical Imaging Center, New York, NY (United States); Weill Cornell Medicine, Meyer Cancer Center, New York, NY (United States)

    2017-06-15

    Prostate-specific membrane antigen (PSMA)-targeting radioligand therapy (RLT) was introduced in 2011. The first report described the antitumor and side effects of a single dose. The aim of this analysis was to evaluate toxicity and antitumor activity after single and repetitive therapies. Thirty-four men with metastatic castration-resistant prostate cancer received PSMA-RLT with {sup 131}I-MIP-1095. Twenty-three patients received a second, and three patients a third dose, timed at PSA progression after an initial response to the preceding therapy. The applied doses were separated in three groups: <3.5, 3.5-5.0 and >5.0 GBq. Antitumor and side-effects were analyzed by blood samples and other clinical data. Follow-up was conducted for up to 5 years. The best therapeutic effect was achieved by the first therapy. A PSA decline of ≥50% was achieved in 70.6% of the patients. The second and third therapies were significantly less effective. There was neither an association between the applied activity and PSA response or the time-to-progression. Hematologic toxicities were less prevalent but presented in a higher percentage of patients with increasing number of therapies. After hematologic toxicities, xerostomia was the second most frequent side effect and presented more often and with higher intensity after the second or third therapy. The first dose of RLT with {sup 131}I-MIP-1095 presented with low side effects and could significantly reduce the tumor burden in a majority of patients. The second and third therapies were less effective and presented with more frequent and more intense side effects, especially hematologic toxicities and xerostomia. (orig.)

  4. Nonlinear joint models for individual dynamic prediction of risk of death using Hamiltonian Monte Carlo: application to metastatic prostate cancer

    Directory of Open Access Journals (Sweden)

    Solène Desmée

    2017-07-01

    Full Text Available Abstract Background Joint models of longitudinal and time-to-event data are increasingly used to perform individual dynamic prediction of a risk of event. However the difficulty to perform inference in nonlinear models and to calculate the distribution of individual parameters has long limited this approach to linear mixed-effect models for the longitudinal part. Here we use a Bayesian algorithm and a nonlinear joint model to calculate individual dynamic predictions. We apply this approach to predict the risk of death in metastatic castration-resistant prostate cancer (mCRPC patients with frequent Prostate-Specific Antigen (PSA measurements. Methods A joint model is built using a large population of 400 mCRPC patients where PSA kinetics is described by a biexponential function and the hazard function is a PSA-dependent function. Using Hamiltonian Monte Carlo algorithm implemented in Stan software and the estimated population parameters in this population as priors, the a posteriori distribution of the hazard function is computed for a new patient knowing his PSA measurements until a given landmark time. Time-dependent area under the ROC curve (AUC and Brier score are derived to assess discrimination and calibration of the model predictions, first on 200 simulated patients and then on 196 real patients that are not included to build the model. Results Satisfying coverage probabilities of Monte Carlo prediction intervals are obtained for longitudinal and hazard functions. Individual dynamic predictions provide good predictive performances for landmark times larger than 12 months and horizon time of up to 18 months for both simulated and real data. Conclusions As nonlinear joint models can characterize the kinetics of biomarkers and their link with a time-to-event, this approach could be useful to improve patient’s follow-up and the early detection of most at risk patients.

  5. The potential of {sup 223}Ra and {sup 18}F-fluoride imaging to predict bone lesion response to treatment with {sup 223}Ra-dichloride in castration-resistant prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Murray, Iain; Chittenden, Sarah J.; Denis-Bacelar, Ana M.; Flux, Glenn D. [Royal Marsden NHS Foundation Trust, Joint Department of Physics, Sutton, Surrey (United Kingdom); The Institute of Cancer Research, London (United Kingdom); Hindorf, Cecilia [Royal Marsden NHS Foundation Trust, Joint Department of Physics, Sutton, Surrey (United Kingdom); The Institute of Cancer Research, London (United Kingdom); Skaane University Hospital, Department of Radiation Physics, Lund (Sweden); Parker, Christopher C. [Royal Marsden NHS Foundation Trust, Department of Urology, Sutton (United Kingdom); Chua, Sue [Royal Marsden NHS Foundation Trust, Department of Nuclear Medicine, Sutton (United Kingdom)

    2017-10-15

    The aims of this study were to calculate bone lesion absorbed doses resulting from a weight-based administration of {sup 223}Ra-dichloride, to assess the relationship between those doses and corresponding {sup 18}F-fluoride uptake and to assess the potential of quantitative {sup 18}F-fluoride imaging to predict response to treatment. Five patients received two intravenous injections of {sup 223}Ra-dichloride, 6 weeks apart, at 110 kBq/kg whole-body weight. The biodistribution of {sup 223}Ra in metastatic lesions as a function of time after administration as well as associated lesion dosimetry were determined from serial {sup 223}Ra scans. PET/CT imaging using {sup 18}F-fluoride was performed prior to the first treatment (baseline), and at week 6 immediately before the second treatment and at week 12 after baseline. Absorbed doses to metastatic bone lesions ranged from 0.6 Gy to 44.1 Gy. For individual patients, there was an average factor difference of 5.3 (range 2.5-11.0) between the maximum and minimum lesion dose. A relationship between lesion-absorbed doses and serial changes in {sup 18}F-fluoride uptake was demonstrated (r{sup 2} = 0.52). A log-linear relationship was demonstrated (r{sup 2} = 0.77) between baseline measurements of {sup 18}F-fluoride uptake prior to {sup 223}Ra-dichloride therapy and changes in uptake 12 weeks after the first cycle of therapy. Correlations were also observed between both {sup 223}Ra and {sup 18}F-fluoride uptake in lesions (r = 0.75) as well as between {sup 223}Ra absorbed dose and {sup 18}F-fluoride uptake (r = 0.96). There is both inter-patient and intra-patient heterogeneity of absorbed dose estimates to metastatic lesions. A relationship between {sup 223}Ra lesion absorbed dose and subsequent lesion response was observed. Analysis of this small group of patients suggests that baseline uptake of {sup 18}F-fluoride in bone metastases is significantly correlated with corresponding uptake of {sup 223}Ra, the associated {sup 223

  6. Intrahepatic portal hypertension secondary to metastatic carcinoma of the prostate.

    Science.gov (United States)

    Attila, Tan; Datta, Milton W; Sudakoff, Gary; Abu-Hajir, Majed; Massey, Benson T

    2007-02-01

    While the liver is a common site of metastasis, tumor metastases are not a common cause of portal hypertension. We report a case of a patient with symptomatic portal hypertension due to diffuse metastatic prostate carcinoma infiltration of liver parenchyma that was not appreciated with routine imaging.

  7. New Prostate Cancer Treatment Target

    Science.gov (United States)

    Researchers have identified a potential alternative approach to blocking a key molecular driver of an advanced form of prostate cancer, called androgen-independent or castration-resistant prostate cancer.

  8. SU-F-T-57: Delivered Activity Accuracy of Radium 223 Dichloride Injections, When Being Administrated for Castration Resistant Prostate Cancer, Symptomatic Bone Metastases. The Impact of Residual Activity in the Spent Syringe and Dispensing Accuracy of Ra 223

    International Nuclear Information System (INIS)

    Jennings, G

    2016-01-01

    Purpose: To quantify the delivered activity accuracy of Radium 223 dichloride injections, when being administrated for castration – resistant prostate cancer, symptomatic bone metastases. The impact of residual activity in the spent syringe and dispensing accuracy of Ra 223. Methods: The administration is by slow intravenous injection over 1 minute followed by double flushing of the 10 mL syringe and IV with saline. Eighty (80) procedures was used to investigate variations in the activity from the amount prescribed (µCi) = 1.35 × Patient weight Kg. The Activity dispensed into a 10mL syringe using a NIST traceable Capintec CRC-25R Chamber and a cross calibrated capintec CRC-15R to measure activity in the syringe immediately before and after administration Results: The patients weight range from 121Ib to 235lb and doses ranging 74.25 µCi to 144.2 µCi. The deviation of dispensed dose vs Prescribed dose average +2.1% with a range of −1.1% to +5.7%. The Dose measured before administration ranges 79.3 µCi to 154.9 µCi. Deviation from the dispensed dose was show to average +2.9% with a range of −0.8% to +7.3%. The average residual dose post injection was 2.5 µCi or 2.2% of the pre injection activity. Ranging from 0.9 µCi to 6.2 µCi, 0.7% to 5.4% respectively. Subtracting the residual activity from that measured activity before injection and comparing it to prescription dose was shown to have an average variation of +2.7% with a range of −0.8% to 7.4%. Conclusion: The case resulted in the 6.2 µCi maximum residual dose had two syringes. A small, 82.8 µCi activity, case resulted in the 7.4% maximum variation in measures less residual verses prescription dose. The average +2.1 % dispenses activity of Ra 223 over the prescription dosage was seen to counteract the average 2.2% residual dosage found to remain in the syringe

  9. SU-F-T-57: Delivered Activity Accuracy of Radium 223 Dichloride Injections, When Being Administrated for Castration Resistant Prostate Cancer, Symptomatic Bone Metastases. The Impact of Residual Activity in the Spent Syringe and Dispensing Accuracy of Ra 223

    Energy Technology Data Exchange (ETDEWEB)

    Jennings, G [Marsden Medical Physics Associates, Denville, NJ (United States)

    2016-06-15

    Purpose: To quantify the delivered activity accuracy of Radium 223 dichloride injections, when being administrated for castration – resistant prostate cancer, symptomatic bone metastases. The impact of residual activity in the spent syringe and dispensing accuracy of Ra 223. Methods: The administration is by slow intravenous injection over 1 minute followed by double flushing of the 10 mL syringe and IV with saline. Eighty (80) procedures was used to investigate variations in the activity from the amount prescribed (µCi) = 1.35 × Patient weight Kg. The Activity dispensed into a 10mL syringe using a NIST traceable Capintec CRC-25R Chamber and a cross calibrated capintec CRC-15R to measure activity in the syringe immediately before and after administration Results: The patients weight range from 121Ib to 235lb and doses ranging 74.25 µCi to 144.2 µCi. The deviation of dispensed dose vs Prescribed dose average +2.1% with a range of −1.1% to +5.7%. The Dose measured before administration ranges 79.3 µCi to 154.9 µCi. Deviation from the dispensed dose was show to average +2.9% with a range of −0.8% to +7.3%. The average residual dose post injection was 2.5 µCi or 2.2% of the pre injection activity. Ranging from 0.9 µCi to 6.2 µCi, 0.7% to 5.4% respectively. Subtracting the residual activity from that measured activity before injection and comparing it to prescription dose was shown to have an average variation of +2.7% with a range of −0.8% to 7.4%. Conclusion: The case resulted in the 6.2 µCi maximum residual dose had two syringes. A small, 82.8 µCi activity, case resulted in the 7.4% maximum variation in measures less residual verses prescription dose. The average +2.1 % dispenses activity of Ra 223 over the prescription dosage was seen to counteract the average 2.2% residual dosage found to remain in the syringe.

  10. Impact of Phosphoproteomics in the Era of Precision Medicine for Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Johnny R. Ramroop

    2018-02-01

    Full Text Available Prostate cancer is the most common malignancy in men in the United States. While androgen deprivation therapy results in tumor responses initially, there is relapse and progression to metastatic castration-resistant prostate cancer. Currently, all prostate cancer patients receive essentially the same treatment, and there is a need for clinically applicable technologies to provide predictive biomarkers toward personalized therapies. Genomic analyses of tumors are used for clinical applications, but with a paucity of obvious driver mutations in metastatic castration-resistant prostate cancer, other applications, such as phosphoproteomics, may complement this approach. Immunohistochemistry and reverse phase protein arrays are limited by the availability of reliable antibodies and evaluates a preselected number of targets. Mass spectrometry-based phosphoproteomics has been used to profile tumors consisting of thousands of phosphopeptides from individual patients after surgical resection or at autopsy. However, this approach is time consuming, and while a large number of candidate phosphopeptides are obtained for evaluation, limitations are reduced reproducibility, sensitivity, and precision. Targeted mass spectrometry can help eliminate these limitations and is more cost effective and less time consuming making it a practical platform for future clinical testing. In this review, we discuss the use of phosphoproteomics in prostate cancer and other clinical cancer tissues for target identification, hypothesis testing, and possible patient stratification. We highlight the majority of studies that have used phosphoproteomics in prostate cancer tissues and cell lines and propose ways forward to apply this approach in basic and clinical research. Overall, the implementation of phosphoproteomics via targeted mass spectrometry has tremendous potential to aid in the development of more rational, personalized therapies that will result in increased survival

  11. Gene Delivery for Metastatic Prostate Cancer Cells

    National Research Council Canada - National Science Library

    Pang, Shen

    2001-01-01

    .... Enhanced by the bystander effect, the specific expression of the DTA gene causes significant cell death in prostate cancer cell cultures, with very low background cell eradication in control cell lines...

  12. Controversies and consensus in the innovation access for cancer therapy in the European countries: on the subject of metastatic prostate cancer.

    Science.gov (United States)

    Oudard, S; Courbon, F

    2017-02-01

    Innovative cancer therapies and advances in drug development have created new hopes for patients and health providers. The purpose of this article was to evaluate the discrepancies in the assessment of the magnitude of benefit of four new drugs (abiraterone acetate, enzalutamide, cabazitaxel, radium-223 dichloride) for the treatment of metastatic castration-resistant prostate cancer (mCRPC). The comparison was done among three European countries (UK, Germany and France) and Canada, according to the statement of each country and to the European Society of Medical Oncology (ESMO) Magnitude of Clinical Benefit Scale. Whereas those drugs are authorized by the European Medical Agency, one can observed that clear discrepancies in the magnitude of benefit assessment exist between selected countries, as well as between national pricing evaluation agencies and ESMO. However, price setting and reimbursement decisions remain national responsibility with differences in assessment of the medical value of new treatment across countries, leading to a heterogeneous accessibility to cancer treatments. In conclusion, several procedures have to be implemented to overcome the patchwork of administrative assessments. Among them, the assessment of medical value should be based on independent statements of learned societies, and the harmonization of access to cancer therapy in Europe has to be driven by a common European reimbursement and pricing policy. © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  13. The impact of repeated cycles of radioligand therapy using [{sup 177}Lu]Lu-PSMA-617 on renal function in patients with hormone refractory metastatic prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Yordanova, Anna; Becker, Anja; Eppard, Elisabeth; Kuerpig, Stefan; Essler, Markus; Ahmadzadehfar, Hojjat [University Hospital Bonn, Department of Nuclear Medicine, Bonn (Germany); Fisang, Christian [University Hospital Bonn, Department of Urology, Bonn (Germany); Feldmann, Georg [University Hospital Bonn, Department of Internal Medicine, MED3, Bonn (Germany)

    2017-08-15

    [{sup 177}Lu]Lu-PSMA-617 is a well-tolerated therapy for the treatment of metastatic prostate cancer. However, because of the mainly renal excretion of the tracer, the kidneys are one of the most limiting organs. The purpose of this study was to examine the post-therapeutic changes in renal function over time and to identify risk factors for developing renal toxicity. We also tested the reliability of markers for renal function monitoring. Fifty-five patients with castrate-resistant metastatic prostate cancer treated with at least three cycles of [{sup 177}Lu]Lu-PSMA-617 were investigated. Renal function was assessed through laboratory tests (creatinine, GFR, cystatin C) and Tc-99 m-MAG3 measurements. Adverse events were classified according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. To identify risk factors for renal toxicity, we used Pearson's correlation coefficient and the corresponding p values. None of the 55 patients experienced severe nephrotoxicity (grade 3/4). In 14 patients (25%), we observed increased creatinine levels of CTC 1 or 2 . There were 16 cases of increased GFR (grade 1/2). At the baseline, only 14 patients had elevated cystatin C. However, post-therapeutic cystatin C was elevated in 32 patients (58%). A significant effect on renal function was found for age (p = 0.049), hypertension (p = 0.001) and pre-existing kidney disease (p = 0.001). The most reliable predictive markers of nephrotoxicity were TER-MAG3 and cystatin C. Renal toxicity in patients treated with [{sup 177}Lu]Lu-PSMA-617 was low. There was no (sub)acute grade 3 or 4 nephrotoxicity. (orig.)

  14. Metastatic Breast Carcinoma to the Prostate Gland

    Directory of Open Access Journals (Sweden)

    Meghan E. Kapp

    2016-01-01

    Full Text Available Cancer of the male breast is an uncommon event with metastases to the breast occurring even less frequently. Prostate carcinoma has been reported as the most frequent primary to metastasize to the breast; however, the reverse has not been previously reported. Herein, we present, for the first time, a case of breast carcinoma metastasizing to the prostate gland. Prostate needle core biopsy revealed infiltrative nests of neoplastic epithelioid cells, demonstrated by immunohistochemistry (IHC to be positive for GATA3 and ER and negative for PSA and P501S. A prostate cocktail by IHC study demonstrated lack of basal cells (p63 and CK903 and no expression of P501S. The patient’s previous breast needle core biopsy showed strong ER positivity and negative staining for PR and HER2. Similar to the prostate, the breast was negative for CK5/6, p63, and p40. This case demonstrates the importance of considering a broad differential diagnosis and comparing histology and IHC to prior known malignancies in the setting of atypical presentation or rare tumors.

  15. Cytoreductive prostatectomy in metastatic prostate cancer

    DEFF Research Database (Denmark)

    Becker, Joachim Aidt; Berg, Kasper Drimer; Røder, Martin Andreas

    2018-01-01

    The impact of cytoreductive radical prostatectomy on oncological outcome in patients with prostate cancer and limited number of bone metastases is unclear. Data from cancer registries, multi-institutional databases and a single institutional case-control study indicate a possible benefit of combi......The impact of cytoreductive radical prostatectomy on oncological outcome in patients with prostate cancer and limited number of bone metastases is unclear. Data from cancer registries, multi-institutional databases and a single institutional case-control study indicate a possible benefit...

  16. Molecular Indicators of Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2015-12-01

    Kaplan –Meier methods, and sur- vival-time differences were compared with the use of the log...ol ut e C op y N o. 10 8 6 4 2 0 P2 6 P3 5 P3 6 P4 6 P5 1 P6 0 P8 4 P9 1 P9 3 P1 3 P5 7 P7 5 P7 9 P5 6 P6 4 P8 8 P2 9 P8 3 P0 6 P2 0 P7 1 P7 4 P8 6...P1 0 P1 9 P0 2 P4 0 P4 1 P0 4 P5 0 P5 2 P5 5 P5 8 P5 9 P9 4 P1 8 P8 7 P4 9 P4 8 P4 4 P7 0 P8 5 P3 2 P3 7

  17. Characterization of KRAS Rearrangements in Metastatic Prostate Cancer

    Science.gov (United States)

    Wang, Xiao-Song; Shankar, Sunita; Dhanasekaran, Saravana M.; Ateeq, Bushra; Sasaki, Atsuo T.; Jing, Xiaojun; Robinson, Daniel; Cao, Qi; Prensner, John R.; Yocum, Anastasia K.; Wang, Rui; Fries, Daniel F.; Han, Bo; Asangani, Irfan A.; Cao, Xuhong; Li, Yong; Omenn, Gilbert S.; Pflueger, Dorothee; Gopalan, Anuradha; Reuter, Victor E.; Kahoud, Emily Rose; Cantley, Lewis C.; Rubin, Mark A.; Palanisamy, Nallasivam; Varambally, Sooryanarayana; Chinnaiyan, Arul M.

    2011-01-01

    Using an integrative genomics approach called Amplification Breakpoint Ranking and Assembly (ABRA) analysis, we nominated KRAS as a gene fusion with the ubiquitin-conjugating enzyme UBE2L3 in the DU145 cell line, originally derived from prostate cancer metastasis to the brain. Interestingly, analysis of tissues revealed that 2 of 62 metastatic prostate cancers harbored aberrations at the KRAS locus. In DU145 cells, UBE2L3-KRAS produces a fusion protein, specific knock-down of which, attenuates cell invasion and xenograft growth. Ectopic expression of the UBE2L3-KRAS fusion protein exhibits transforming activity in NIH 3T3 fibroblasts and RWPE prostate epithelial cells in vitro and in vivo. In NIH 3T3 cells, UBE2L3-KRAS attenuates MEK/ERK signaling, commonly engaged by oncogenic mutant KRAS, and instead signals via AKT and p38 MAPK pathways. This is the first report of a gene fusion involving Ras family suggesting that this aberration may drive metastatic progression in a rare subset of prostate cancers. PMID:22140652

  18. Hormone therapy in metastatic prostate cancer

    Directory of Open Access Journals (Sweden)

    Jebelameli P

    1997-09-01

    Full Text Available Only orchiectomy is still commonly used today either as a single therapy or in combination regimens. Hypophysectomy & adrenalectomy showed such devastating effects on the endocrine equilibrium as to be inconsistent with an acceptable quality of life or even with survival. Chemical adrenalectomy was also tried with drugs (eg. aminoglutethmide, spironolactone leading to consequences superimposable to those of surgical adrenalectomy. Along with orchiectomy, three groups of substances are commonly used today for the hormonal therapy of prostate cancer: estrogens, LHRH agonists & anti androgens. Bilateral orchiectomy removes 90-95% of circulating testosterone. Clinical studies document 60-80% of positive responders to castration, on continued evaluation, relapse occurs usually within 6-24 months in responders, with a death rate of 50% within 6 months. The androgenic activity still remaining after castration may explain the partial & progressively decreasing effectiveness of this & other testosterone reducing therapies. Antiandrogens define substances that act directly at the target site, where interacting with steroid hormone receptors, they impede the binding of androgens. A trend towards the combination of testosterone-reducing & androgen-blocking treatment is developing in modern therapy of prostate cancer. This is due to the complementary characteristics of the two different pharmacological mechanisms that are involved. In this study castration+antiandrogen is compared to castration alone. The results demonstrate a significantly greater percentage of positive objective & subjective responses with antiandrogen than with placebo. In addition survival time was increased in patients treated with castration+antiandrogen than castration+placebo.

  19. Metastatic prostate cancer in the modern era of PSA screening

    Directory of Open Access Journals (Sweden)

    Philip A. Fontenot Jr

    Full Text Available ABSTRACT Introduction To characterize initial presentation and PSA screening status in a contemporary cohort of men treated for metastatic prostate cancer at our institution. Materials and methods We reviewed records of 160 men treated for metastatic prostate cancer between 2008-2014 and assessed initial presentation, categorizing patients into four groups. Groups 1 and 2 presented with localized disease and received treatment. These men suffered biochemical recurrence late (>1 year or earlier (<1 year, respectively, and developed metastases. Groups 3 and 4 had asymptomatic and symptomatic metastases at the outset of their diagnosis. Patients with a first PSA at age 55 or younger were considered to have guideline-directed screening. Results Complete records were available on 157 men for initial presentation and 155 men for PSA screening. Groups 1, 2, 3 and 4 included 27 (17%, 7 (5%, 69 (44% and 54 (34% patients, respectively. Twenty (13% patients received guideline-directed PSA screening, 5/155 (3% patients presented with metastases prior to age 55 with their first PSA, and 130/155 (84% had their first PSA after age 55, of which 122/130 (94% had metastasis at the time of diagnosis. Conclusion Despite widespread screening, most men treated for metastatic prostate cancer at our institution presented with metastases rather than progressed after definitive treatment. Furthermore, 25 (16% patients received guideline-directed PSA screening at or before age 55. These data highlight that, despite mass screening efforts, patients treated for incurable disease at our institution may not have been a result of a failed screening test, but a failure to be screened.

  20. Metastatic prostate cancer in the modern era of PSA screening

    Science.gov (United States)

    Fontenot, Philip A.; Nehra, Avinash; Parker, William; Wyre, Hadley; Mirza, Moben; Duchene, David A.; Holzbeierlein, Jeffrey; Thrasher, James Brantley; Veldhuizen, Peter Van; Lee, Eugene K.

    2017-01-01

    ABSTRACT Introduction To characterize initial presentation and PSA screening status in a contemporary cohort of men treated for metastatic prostate cancer at our institution. Materials and methods We reviewed records of 160 men treated for metastatic prostate cancer between 2008-2014 and assessed initial presentation, categorizing patients into four groups. Groups 1 and 2 presented with localized disease and received treatment. These men suffered biochemical recurrence late (>1 year) or earlier (<1 year), respectively, and developed metastases. Groups 3 and 4 had asymptomatic and symptomatic metastases at the outset of their diagnosis. Patients with a first PSA at age 55 or younger were considered to have guideline-directed screening. Results Complete records were available on 157 men for initial presentation and 155 men for PSA screening. Groups 1, 2, 3 and 4 included 27 (17%), 7 (5%), 69 (44%) and 54 (34%) patients, respectively. Twenty (13%) patients received guideline-directed PSA screening, 5/155 (3%) patients presented with metastases prior to age 55 with their first PSA, and 130/155 (84%) had their first PSA after age 55, of which 122/130 (94%) had metastasis at the time of diagnosis. Conclusion Despite widespread screening, most men treated for metastatic prostate cancer at our institution presented with metastases rather than progressed after definitive treatment. Furthermore, 25 (16%) patients received guideline-directed PSA screening at or before age 55. These data highlight that, despite mass screening efforts, patients treated for incurable disease at our institution may not have been a result of a failed screening test, but a failure to be screened. PMID:28338310

  1. Immune Response to Sipuleucel-T in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    David I. Quinn

    2012-04-01

    Full Text Available Historically, chemotherapy has remained the most commonly utilized therapy in patients with metastatic cancers. In prostate cancer, chemotherapy has been reserved for patients whose metastatic disease becomes resistant to first line castration or androgen deprivation. While chemotherapy palliates, decreases serum prostate specific antigen and improves survival, it is associated with significant side effects and is only suitable for approximately 60% of patients with castrate-resistant prostate cancer. On that basis, exploration of other therapeutic options such as active secondary hormone therapy, bone targeted treatments and immunotherapy are important. Until recently, immunotherapy has had no role in the treatment of solid malignancies aside from renal cancer and melanoma. The FDA-approved autologous cellular immunotherapy sipuleucel-T has demonstrated efficacy in improving overall survival in patients with metastatic castrate-resistant prostate cancer in randomized clinical trials. The proposed mechanism of action is reliant on activating the patients’ own antigen presenting cells (APCs to prostatic acid phosphatase (PAP fused with granulocyte-macrophage colony stimulating factor (GM-CSF and subsequent triggered T-cell response to PAP on the surface of prostate cancer cells in the patients body. Despite significant prolongation of survival in Phase III trials, the challenge to health care providers remains the dissociation between objective changes in serum PSA or on imaging studies after sipleucel-T and survival benefit. On that basis there is an unmet need for markers of outcome and a quest to identify immunologic or clinical surrogates to fill this role. This review focuses on the impact of sipuleucel-T on the immune system, the T and B cells, and their responses to relevant antigens and prostate cancer. Other therapeutic modalities such as chemotherapy, corticosteroids and GM-CSF and host factors can also affect immune response. The

  2. ONC201 Targets AR and AR-V7 Signaling, Reduces PSA, and Synergizes with Everolimus in Prostate Cancer.

    Science.gov (United States)

    Lev, Avital; Lulla, Amriti R; Ross, Brian C; Ralff, Marie D; Makhov, Petr B; Dicker, David T; El-Deiry, Wafik S

    2018-05-01

    Androgen receptor (AR) signaling plays a key role in prostate cancer progression, and androgen deprivation therapy (ADT) is a mainstay clinical treatment regimen for patients with advanced disease. Unfortunately, most prostate cancers eventually become androgen-independent and resistant to ADT with patients progressing to metastatic castration-resistant prostate cancer (mCRPC). Constitutively activated AR variants (AR-V) have emerged as mediators of resistance to AR-targeted therapy and the progression of mCRPC, and they represent an important therapeutic target. Out of at least 15 AR-Vs described thus far, AR-V7 is the most abundant, and its expression correlates with ADT resistance. ONC201/TIC10 is the founding member of the imipridone class of small molecules and has shown anticancer activity in a broad range of tumor types. ONC201 is currently being tested in phase I/II clinical trials for advanced solid tumors, including mCRPC, and hematologic malignancies. There has been promising activity observed in patients in early clinical testing. This study demonstrates preclinical single-agent efficacy of ONC201 using in vitro and in vivo models of prostate cancer. ONC201 has potent antiproliferative and proapoptotic effects in both castration-resistant and -sensitive prostate cancer cells. Furthermore, the data demonstrate that ONC201 downregulates the expression of key drivers of prostate cancer such as AR-V7 and downstream target genes including the clinically used biomarker PSA (KLK3). Finally, the data also provide a preclinical rationale for combination of ONC201 with approved therapeutics for prostate cancer such as enzalutamide, everolimus (mTOR inhibitor), or docetaxel. Implications: The preclinical efficacy of ONC201 as a single agent or in combination, in hormone-sensitive or castration-resistant prostate cancer, suggests the potential for immediate clinical translation. Mol Cancer Res; 16(5); 754-66. ©2018 AACR . ©2018 American Association for Cancer

  3. Neoadjuvant Treatment of High-Risk, Clinically Localized Prostate Cancer Prior to Radical Prostatectomy.

    Science.gov (United States)

    Pietzak, Eugene J; Eastham, James A

    2016-05-01

    Multimodal strategies combining local and systemic therapy offer the greatest chance of cure for many with men with high-risk prostate cancer who may harbor occult metastatic disease. However, no systemic therapy combined with radical prostatectomy has proven beneficial. This was in part due to a lack of effective systemic agents; however, there have been several advancements in the metastatic and castrate-resistant prostate cancer that might prove beneficial if given earlier in the natural history of the disease. For example, novel hormonal agents have recently been approved for castration-resistant prostate cancer with some early phase II neoadjuvant showing promise. Additionally, combination therapy with docetaxel-based chemohormonal has demonstrated a profound survival benefit in metastatic hormone-naïve patients and might have a role in eliminating pre-existing ADT-resistant tumor cells in the neoadjuvant setting. The Cancer and Leukemia Group B (CALGB)/Alliance 90203 trial has finished accrual and should answer the question as to whether neoadjuvant docetaxel-based chemohormonal therapy provides an advantage over prostatectomy alone. There are also several promising targeted agents and immunotherapies under investigation in phase I/II trials with the potential to provide benefit in the neoadjuvant setting.

  4. PROSTVAC® targeted immunotherapy candidate for prostate cancer.

    Science.gov (United States)

    Shore, Neal D

    2014-01-01

    Targeted immunotherapies represent a valid strategy for the treatment of metastatic castrate-resistant prostate cancer. A randomized, double-blind, Phase II clinical trial of PROSTVAC® demonstrated a statistically significant improvement in overall survival and a large, global, Phase III trial with overall survival as the primary end point is ongoing. PROSTVAC immunotherapy contains the transgenes for prostate-specific antigen and three costimulatory molecules (designated TRICOM). Research suggests that PROSTVAC not only targets prostate-specific antigen, but also other tumor antigens via antigen cascade. PROSTVAC is well tolerated and has been safely combined with other cancer therapies, including hormonal therapy, radiotherapy, another immunotherapy and chemotherapy. Even greater benefits of PROSTVAC may be recognized in earlier-stage disease and low-disease burden settings where immunotherapy can trigger a long-lasting immune response.

  5. The epigenome as a therapeutic target in prostate cancer.

    Science.gov (United States)

    Perry, Antoinette S; Watson, R William G; Lawler, Mark; Hollywood, Donal

    2010-12-01

    During cancer development and progression, tumor cells undergo abnormal epigenetic modifications, including DNA methylation, histone deacetylation and nucleosome remodeling. Collectively, these aberrations promote genomic instability and lead to silencing of tumor-suppressor genes and reactivation of oncogenic retroviruses. Epigenetic modifications, therefore, provide exciting new avenues for prostate cancer research. Promoter hypermethylation is widespread during neoplastic transformation of prostate cells, which suggests that restoration of a 'normal' epigenome through treatment with inhibitors of the enzymes involved could be clinically beneficial. Global patterns of histone modifications are also being defined and have been associated with clinical and pathologic predictors of prostate cancer outcome. Although treatment for localized prostate cancer can be curative, the development of successful therapies for the management of castration-resistant metastatic disease is urgently needed. Reactivation of tumor-suppressor genes by demethylating agents and histone deacetylase inhibitors could be a potential treatment option for patients with advanced disease.

  6. Galeterone for the treatment of advanced prostate cancer: the evidence to date

    Directory of Open Access Journals (Sweden)

    Bastos DA

    2016-07-01

    Full Text Available Diogo A Bastos,1 Emmanuel S Antonarakis2 1Department of Oncology, Hospital Sirio-Libanes, Sao Paulo, Brazil; 2Department of Oncology and Urology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA Abstract: Major advances have been achieved recently in the treatment of metastatic castration-resistant prostate cancer, resulting in significant improvements in quality of life and survival with the use of several new agents, including the next-generation androgen receptor (AR-targeted drugs abiraterone and enzalutamide. However, virtually all patients will eventually progress on these therapies and most will ultimately die of treatment-refractory metastatic disease. Recently, several mechanisms of resistance to AR-directed therapies have been uncovered, including the AR splice variant 7 (AR-V7, which is a ligand-independent constitutionally-active form of the AR that has been associated with poor outcomes to abiraterone and enzalutamide. Galeterone, a potent anti-androgen with three modes of action (CYP17 lyase inhibition, AR antagonism, and AR degradation, is a novel agent under clinical development that could potentially target both full-length AR and aberrant AR, including AR-V7. In this manuscript, we will first discuss the biological mechanisms of action of galeterone and then review the safety and efficacy data from Phase I and II clinical studies of galeterone in patients with metastatic castration-resistant prostate cancer. A Phase III study of galeterone (compared against enzalutamide in AR-V7-positive patients is currently underway, and represents the first pivotal trial using a biomarker-selection design in this disease. Keywords: galeterone, AR splice variants, AR-V7, castration-resistant prostate cancer

  7. Surgical management of prostate cancer metastatic to the spine.

    Science.gov (United States)

    Williams, Brian J; Fox, Benjamin D; Sciubba, Daniel M; Suki, Dima; Tu, Shi Ming; Kuban, Deborah; Gokaslan, Ziya L; Rhines, Laurence D; Rao, Ganesh

    2009-05-01

    Significant improvements in neurological function and pain relief are the benefits of aggressive surgical management of spinal metastatic disease. However, there is limited literature regarding the management of tumors with specific histological features. In this study, a series of patients undergoing spinal surgery for metastatic prostate cancer were reviewed to identify predictors of survival and functional outcome. The authors retrospectively reviewed the records of all patients who were treated with surgery for prostate cancer metastases to the spine between 1993 and 2005 at a single institution. Particular attention was given to initial presentation, operative management, clinical and neurological outcomes, and factors associated with complications and overall survival. Forty-four patients underwent a total of 47 procedures. The median age at spinal metastasis was 66 years (range 50-84 years). Twenty-four patients had received previous external-beam radiation to the site of spinal involvement, with a median dose of 70 Gy (range 30-74 Gy). Frankel scores on discharge were significantly improved when compared with preoperative scores (p = 0.001). Preoperatively, 32 patients (73%) were walking and 33 (75%) were continent. On discharge, 36 (86%) of 42 patients were walking, and 37 (88%) of 42 were continent. Preoperatively, 40 patients (91%) were taking narcotics, with a median morphine equivalent dose of 21.5 mg/day, and 28 patients (64%) were taking steroids, with a median dose of 16 mg/day. At discharge, the median postoperative morphine equivalent dose was 12 mg/day, and the median steroid dose was 0 mg/day (p or = 65 years at the time of surgery was an independent predictor of a postoperative complication (p = 0.005). In selected patients with prostate cancer metastases to the spine, aggressive surgical decompression and spinal reconstruction is a useful treatment option. The results show that on average, neurological outcome is improved and use of analgesics

  8. Immunohistochemical staining of precursor forms of prostate-specific antigen (proPSA) in metastatic prostate cancer.

    Science.gov (United States)

    Parwani, Anil V; Marlow, Cameron; Demarzo, Angelo M; Mikolajczyk, Stephen D; Rittenhouse, Harry G; Veltri, Robert W; Chan, Theresa Y

    2006-10-01

    Precursors of prostate-specific antigen (proPSA) have been previously shown to be more concentrated in prostate cancer tissue. This study characterizes the immunohistochemical staining (IHS) of proPSA forms in metastatic prostate cancer compared with prostate specific antigen (PSA) and prostatic acid phosphatase (PAP). A tissue microarray, consisting of 74 cases of metastatic prostate carcinoma and control tissues, was used. IHS, using monoclonal antibodies against proPSA with a truncated proleader peptide containing 2 amino acids ([-2]pPSA), native ([-5/-7]pPSA), PSA, and PAP, was analyzed. The monoclonal antibodies were specific for both benign and malignant prostatic glandular tissue. IHS with [-5/-7]pPSA showed the least number of cases with negative staining (3%), and the most number of cases with moderate or strong staining (76%). In the 60 cases where all 4 stains could be evaluated, none of them were negative for proPSA and positive for PSA or PAP, and all 7 cases that were negative for both PSA and PAP showed IHS to proPSA. [-5/-7]pPSA (native proPSA) may be a better marker than PSA and PAP in characterizing metastatic prostate adenocarcinoma, with most of the cases showing positivity for the marker. Even cases that were negative for PSA and PAP, were reactive for proPSA. Such enhanced detection is particularly important in poorly differentiated carcinomas involving metastatic sites where prostate carcinoma is a consideration. A panel of markers, including proPSA, should be performed when metastatic prostate carcinoma is in the differential diagnosis.

  9. Benzimidazole as Novel Therapy for Hormone-Refractory Metastatic Prostate Cancer

    Science.gov (United States)

    2011-05-01

    8 4 INTRODUCTION The focus of this project is to evaluate the anti-tumor effects of benzimidazoles as a...potential anti-metastatic prostate cancer therapy. We identified benzimidazoles , a class of anti-parasitic drug, in a drug screening process for...preferential anti-tumor activity on metastatic prostate cancer cells. We have data indicate that benzimidazoles have potent anti-tumor activities

  10. Human Prostate Cancer Hallmarks Map

    Science.gov (United States)

    Datta, Dipamoy; Aftabuddin, Md.; Gupta, Dinesh Kumar; Raha, Sanghamitra; Sen, Prosenjit

    2016-01-01

    Human prostate cancer is a complex heterogeneous disease that mainly affects elder male population of the western world with a high rate of mortality. Acquisitions of diverse sets of hallmark capabilities along with an aberrant functioning of androgen receptor signaling are the central driving forces behind prostatic tumorigenesis and its transition into metastatic castration resistant disease. These hallmark capabilities arise due to an intense orchestration of several crucial factors, including deregulation of vital cell physiological processes, inactivation of tumor suppressive activity and disruption of prostate gland specific cellular homeostasis. The molecular complexity and redundancy of oncoproteins signaling in prostate cancer demands for concurrent inhibition of multiple hallmark associated pathways. By an extensive manual curation of the published biomedical literature, we have developed Human Prostate Cancer Hallmarks Map (HPCHM), an onco-functional atlas of human prostate cancer associated signaling and events. It explores molecular architecture of prostate cancer signaling at various levels, namely key protein components, molecular connectivity map, oncogenic signaling pathway map, pathway based functional connectivity map etc. Here, we briefly represent the systems level understanding of the molecular mechanisms associated with prostate tumorigenesis by considering each and individual molecular and cell biological events of this disease process. PMID:27476486

  11. Urothelial-Type adenocarcinoma of the prostate mimicking metastatic colorectal adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Brian P. Adley

    2006-12-01

    Full Text Available Adenocarcinoma arising in urinary bladder or prostatic urethra is uncommon. When they occur, the tumor can be mistaken for metastatic lesions, especially from the colon. Here we report the fifth case of a primary urothelial-type adenocarcinoma arising in the prostate which showed enteric differentiation. The patient was a 55 year-old male whose prostatic needle core biopsy showed a high grade adenocarcinoma which was initially thought to be metastatic colon cancer. A follow-up colonoscopy was unremarkable. Subsequent prostatectomy revealed a high grade adenocarcinoma which was positive for cytokeratins 7 and 20, carcinoembryonic antigen, CDX2, and high molecular weight cytokeratin, and negative for prostate specific antigen, prostate specific acid phosphatase and AMACR. A diagnosis of urothelial-type adenocarcinoma of the prostate was rendered. We review the literature regarding this entity, and discuss the differential diagnosis, emphasizing utility of immunohistochemistry in making the diagnosis. Finally, we speculate on the behavior of these rare tumors.

  12. CURRENT POSSIBILITIES OF TREATMENT FOR VISCERAL METASTASES IN PATIENTS WITH METASTATIC CASTRATION-REFRACTORY PROSTATE CANCER

    Directory of Open Access Journals (Sweden)

    A. V. Govorov

    2014-07-01

    Full Text Available Medications increasing the survival of patients with metastatic castration-refractory prostate cancer (CRPC are lacking today. In the past 3 years, in the pharmaceutical market there have been a few novel drugs to treat progressive prostate cancer. Abiraterone acetate is an androgen synthesis inhibitor, which is also used to increase the survival of patients with metastatic CRPC that progresses after chemotherapy. The results of treatment for metastatic CRPC depend on a number of factors. Visceral metastases are poor predictors of the course of the disease. The results of abiraterone acetate treatment were analyzed in CRPC patients with visceral metastases.

  13. A randomized, double-blind, placebo-controlled phase 2 study of maintenance therapy with tasquinimod in patients with metastatic castration-resistant prostate cancer responsive to or stabilized during first-line docetaxel chemotherapy

    DEFF Research Database (Denmark)

    Fizazi, K; Ulys, A; Sengeløv, L

    2017-01-01

    ) to receive tasquinimod (0.25-1.0 mg/day orally) or placebo. The primary end point was radiologic progression-free survival (rPFS); secondary efficacy end points included: overall survival (OS); PFS on next-line therapy (PFS 2) and symptomatic PFS, assessed using the Brief Pain Inventory (BPI) questionnaire...... duration of treatment was 18.7 weeks (range 0.6-102.7 weeks) for the tasquinimod arm and 19.2 weeks (range 0.4-80.0 weeks) for the placebo arm. Median (90% CI) rPFS was 31.7 (24.3-53.7) and 22.7 (16.1-25.9) weeks in the tasquinimod and placebo arms, respectively [HR (90% CI) 0.6 (0.4-0.9), P = 0...... in the tasquinimod and placebo arms (97.2% versus 94.3%, respectively), whereas severe TEAEs (NCI-CTC Grade 3-5) incidence was higher in the tasquinimod group (50.7% versus 27.1%). Conclusions: Randomized trials testing new drugs as maintenance can be successfully conducted after chemotherapy in castrate...

  14. Gene expression profiles of prostate cancer reveal involvement of multiple molecular pathways in the metastatic process

    International Nuclear Information System (INIS)

    Chandran, Uma R; Ma, Changqing; Dhir, Rajiv; Bisceglia, Michelle; Lyons-Weiler, Maureen; Liang, Wenjing; Michalopoulos, George; Becich, Michael; Monzon, Federico A

    2007-01-01

    Prostate cancer is characterized by heterogeneity in the clinical course that often does not correlate with morphologic features of the tumor. Metastasis reflects the most adverse outcome of prostate cancer, and to date there are no reliable morphologic features or serum biomarkers that can reliably predict which patients are at higher risk of developing metastatic disease. Understanding the differences in the biology of metastatic and organ confined primary tumors is essential for developing new prognostic markers and therapeutic targets. Using Affymetrix oligonucleotide arrays, we analyzed gene expression profiles of 24 androgen-ablation resistant metastatic samples obtained from 4 patients and a previously published dataset of 64 primary prostate tumor samples. Differential gene expression was analyzed after removing potentially uninformative stromal genes, addressing the differences in cellular content between primary and metastatic tumors. The metastatic samples are highly heterogenous in expression; however, differential expression analysis shows that 415 genes are upregulated and 364 genes are downregulated at least 2 fold in every patient with metastasis. The expression profile of metastatic samples reveals changes in expression of a unique set of genes representing both the androgen ablation related pathways and other metastasis related gene networks such as cell adhesion, bone remodelling and cell cycle. The differentially expressed genes include metabolic enzymes, transcription factors such as Forkhead Box M1 (FoxM1) and cell adhesion molecules such as Osteopontin (SPP1). We hypothesize that these genes have a role in the biology of metastatic disease and that they represent potential therapeutic targets for prostate cancer

  15. Defective DNA repair mechanisms in prostate cancer: impact of olaparib

    Directory of Open Access Journals (Sweden)

    De Felice F

    2017-03-01

    Full Text Available Francesca De Felice,1 Vincenzo Tombolini,1 Francesco Marampon,2 Angela Musella,3 Claudia Marchetti3 1Department of Radiotherapy, Policlinico Umberto I, “Sapienza” University of Rome, Rome, 2Department of Biotechnological and Applied Clinical Sciences, Laboratory of Radiobiology, University of L’Aquila, L’Aquila, 3Department of Gynecological and Obstetrical Sciences and Urological Sciences, “Sapienza” University of Rome, Rome, Italy Abstract: The field of prostate oncology has continued to change dramatically. It has truly become a field that is intensely linked to molecular genetic alterations, especially DNA-repair defects. Germline breast cancer 1 gene (BRCA1 and breast cancer 2 gene (BRCA2 mutations are implicated in the highest risk of prostate cancer (PC predisposition and aggressiveness. Poly adenosine diphosphate ribose polymerase (PARP proteins play a key role in DNA repair mechanisms and represent a valid target for new therapies. Olaparib is an oral PARP inhibitor that blocks DNA repair pathway and coupled with BRCA mutated-disease results in tumor cell death. In phase II clinical trials, including patients with advanced castration-resistant PC, olaparib seems to be efficacious and well tolerated. Waiting for randomized phase III trials, olaparib should be considered as a promising treatment option for PC. Keywords: prostate cancer, metastatic disease, castration resistant, BRCA, DNA-repair, PARP, olaparib

  16. Stable and high expression of Galectin-8 tightly controls metastatic progression of prostate cancer

    Science.gov (United States)

    Gentilini, Lucas Daniel; Pérez, Ignacio González; Kotler, Monica Lidia; Chauchereau, Anne; Laderach, Diego Jose; Compagno, Daniel

    2017-01-01

    Two decades ago, Galectin-8 was described as a prostate carcinoma biomarker since it is only expressed in the neoplastic prostate, but not in the healthy tissue. To date, no biological function has been attributed to Galectin-8 that could explain this differential expression. In this study we silenced Galectin-8 in two human prostate cancer cell lines, PC3 and IGR-CaP1, and designed a pre-clinical experimental model that allows monitoring the pathology from its early steps to the long-term metastatic stages. We show for the first time that the natural and conserved expression of Gal-8 in tumour cells is responsible for the metastatic evolution of prostate cancer. In fact, Gal-8 controls the rearrangement of the cytoskeleton and E-Cadherin expression, with a major impact on anoikis and homotypic aggregation of tumour cells, both being essential processes for the survival of circulating tumour cells during metastasis. While localized prostate cancer can be cured, metastatic and advanced disease remains a significant therapeutic challenge, urging for the identification of prognostic markers of the metastatic process. Collectively, our results highlight Galectin-8 as a potential target for anti-metastatic therapy against prostate cancer. PMID:28591719

  17. Prospective Genomic Profiling of Prostate Cancer Across Disease States Reveals Germline and Somatic Alterations That May Affect Clinical Decision Making.

    Science.gov (United States)

    Abida, Wassim; Armenia, Joshua; Gopalan, Anuradha; Brennan, Ryan; Walsh, Michael; Barron, David; Danila, Daniel; Rathkopf, Dana; Morris, Michael; Slovin, Susan; McLaughlin, Brigit; Curtis, Kristen; Hyman, David M; Durack, Jeremy C; Solomon, Stephen B; Arcila, Maria E; Zehir, Ahmet; Syed, Aijazuddin; Gao, Jianjiong; Chakravarty, Debyani; Vargas, Hebert Alberto; Robson, Mark E; Joseph, Vijai; Offit, Kenneth; Donoghue, Mark T A; Abeshouse, Adam A; Kundra, Ritika; Heins, Zachary J; Penson, Alexander V; Harris, Christopher; Taylor, Barry S; Ladanyi, Marc; Mandelker, Diana; Zhang, Liying; Reuter, Victor E; Kantoff, Philip W; Solit, David B; Berger, Michael F; Sawyers, Charles L; Schultz, Nikolaus; Scher, Howard I

    2017-07-01

    A long natural history and a predominant osseous pattern of metastatic spread are impediments to the adoption of precision medicine in patients with prostate cancer. To establish the feasibility of clinical genomic profiling in the disease, we performed targeted deep sequencing of tumor and normal DNA from patients with locoregional, metastatic non-castrate, and metastatic castration-resistant prostate cancer (CRPC). Patients consented to genomic analysis of their tumor and germline DNA. A hybridization capture-based clinical assay was employed to identify single nucleotide variations, small insertions and deletions, copy number alterations and structural rearrangements in over 300 cancer-related genes in tumors and matched normal blood. We successfully sequenced 504 tumors from 451 patients with prostate cancer. Potentially actionable alterations were identified in DNA damage repair (DDR), PI3K, and MAP kinase pathways. 27% of patients harbored a germline or a somatic alteration in a DDR gene that may predict for response to PARP inhibition. Profiling of matched tumors from individual patients revealed that somatic TP53 and BRCA2 alterations arose early in tumors from patients who eventually developed metastatic disease. In contrast, comparative analysis across disease states revealed that APC alterations were enriched in metastatic tumors, while ATM alterations were specifically enriched in CRPC. Through genomic profiling of prostate tumors representing the disease clinical spectrum, we identified a high frequency of potentially actionable alterations and possible drivers of disease initiation, metastasis and castration-resistance. Our findings support the routine use of tumor and germline DNA profiling for patients with advanced prostate cancer, for the purpose of guiding enrollment in targeted clinical trials and counseling families at increased risk of malignancy.

  18. Beyond Seed and Soil: Understanding and Targeting Metastatic Prostate Cancer; Report From the 2016 Coffey-Holden Prostate Cancer Academy Meeting.

    Science.gov (United States)

    Miyahira, Andrea K; Roychowdhury, Sameek; Goswami, Sangeeta; Ippolito, Joseph E; Priceman, Saul J; Pritchard, Colin C; Sfanos, Karen S; Subudhi, Sumit K; Simons, Jonathan W; Pienta, Kenneth J; Soule, Howard R

    2017-02-01

    The 2016 Coffey-Holden Prostate Cancer Academy (CHPCA) Meeting, "Beyond Seed and Soil: Understanding and Targeting Metastatic Prostate Cancer," was held from June 23 to June 26, 2016, in Coronado, California. For the 4th year in a row, the Prostate Cancer Foundation (PCF) hosted the CHPCA Meeting, a think tank-structured scientific conference, which focuses on a specific topic of critical unmet need on the biology and treatment of advanced prostate cancer. The 2016 CHPCA Meeting was attended by 71 investigators from prostate cancer and other fields, who discussed the biology, study methodologies, treatment strategies, and critical unmet needs concerning metastatic prostate cancer, with the ultimate goal of advancing strategies to treat and eliminate this disease. The major topics of discussion included: the molecular landscape and molecular heterogeneity of metastatic prostate cancer, the role of the metastatic microenvironment, optimizing immunotherapy in metastatic prostate cancer, learning from exceptional responders and non-responders, targeting DNA repair deficiency in advanced prostate cancer, developing and applying novel biomarkers and imaging techniques, and potential roles for the microbiome in prostate cancer. This article reviews the topics presented and discussions held at the CHPCA Meeting, with a focus on the unknowns and next steps needed to advance our understanding of the biology and most effective treatment strategies for metastatic prostate cancer. Prostate 77:123-144, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  19. The role of serum osteoprotegerine in metastatic prostate cancer - a case control study.

    Science.gov (United States)

    Siampanopoulou, M; El, Mantani; Moustakas, G; Haritanti, A; Gotzamani-Psarrakou, A

    2016-01-01

    Prostate cancer is one of the most common malignant neoplastic diseases in men. Early control of the disease progression contributes significantly to survival rates and patients' quality of life. Osteoprotegerin is a dimeric glycoprotein, which affects bone metabolism and inhibits osteoclastogenesis. In the present study, we evaluated the expression of osteoprotegerin in the serum of prostate cancer patients with or without skeletal metastases. The expression of serum osteoprotegerin, as measured by enzyme-linked immunosorbent assay, has been studied in 82 patients with locally controlled prostate cancer, in 49 patients with metastatic bone disease and in a control group of 41 healthy males. At sampling time 65/131 of included patients were newly diagnosed, while 66/131 patients were already under hormonal therapy. All eligible prostate cancer patients had histologically confirmed malignancy. Serum total prostate-specific antigen (PSA) was determined by an immunoradiometric assay. We investigated the expression of osteoprotegerin in hormone-dependent and hormone-refractory prostate cancer and its relation to disease progression. Among the 131 patients with prostate cancer, higher osteoprotegerin and PSA concentrations have been observed in metastatic bone patients' sera (p cancer patients has shown a statistically significant area curve (p cancer patients (p cancer reflect the bone metastatic extent and may potentially be used in metastatic patients' follow-ups. Hippokratia 2016, 20(2): 133-138.

  20. A randomised comparison of 'Casodex' (bicalutamide) 150 mg monotherapy versus castration in the treatment of metastatic and locally advanced prostate cancer

    DEFF Research Database (Denmark)

    Tyrrell, C J; Kaisary, A V; Iversen, P

    1998-01-01

    To evaluate the efficacy and tolerability of 'Casodex' monotherapy (150 mg daily) for metastatic and locally advanced prostate cancer.......To evaluate the efficacy and tolerability of 'Casodex' monotherapy (150 mg daily) for metastatic and locally advanced prostate cancer....

  1. Is there a role for antiandrogen monotherapy in patients with metastatic prostate cancer?

    DEFF Research Database (Denmark)

    Kaisary, A V; Iversen, P; Tyrrell, C J

    2001-01-01

    with a prostate specific antigen (PSA) level 400 ng/ml) may decide that quality of life and symptomatic benefits outweigh the slight survival disadvantage seen in clinical trials and opt for bicalutamide monotherapy as an alternative to castration.Prostate Cancer and Prostatic Diseases (2001) 4, 196-203.......Castration is the most widely used form of androgen ablation employed in the treatment of metastatic (M1) prostate cancer. Non-steroidal antiandrogen monotherapy is a potential alternative treatment option for men for whom castration is unacceptable or not indicated. Of the three non...

  2. Long-term Efficacy and Safety of Enzalutamide Monotherapy in Hormone-naïve Prostate Cancer

    DEFF Research Database (Denmark)

    Tombal, Bertrand; Borre, Michael; Rathenborg, Per

    2015-01-01

    BACKGROUND: Enzalutamide is an androgen receptor inhibitor with a demonstrated overall survival benefit in metastatic castration-resistant prostate cancer. A phase 2 study of enzalutamide monotherapy in patients with hormone-naïve prostate cancer (HNPC) showed a high response rate...... cancer, enzalutamide maintained long-term reductions in prostate-specific antigen, with a minimal impact on total-body bone mineral density. TRIAL REGISTRATION: NCT01302041....... for the prespecified primary endpoint (ie, prostate-specific antigen [PSA] response at week 25), regardless of metastases at baseline, and favorable tolerability. OBJECTIVE: To determine the long-term efficacy and safety of enzalutamide monotherapy at 1 and 2 yr. DESIGN, SETTING, AND PARTICIPANTS: Open-label, single...

  3. Adenosine deaminase complexing protein (ADCP) expression and metastatic potential in prostatic adenocarcinomas.

    Science.gov (United States)

    Dinjens, W N; Ten Kate, J; Kirch, J A; Tanke, H J; Van der Linden, E P; Van den Ingh, H F; Van Steenbrugge, G J; Meera Khan, P; Bosman, F T

    1990-03-01

    The expression of the adenosine deaminase complexing protein (ADCP) was investigated by immunohistochemistry in the normal and hyperplastic human prostate, in 30 prostatic adenocarcinomas, and in seven human prostatic adenocarcinoma cell lines grown as xenografts in athymic nude mice. In the normal and hyperplastic prostate, ADCP was localized exclusively in the apical membrane and the apical cytoplasm of the glandular epithelial cells. In prostatic adenocarcinomas, four distinct ADCP expression patterns were observed: diffuse cytoplasmic, membranous, both cytoplasmic and membranous, and no ADCP expression. The expression patterns were compared with the presence of metastases. We found an inverse correlation between membranous ADCP immunoreactivity and metastatic propensity. Exclusively membranous ADCP immunoreactivity occurred only in non-metastatic tumours. In contrast, the metastatic tumours showed no or diffuse cytoplasmic ADCP immunoreactivity. This suggests that immunohistochemical detection of ADCP might predict the biological behaviour of prostatic cancer. However, the occurrence of membranous ADCP immunoreactivity in the xenograft of a cell line (PC-EW), derived from a prostatic carcinoma metastasis, indicates that not only the tendency to metastasize modulates ADCP expression.

  4. [New Radiopharmaceuticals Based on Prostate-Specific Inhibitors of Membrane Antigen for Diagnostics and Therapy of Metastatic Prostate Cancer].

    Science.gov (United States)

    Vlasova, O P; German, K E; Krilov, V V; Petriev, V M; Epstein, N B

    2015-01-01

    About 10.7% cases of prostate cancer were registered in Russia in 2011 (40,000 patients). More than half of cancer cases were revealed in advanced (III-IV) stages when metastases inevitably developed quickly. Clinical problem of early diagnostics and treatment of metastatic prostate cancer is still not solved. Anatomical imaging techniques have low sensitivity and specificity for the detection of this disease. Metabolic visualization methods which use prostate specific antigen (PSA) as a marker are also ineffective. This article describes prostate-specific membrane antigens (PSMA) that are proposed as a marker for diagnostics and therapy of prostate cancer. The most promising PSMA-based radiopharmaceutical agent for diagnostics has been developed and clinically tested in the European countries. These pharmaceuticals are based on small peptide molecules modified with urea, and have the highest affinity to PSMA. Favorable phannacokinetics, rapid accumulation in the tumor and rapid excretion from the body are beneficial features of these pharmaceuticals.

  5. To Die or to Survive, a Fatal Question for the Destiny of Prostate Cancer Cells after Androgen Deprivation Therapy

    International Nuclear Information System (INIS)

    Zhang, Kai-Xin; Firus, Jessica; Prieur, Brenda; Jia, William; Rennie, Paul S.

    2011-01-01

    Prostate cancer is the most frequently diagnosed non-skin cancer in adult males in North America and is the second leading cause of cancer-related mortality. For locally advanced or metastatic disease, androgen deprivation, through medical or surgical castration, is the primary treatment to induce prostate cancer cell death and extend patient survival. However, the vast majority of cancers progress to a castration-resistant/androgen-independent state where the cell death processes are no longer active. This review describes the main cell death processes, apoptosis, autophagy, necrosis and necroptosis, which may be activated in prostate cancers after androgen deprivation therapy as well as the molecular mechanisms through which the cancers progress to become castration resistant. In particular, the central role of persistent androgen receptor (AR)-mediated signaling and AR crosstalk with other critical cell signaling pathways, including (i) the PI3K/Akt pathway, (ii) receptor tyrosine kinases, (iii) the p38 MAPK pathway, and (iv) the Wnt/β-catenin pathway, as well as reactivation of AR by de novo synthesized androgen are discussed in this context. Understanding the molecular changes that subvert normal cell death mechanisms and thereby compromise the survival of prostate cancer patients continues to be a major challenge

  6. To Die or to Survive, a Fatal Question for the Destiny of Prostate Cancer Cells after Androgen Deprivation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Kai-Xin; Firus, Jessica; Prieur, Brenda [The Vancouver Prostate Centre, 2660 Oak St., Vancouver, BC V6H 3Z6 (Canada); Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6 (Canada); Jia, William [Department of Surgery and Brain Research Centre, University of British Columbia, Vancouver, BC V6H 3Z6 (Canada); Rennie, Paul S., E-mail: prennie@interchange.ubc.ca [The Vancouver Prostate Centre, 2660 Oak St., Vancouver, BC V6H 3Z6 (Canada); Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6 (Canada)

    2011-03-24

    Prostate cancer is the most frequently diagnosed non-skin cancer in adult males in North America and is the second leading cause of cancer-related mortality. For locally advanced or metastatic disease, androgen deprivation, through medical or surgical castration, is the primary treatment to induce prostate cancer cell death and extend patient survival. However, the vast majority of cancers progress to a castration-resistant/androgen-independent state where the cell death processes are no longer active. This review describes the main cell death processes, apoptosis, autophagy, necrosis and necroptosis, which may be activated in prostate cancers after androgen deprivation therapy as well as the molecular mechanisms through which the cancers progress to become castration resistant. In particular, the central role of persistent androgen receptor (AR)-mediated signaling and AR crosstalk with other critical cell signaling pathways, including (i) the PI3K/Akt pathway, (ii) receptor tyrosine kinases, (iii) the p38 MAPK pathway, and (iv) the Wnt/β-catenin pathway, as well as reactivation of AR by de novo synthesized androgen are discussed in this context. Understanding the molecular changes that subvert normal cell death mechanisms and thereby compromise the survival of prostate cancer patients continues to be a major challenge.

  7. To Die or to Survive, a Fatal Question for the Destiny of Prostate Cancer Cells after Androgen Deprivation Therapy

    Directory of Open Access Journals (Sweden)

    Paul S. Rennie

    2011-03-01

    Full Text Available Prostate cancer is the most frequently diagnosed non-skin cancer in adult males in North America and is the second leading cause of cancer-related mortality. For locally advanced or metastatic disease, androgen deprivation, through medical or surgical castration, is the primary treatment to induce prostate cancer cell death and extend patient survival. However, the vast majority of cancers progress to a castration-resistant/androgen-independent state where the cell death processes are no longer active. This review describes the main cell death processes, apoptosis, autophagy, necrosis and necroptosis, which may be activated in prostate cancers after androgen deprivation therapy as well as the molecular mechanisms through which the cancers progress to become castration resistant. In particular, the central role of persistent androgen receptor (AR-mediated signaling and AR crosstalk with other critical cell signaling pathways, including (i the PI3K/Akt pathway, (ii receptor tyrosine kinases, (iii the p38 MAPK pathway, and (iv the Wnt/β-catenin pathway, as well as reactivation of AR by de novo synthesized androgen are discussed in this context. Understanding the molecular changes that subvert normal cell death mechanisms and thereby compromise the survival of prostate cancer patients continues to be a major challenge.

  8. Potential use of custirsen to treat prostate cancer

    Directory of Open Access Journals (Sweden)

    Higano CS

    2013-06-01

    Full Text Available Celestia S Higano Department of Medicine, University of Washington, and Fred Hutchinson Cancer Research Center, Seattle, WA, USA Abstract: Over the last few years, five agents have demonstrated a survival benefit over a comparator treatment or placebo in the treatment of metastatic castration-resistant prostate cancer and have been approved by the US Food and Drug Administration: sipuleucel-T (a dendritic cell immunotherapy; cabazitaxel; abiraterone acetate and enzalutamide (both hormonal agents; and radium 223 (an alpha emitter. The development of these agents pivoted on whether patients had been treated with docetaxel, which remains the first-line chemotherapy of choice. To date, no combination of docetaxel and another active agent has demonstrated superiority to docetaxel alone despite numerous Phase III trials. Clusterin is a cytoprotective chaperone protein that is upregulated in response to various anticancer therapies. When overexpressed, clusterin interferes with apoptotic signaling, thereby promoting cell survival and conferring broad-spectrum resistance in cancer cell lines. Custirsen (OGX-011 is a second-generation 2´-methoxyethyl modified phosphorothioate antisense oligonucleotide that inhibits expression of clusterin. This review presents the preclinical and clinical data that provided the rationale for the combination of custirsen with chemotherapy in ongoing Phase III trials. Keywords: castration-resistant prostate cancer, clusterin, custirsen, OGX-011, antisense, OGX-427, apoptosis

  9. Extratumoral Heme Oxygenase-1 (HO-1 Expressing Macrophages Likely Promote Primary and Metastatic Prostate Tumor Growth.

    Directory of Open Access Journals (Sweden)

    Sofia Halin Bergström

    Full Text Available Aggressive tumors induce tumor-supporting changes in the benign parts of the prostate. One factor that has increased expression outside prostate tumors is hemoxygenase-1 (HO-1. To investigate HO-1 expression in more detail, we analyzed samples of tumor tissue and peritumoral normal prostate tissue from rats carrying cancers with different metastatic capacity, and human prostate cancer tissue samples from primary tumors and bone metastases. In rat prostate tumor samples, immunohistochemistry and quantitative RT-PCR showed that the main site of HO-1 synthesis was HO-1+ macrophages that accumulated in the tumor-bearing organ, and at the tumor-invasive front. Small metastatic tumors were considerably more effective in attracting HO-1+ macrophages than larger non-metastatic ones. In clinical samples, accumulation of HO-1+ macrophages was seen at the tumor invasive front, almost exclusively in high-grade tumors, and it correlated with the presence of bone metastases. HO-1+ macrophages, located at the tumor invasive front, were more abundant in bone metastases than in primary tumors. HO-1 expression in bone metastases was variable, and positively correlated with the expression of macrophage markers but negatively correlated with androgen receptor expression, suggesting that elevated HO-1 could be a marker for a subgroup of bone metastases. Together with another recent observation showing that selective knockout of HO-1 in macrophages reduced prostate tumor growth and metastatic capacity in animals, the results of this study suggest that extratumoral HO-1+ macrophages may have an important role in prostate cancer.

  10. Prostate extracellular vesicles in patient plasma as a liquid biopsy platform for prostate cancer using nanoscale flow cytometry

    Science.gov (United States)

    Al-Zahrani, Ali A.; Pardhan, Siddika; Brett, Sabine I.; Guo, Qiu Q.; Yang, Jun; Wolf, Philipp; Power, Nicholas E.; Durfee, Paul N.; MacMillan, Connor D.; Townson, Jason L.; Brinker, Jeffrey C.; Fleshner, Neil E.; Izawa, Jonathan I.; Chambers, Ann F.; Chin, Joseph L.; Leong, Hon S.

    2016-01-01

    Background Extracellular vesicles released by prostate cancer present in seminal fluid, urine, and blood may represent a non-invasive means to identify and prioritize patients with intermediate risk and high risk of prostate cancer. We hypothesize that enumeration of circulating prostate microparticles (PMPs), a type of extracellular vesicle (EV), can identify patients with Gleason Score≥4+4 prostate cancer (PCa) in a manner independent of PSA. Patients and Methods Plasmas from healthy volunteers, benign prostatic hyperplasia patients, and PCa patients with various Gleason score patterns were analyzed for PMPs. We used nanoscale flow cytometry to enumerate PMPs which were defined as submicron events (100-1000nm) immunoreactive to anti-PSMA mAb when compared to isotype control labeled samples. Levels of PMPs (counts/μL of plasma) were also compared to CellSearch CTC Subclasses in various PCa metastatic disease subtypes (treatment naïve, castration resistant prostate cancer) and in serially collected plasma sets from patients undergoing radical prostatectomy. Results PMP levels in plasma as enumerated by nanoscale flow cytometry are effective in distinguishing PCa patients with Gleason Score≥8 disease, a high-risk prognostic factor, from patients with Gleason Score≤7 PCa, which carries an intermediate risk of PCa recurrence. PMP levels were independent of PSA and significantly decreased after surgical resection of the prostate, demonstrating its prognostic potential for clinical follow-up. CTC subclasses did not decrease after prostatectomy and were not effective in distinguishing localized PCa patients from metastatic PCa patients. Conclusions PMP enumeration was able to identify patients with Gleason Score ≥8 PCa but not patients with Gleason Score 4+3 PCa, but offers greater confidence than CTC counts in identifying patients with metastatic prostate cancer. CTC Subclass analysis was also not effective for post-prostatectomy follow up and for

  11. Phase I/II study on docetaxel, gemcitabine and prednisone in castrate refractory metastatic prostate cancer

    DEFF Research Database (Denmark)

    Buch-Hansen, Trine Zeeberg; Bentzen, Lise Nørgaard; Hansen, Steinbjoern

    2010-01-01

    DGP, maximum of eight courses, until progression or unacceptable toxicity. Docetaxel 75 mg/m(2) was administered intravenously day 1, gemcitabine was given day 1 and 8 in doses increasing from 600 to 1,000 mg/m(2) every third week. Patients had castrate refractory metastatic prostate cancer (CRMPC......), adequate function of liver, kidney and bone marrow; ECOG performance status...

  12. Immunohistochemical profiles of claudin-3 in primary and metastatic prostatic adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Becich Michael J

    2011-01-01

    Full Text Available Abstract Background Claudins are integral membrane proteins that are involved in forming cellular tight junctions. One member of the claudin family, claudin-3, has been shown to be overexpressed in breast, ovarian, and pancreatic cancer. Here we use immunohistochemistry to evaluate its expression in benign prostatic hyperplasia (BPH, prostatic intraepithelial neoplasia (PIN, normal tissue adjacent to prostatic adenocarcinoma (NAC, primary prostatic adenocarcinoma (PCa, and metastatic prostatic adenocarcinoma (Mets. Methods Tissue microarrays were immunohistochemically stained for claudin-3, with the staining intensities subsequently quantified and statistically analyzed using a one-way ANOVA with subsequent Tukey tests for multiple comparisons or a nonparametric equivalent. Fifty-three cases of NAC, 17 cases of BPH, 35 cases of PIN, 107 cases of PCa, and 55 cases of Mets were analyzed in the microarrays. Results PCa and Mets had the highest absolute staining for claudin-3. Both had significantly higher staining than BPH (p Conclusions To our knowledge, this represents one of the first studies comparing the immunohistochemical profiles of claudin-3 in PCa and NAC to specimens of PIN, BPH, and Mets. These findings provide further evidence that claudin-3 may serve as an important biomarker for prostate cancer, both primary and metastatic, but does not provide evidence that claudin-3 can be used to predict risk of metastasis.

  13. Cancer of the prostate presenting with diffuse osteolytic metastatic bone lesions: a case report

    Directory of Open Access Journals (Sweden)

    Segamwenge Innocent Lule

    2012-12-01

    Full Text Available Abstract Introduction Prostate cancer is the second most common cancer in men and the fifth most common cancer worldwide. In the USA it is more common in African-American men than in Caucasian men. Prostate cancer frequently metastasizes to bone and the lesions appear osteoblastic on radiographs. Presentation with diffuse osteolytic bone lesions is rare. We describe an unusual presentation of metastatic prostate cancer with diffuse osteolytic bone lesions. Case presentation A 65-year-old Namibian man presented with anemia, thrombocytopenia and worsening back pains. In addition he had complaints of effort intolerance, palpitations, dysuria and mild symptoms of bladder outlet obstruction. On examination he was found to be anemic, had a swollen tender right shoulder joint and spine tenderness to percussion. On digital rectal examination he had asymmetrical enlargement of the prostate which felt nodular and hard with diffuse firmness in some parts. His prostate-specific antigen was greater than 100ng/mL and he had diffuse osteolytic lesions involving the right humerus, and all vertebral, femur and pelvic bones. His screen for multiple myeloma was negative and the prostate biopsy confirmed prostate cancer. Conclusion Prostate cancer rarely presents with diffuse osteolytic bone lesions and should be considered in the differential diagnosis when evaluating male patients with osteolytic bone lesions.

  14. Hyaluronan-Based Therapy for Metastatic Prostate Cancer

    Science.gov (United States)

    2016-09-01

    Importantly, the system can target CD44+ prostate cancer stem cells through intrinsic HA-CD44 receptor interactions and deliver drugs directly to...be released by enzymatic degradation via HYAL1. Importantly, the system can target CD44+ prostate cancer stem cells through intrinsic HA-CD44...In Situ DNA Strand Break Labeling (TUNEL assay)—Tumor tissues were recovered from euthanized animals. Sections (5 μm) were cut from 10% neutral

  15. Metastatic prostatic adenocarcinoma diagnosed in a bronchoalveolar lavage specimen: An unusual presentation of a common tumor

    Directory of Open Access Journals (Sweden)

    Adrienne E Moul

    2016-01-01

    Full Text Available Metastatic prostatic adenocarcinoma presenting as a primary lung disease is rare. We present a 52-year-old male with a 3-month history of cough, shortness of breath, and weight loss with clinical and radiological findings suggestive of a primary lung disease: Bilateral interstitial and alveolar opacities with blunting of the costophrenic angles, multiple diffuse foci of consolidations and nodules, predominantly subpleural and located in the lower lobes, and diffuse interlobular septal thickening and peribronchial thickening. The patient underwent bronchoscopy and bronchoalveolar lavage (BAL was obtained. Cytospin smears were diagnostic for a low-grade adenocarcinoma. Clinically, the patient had elevated serum prostate-specific antigen (PSA levels greater than 5,000 ng/mL. Because of this, immunocytochemistry for PSA was performed which was positive, confirming the diagnosis of metastatic prostatic adenocarcinoma. This unusual case of metastatic adenocarcinoma of the prostate first diagnosed by BAL highlights the significance of available clinical information and the use of immunocytochemistry for proper diagnosis.

  16. Multidisciplinary Intervention of Early, Lethal Metastatic Prostate Cancer: Report From the 2015 Coffey-Holden Prostate Cancer Academy Meeting

    Science.gov (United States)

    Miyahira, Andrea K.; Lang, Joshua M.; Den, Robert B.; Garraway, Isla P.; Lotan, Tamara L.; Ross, Ashley E.; Stoyanova, Tanya; Cho, Steve Y.; Simons, Jonathan W.; Pienta, Kenneth J.; Soule, Howard R.

    2018-01-01

    BACKGROUND The 2015 Coffey-Holden Prostate Cancer Academy Meeting, themed: “Multidisciplinary Intervention of Early, Lethal Metastatic Prostate Cancer,” was held in La Jolla, California from June 25 to 28, 2015. METHODS The Prostate Cancer Foundation (PCF) sponsors an annual, invitation-only, action-tank-structured meeting on a critical topic concerning lethal prostate cancer. The 2015 meeting was attended by 71 basic, translational, and clinical investigators who discussed the current state of the field, major unmet needs, and ideas for addressing earlier diagnosis and treatment of men with lethal prostate cancer for the purpose of extending lives and making progress toward a cure. RESULTS The questions addressed at the meeting included: cellular and molecular mechanisms of tumorigenesis, evaluating, and targeting the microenvironment in the primary tumor, advancing biomarkers for clinical integration, new molecular imaging technologies, clinical trials, and clinical trial design in localized high-risk and oligometastatic settings, targeting the primary tumor in advanced disease, and instituting multi-modal care of high risk and oligometastatic patients. DISCUSSION This article highlights the current status, greatest unmet needs, and anticipated field changes that were discussed at the meeting toward the goal of optimizing earlier interventions to potentiate cures in high-risk and oligometastatic prostate cancer patients. PMID:26477609

  17. Trading in your spindles for blebs: the amoeboid tumor cell phenotype in prostate cancer

    Directory of Open Access Journals (Sweden)

    Samantha Morley

    2014-08-01

    Full Text Available Prostate cancer (PCa remains a principal cause of mortality in developed countries. Because no clinical interventions overcome resistance to androgen ablation therapy, management of castration resistance and metastatic disease remains largely untreatable. Metastasis is a multistep process in which tumor cells lose cell-cell contacts, egress from the primary tumor, intravasate, survive shear stress within the vasculature and extravasate into tissues to colonize ectopic sites. Tumor cells reestablish migratory behaviors employed during nonneoplastic processes such as embryonic development, leukocyte trafficking and wound healing. While mesenchymal motility is an established paradigm of dissemination, an alternate, 'amoeboid' phenotype is increasingly appreciated as relevant to human cancer. Here we discuss characteristics and pathways underlying the phenotype, and highlight our findings that the cytoskeletal regulator DIAPH3 governs the mesenchymal-amoeboid transition. We also describe our identification of a new class of tumor-derived microvesicles, large oncosomes, produced by amoeboid cells and with potential clinical utility in prostate and other cancers.

  18. Successful Treatment of Advanced Metastatic Prostate Cancer following Chemotherapy Based on Molecular Profiling

    Directory of Open Access Journals (Sweden)

    Charles E. Myers

    2012-03-01

    Full Text Available After Taxotere fails, treatment options for metastatic prostate cancer are limited. The three drugs with FDA approval in this setting, Jevtana, Provenge and Zytiga, are associated with median survivals of less than 2 years. In part, the impact on survival is the result of low response rates, indicating a significant proportion of patients exhibiting de novo resistance to these agents. An alternate approach is to let treatment selection be governed by gene expression profiling so that the treatment is tailored to the specific patient. Here, we report a case of metastatic prostate cancer with a dramatic response to treatment selected based on molecular profiling. This patient had failed LHRH agonist, bicalutamide, Taxotere, and doxorubicin. Molecular profiling showed overexpression of the androgen receptor and he had a dramatic response of measurable disease to second-line hormonal therapy with ketoconazole, estrogen and Leukine.

  19. Bone-targeted cabazitaxel nanoparticles for metastatic prostate cancer skeletal lesions and pain.

    Science.gov (United States)

    Gdowski, Andrew S; Ranjan, Amalendu; Sarker, Marjana R; Vishwanatha, Jamboor K

    2017-09-01

    The aim of this study was to develop a novel cabazitaxel bone targeted nanoparticle (NP) system for improved drug delivery to the bone microenvironment. Nanoparticles were developed using poly(D,L-lactic-co-glycolic acid) and cabazitaxel as the core with amino-bisphosphonate surface conjugation. Optimization of nanoparticle physiochemical properties, in vitro evaluation in prostate cancer cell lines and in vivo testing in an intraosseous model of metastatic prostate cancer was performed. This bone targeted cabazitaxel nanocarrier system showed significant reduction in tumor burden, while at the same time maintaining bone structure integrity and reducing pain in the mouse tumor limb. This bone microenvironment targeted nanoparticle system and clinically relevant approach of evaluation represents a promising advancement for treating bone metastatic cancer.

  20. Half-body irradiation in the treatment of metastatic prostatic carcinoma

    International Nuclear Information System (INIS)

    Rowland, C.G.; Bullimore, J.A.; Smith, P.J.B.; Roberts, J.B.M.

    1981-01-01

    High dose radiation therapy given as a single fraction to the upper and lower halves of the body gives effective palliation for metastatic solid tumours. This treatment modality appears to be particularly effective in tumours which may have a slow doubling time such as carcinoma of the prostate. Fifty-two patients with metastatic carcinoma of the prostate involving the skeletal system have received half-body irradiation (8 MeV X-rays at a dose rate of about 100 cGy/min). All had prior treatment with additive hormones or orchiectomy and the majority had received localised irradiation and/or chemotherapy. Significant immediate pain relief was achieved in 42 out of 52 patients (80%). This pain relief was maintained until death in 29 out of 43 patients (67%). Pain relief in responders appears to occur within 24 to 48 h of treatment. (author)

  1. Cytoreductive prostate radiotherapy in oligometastatic prostate cancer: a single centre analysis of toxicity and clinical outcome.

    Science.gov (United States)

    Riva, Giulia; Marvaso, Giulia; Augugliaro, Matteo; Zerini, Dario; Fodor, Cristiana; Musi, Gennaro; De Cobelli, Ottavio; Orecchia, Roberto; Jereczek-Fossa, Barbara Alicja

    2017-01-01

    The current standard of care for patients with metastatic prostate cancer (mPCa) at diagnosis is androgen deprivation therapy (ADT) with or without anti-androgen and chemotherapy. The aim of this study was to define the role of a local radiotherapy (RT) treatment in the mPCa setting. We retrospectively reviewed data of patients with PCa and bone oligometastases at diagnosis treated in our institution with ADT followed by cytoreductive prostate-RT with or without RT on metastases. Biochemical and clinical failure (BF, CF), overall survival (OS) and RT-toxicity were assessed. We identified 22 patients treated with ADT and external-beam RT on primary between June 2008 and March 2016. All of them but four were also treated for bone metastases. RT on primary with moderately and extremely hypofractionated regimes started after 10.3 months (3.9-51.7) from ADT. After a median follow-up of 26.4 months (10.3-55.5), 20 patients are alive. Twelve patients showed BF after a median time of 23 months (14.5-104) and CF after a median of 23.6 months (15.3-106.1) from the start of ADT. Three patients became castration resistant, starting a new therapy; median time to castration resistance was 31.03 months (range: 29.9-31.5 months). According to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC), only one patient developed acute grade 3 genitourinary toxicity. No late grade >2 adverse events were observed. Prostate RT in oligometastatic patients is safe and offers long-lasting local control. When compared to ADT alone, RT on primary seems to improve biochemical control and long-term survival; however, this hypothesis should be investigated in prospective studies. Further research is warranted.

  2. Deconvoluting the Complexity of Bone Metastatic Prostate Cancer via Computational Modeling

    Science.gov (United States)

    2016-09-01

    fluent in English and Spanish and have experience in IT, programming, cell culture, teaching , art, graphic design, and leadership skills. Personal...2007) Teacher programme for the translation of science into classrooms University of Notre Dame, Indiana, USA (2004-2005) One-Year Academic Exchange...integrated computational modeling approach can be used to predict the temporal behavior of bone metastatic prostate cancer heterogeneous for TGFβ and

  3. Effects of occupational therapy on quality of life of patients with metastatic prostate cancer

    OpenAIRE

    Huri, Meral; Huri, Emre; Kayihan, Hulya; Altuntas, Onur

    2015-01-01

    Objectives: To evaluate the efficiency of occupational therapy relative to a home program in improving quality of life (QoL) among men who were treated for metastatic prostate cancer (MPC). Methods: Fifty-five men were assigned randomly to either the 12-week cognitive behavioral therapy based occupational therapy (OT-CBSM) intervention (treatment group) or a home program (control group) between March 2012 and August 2014 in the Department of Occupational Therapy, Faculty of Health Sciences, H...

  4. Identification of genes regulating migration and invasion using a new model of metastatic prostate cancer

    International Nuclear Information System (INIS)

    Banyard, Jacqueline; Chung, Ivy; Migliozzi, Matthew; Phan, Derek T; Wilson, Arianne M; Zetter, Bruce R; Bielenberg, Diane R

    2014-01-01

    Understanding the complex, multistep process of metastasis remains a major challenge in cancer research. Metastasis models can reveal insights in tumor development and progression and provide tools to test new intervention strategies. To develop a new cancer metastasis model, we used DU145 human prostate cancer cells and performed repeated rounds of orthotopic prostate injection and selection of subsequent lymph node metastases. Tumor growth, metastasis, cell migration and invasion were analyzed. Microarray analysis was used to identify cell migration- and cancer-related genes correlating with metastasis. Selected genes were silenced using siRNA, and their roles in cell migration and invasion were determined in transwell migration and Matrigel invasion assays. Our in vivo cycling strategy created cell lines with dramatically increased tumorigenesis and increased ability to colonize lymph nodes (DU145LN1-LN4). Prostate tumor xenografts displayed increased vascularization, enlarged podoplanin-positive lymphatic vessels and invasive margins. Microarray analysis revealed gene expression profiles that correlated with metastatic potential. Using gene network analysis we selected 3 significantly upregulated cell movement and cancer related genes for further analysis: EPCAM (epithelial cell adhesion molecule), ITGB4 (integrin β4) and PLAU (urokinase-type plasminogen activator (uPA)). These genes all showed increased protein expression in the more metastatic DU145-LN4 cells compared to the parental DU145. SiRNA knockdown of EpCAM, integrin-β4 or uPA all significantly reduced cell migration in DU145-LN4 cells. In contrast, only uPA siRNA inhibited cell invasion into Matrigel. This role of uPA in cell invasion was confirmed using the uPA inhibitors, amiloride and UK122. Our approach has identified genes required for the migration and invasion of metastatic tumor cells, and we propose that our new in vivo model system will be a powerful tool to interrogate the metastatic

  5. P52 Activation and Enzalutamide Therapy in Prostate Cancer

    Science.gov (United States)

    2017-10-01

    c-Myc:hnRNPA1 pathway regulates expression of androgen receptor splice variants and enzalutamide sensitivity in prostate cancer . Castration resistant... prostate cancer (CRPC) remains dependent on androgen receptor (AR) signaling. Alternative splicing of the AR to generate constitutively active... receptor splice variants and enzalutamide sensitivity in prostate cancer . • We discovered that quercetin, a naturally occurring polyphenolic compound

  6. Apalutamide treatment and metastasis-free survival in prostate cancer

    DEFF Research Database (Denmark)

    Smith, Matthew R.; Saad, Fred; Chowdhury, Simon

    2018-01-01

    BACKGROUND Apalutamide, a competitive inhibitor of the androgen receptor, is under development for the treatment of prostate cancer. We evaluated the efficacy of apalutamide in men with nonmetastatic castration-resistant prostate cancer who were at high risk for the development of metastasis....... METHODS We conducted a double-blind, placebo-controlled, phase 3 trial involving men with nonmetastatic castration-resistant prostate cancer and a prostate-specific antigen doubling time of 10 months or less. Patients were randomly assigned, in a 2:1 ratio, to receive apalutamide (240 mg per day...... and 7.0% in the placebo group. The following adverse events occurred at a higher rate with apalutamide than with placebo: rash (23.8% vs. 5.5%), hypothyroidism (8.1% vs. 2.0%), and fracture (11.7% vs. 6.5%). CONCLUSIONS Among men with nonmetastatic castration-resistant prostate cancer, metastasis...

  7. uPAR Targeted Radionuclide Therapy with 177Lu-DOTA-AE105 Inhibits Dissemination of Metastatic Prostate Cancer

    DEFF Research Database (Denmark)

    Persson, Morten; Juhl, Karina; Rasmussen, Palle

    2014-01-01

    The urokinase-type plasminogen activator receptor (uPAR) is implicated in cancer invasion and metastatic development in prostate cancer and provides therefore an attractive molecular target for both imaging and therapy. In this study, we provide the first in vivo data on an antimetastatic effect...... of uPAR radionuclide targeted therapy in such lesions and show the potential of uPAR positron emission tomography (PET) imaging for identifying small foci of metastatic cells in a mouse model of disseminating human prostate cancer. Two radiolabeled ligands were generated in high purity and specific...... value of 100 nM in a competitive binding experiment. In vivo, uPAR targeted radionuclide therapy significantly reduced the number of metastatic lesions in the disseminated metastatic prostate cancer model, when compared to vehicle and nontargeted 177Lu groups (p

  8. Metastatic prostate cancer with elevated serum levels of CEA and CA19-9

    Directory of Open Access Journals (Sweden)

    Guang-Dar Juang

    2014-03-01

    Full Text Available Prostate-specific antigen (PSA is well known as a specific tumor marker for prostate cancer, but carcinoembryonic antigen (CEA- and carbohydrate antigen 19-9 (CA19-9-elevating adenocarcinomas originating in the prostate gland are rare. We report a case of metastatic adenocarcinoma of the prostate gland with a high serum level of CEA and CA19-9 in a 78-year-old man in whom prostate cancer (T3N1M1 had been diagnosed 2 years ago and who was treated with androgen deprivation therapy. He visited the emergency department because of a loss of appetite and abdominal pain. The serum CEA and CA19-9 levels were increased to 218.9 ng/mL (normal, <5 ng/mL and 212 ng/mL (normal, <27 ng/mL, respectively. The serum PSA level was slightly elevated (4.41 ng/mL. Computed tomography demonstrated multiple liver metastases, para-aortic lymph node enlargement, and lung metastases. A liver biopsy was performed and the specimen showed high-grade adenocarcinoma with focal positive staining for PSA. Despite chemotherapy with docetaxel, the patient died 3 months after treatment. Based on this case and a review of the literature, an aggressive variant of prostatic carcinoma with a high serum level of CEA and CA19-9 and a low PSA level was shown to progress rapidly with a poor prognosis.

  9. PrognosticValue of PINP,BoneAlkaline Phosphatase, CTX-I, andYKL-40 in Patients With Metastatic Prostate Carcinoma

    DEFF Research Database (Denmark)

    Brasso, Klaus; Christensen, Ib Jarle; Johansen, Julia S

    2006-01-01

    Prognostic value of PINP, bone alkaline phosphatase, CTX-I, and YKL-40 in patients with metastatic prostate carcinoma. Prostate. 2006 Apr 1;66(5):503-13. PMID: 16372331 [PubMed - indexed for MEDLINE]......Prognostic value of PINP, bone alkaline phosphatase, CTX-I, and YKL-40 in patients with metastatic prostate carcinoma. Prostate. 2006 Apr 1;66(5):503-13. PMID: 16372331 [PubMed - indexed for MEDLINE]...

  10. Comparison of miRNA and gene expression profiles between metastatic and primary prostate cancer.

    Science.gov (United States)

    Guo, Kaimin; Liang, Zuowen; Li, Fubiao; Wang, Hongliang

    2017-11-01

    The present study aimed to identify the regulatory mechanisms associated with the metastasis of prostate cancer (PC). The microRNA (miRNA/miR) microarray dataset GSE21036 and gene transcript dataset GSE21034 were downloaded from the Gene Expression Omnibus database. Following pre-processing, differentially expressed miRNAs (DEMs) and differentially expressed genes (DEGs) between samples from patients with primary prostate cancer (PPC) and metastatic prostate cancer (MPC) with |log 2 fold change (FC)| >1 and a false discovery rate terms (36 terms), followed by miR-494 (24 terms), miR-30d (18 terms), miR-181a (15 terms), hsa-miR-196a (8 terms), miR-708 (7 terms) and miR-486-5p (2 terms). Therefore, these miRNAs may serve roles in the metastasis of PC cells via downregulation of their corresponding target DEGs.

  11. An RNA-Based Digital Circulating Tumor Cell Signature Is Predictive of Drug Response and Early Dissemination in Prostate Cancer.

    Science.gov (United States)

    Miyamoto, David T; Lee, Richard J; Kalinich, Mark; LiCausi, Joseph A; Zheng, Yu; Chen, Tianqi; Milner, John D; Emmons, Erin; Ho, Uyen; Broderick, Katherine; Silva, Erin; Javaid, Sarah; Kwan, Tanya Todorova; Hong, Xin; Dahl, Douglas M; McGovern, Francis J; Efstathiou, Jason A; Smith, Matthew R; Sequist, Lecia V; Kapur, Ravi; Wu, Chin-Lee; Stott, Shannon L; Ting, David T; Giobbie-Hurder, Anita; Toner, Mehmet; Maheswaran, Shyamala; Haber, Daniel A

    2018-03-01

    Blood-based biomarkers are critical in metastatic prostate cancer, where characteristic bone metastases are not readily sampled, and they may enable risk stratification in localized disease. We established a sensitive and high-throughput strategy for analyzing prostate circulating tumor cells (CTC) using microfluidic cell enrichment followed by digital quantitation of prostate-derived transcripts. In a prospective study of 27 patients with metastatic castration-resistant prostate cancer treated with first-line abiraterone, pretreatment elevation of the digital CTC M score identifies a high-risk population with poor overall survival (HR = 6.0; P = 0.01) and short radiographic progression-free survival (HR = 3.2; P = 0.046). Expression of HOXB13 in CTCs identifies 6 of 6 patients with ≤12-month survival, with a subset also expressing the ARV7 splice variant. In a second cohort of 34 men with localized prostate cancer, an elevated preoperative CTC L score predicts microscopic dissemination to seminal vesicles and/or lymph nodes ( P digital quantitation of CTC-specific transcripts enables noninvasive monitoring that may guide treatment selection in both metastatic and localized prostate cancer. Significance: There is an unmet need for biomarkers to guide prostate cancer therapies, for curative treatment of localized cancer and for application of molecularly targeted agents in metastatic disease. Digital quantitation of prostate CTC-derived transcripts in blood specimens is predictive of abiraterone response in metastatic cancer and of early dissemination in localized cancer. Cancer Discov; 8(3); 288-303. ©2018 AACR. See related commentary by Heitzer and Speicher, p. 269 This article is highlighted in the In This Issue feature, p. 253 . ©2018 American Association for Cancer Research.

  12. Preliminary results on response assessment using {sup 68}Ga-HBED-CC-PSMA PET/CT in patients with metastatic prostate cancer undergoing docetaxel chemotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Seitz, Anna Katharina [Technical University of Munich, Department of Urology, Klinikum rechts der Isar, Munich (Germany); Julius Maximilians University Medical Centre of Wuerzburg, Department of Urology and Paediatric Urology, Wuerzburg (Germany); Rauscher, Isabel; Kroenke, Markus; Schwaiger, Markus [Technical University of Munich, Department of Nuclear Medicine, Klinikum rechts der Isar, Munich (Germany); Haller, Bernhard [Technical University of Munich, Institute of Medical Informatics, Statistics and Epidemiology, Klinikum rechts der Isar, Munich (Germany); Luther, Sophia; Heck, Matthias M.; Horn, Thomas; Gschwend, Juergen E.; Maurer, Tobias [Technical University of Munich, Department of Urology, Klinikum rechts der Isar, Munich (Germany); Eiber, Matthias [Technical University of Munich, Department of Nuclear Medicine, Klinikum rechts der Isar, Munich (Germany); David Geffen School of Medicine at UCLA, Department of Molecular and Medical Pharmacology, Los Angeles (United States)

    2018-04-15

    To investigate the value of {sup 68}Ga-HBED-CC PSMA ({sup 68}Ga-PSMA) PET/CT for response assessment in metastatic castration-sensitive and castration-resistant prostate cancer (mCSPC and mCRPC) during docetaxel chemotherapy. {sup 68}Ga-PSMA PET/CT was performed in seven mCSPC patients before and after six cycles of upfront docetaxel chemotherapy and in 16 mCRPC patients before and after three cycles of palliative docetaxel chemotherapy. Radiographic treatment response was evaluated separately on the {sup 68}Ga-PSMA PET and CT datasets. Changes in {sup 68}Ga-PSMA uptake (SUVmean) were assessed on a per-patient and a per-lesion basis using the PERCIST scoring system with slight modification. Treatment response was defined as absence of any PSMA uptake in all target lesions on posttreatment PET (complete response, CR) or a decrease in summed SUVmean of ≥30% (partial response, PR). The appearance of a new PET-positive lesion or an increase in summed SUVmean of ≥30% (progressive disease, PD) indicated nonresponse. A moderate change in summed SUVmean (between -30% and +30%) without a change in the number of target lesions was defined as stable disease (SD). For treatment response assessment on CT, RECIST1.1 criteria were used. Radiographic responses on {sup 68}Ga-PSMA PET [RR(PET)] and on CT [RR(CT)] were compared and correlated with biochemical response (BR). A decrease in serum PSA level of ≥50% was defined as biochemical PR. Biochemical PR was found in six of seven patients with mCSPC (86%, 95% confidence interval 42% to 99.6%). The concordance rate was higher between BR and RR(PET) than between BR and RR(CT) (6/7 vs. 3/6 patients). {sup 68}Ga-PSMA PET and CT were concordant in only three patients (50%, 12% to 88%). In mCRPC patients, biochemical PR was found in six of 16 patients (38%, 15% to 65%). Outcome prediction was concordant between BR and RR(PET) in nine of 16 patients (56%), and between BR and RR(CT) in only four of 12 patients (33%) with target

  13. Preliminary results on response assessment using 68Ga-HBED-CC-PSMA PET/CT in patients with metastatic prostate cancer undergoing docetaxel chemotherapy

    International Nuclear Information System (INIS)

    Seitz, Anna Katharina; Rauscher, Isabel; Kroenke, Markus; Schwaiger, Markus; Haller, Bernhard; Luther, Sophia; Heck, Matthias M.; Horn, Thomas; Gschwend, Juergen E.; Maurer, Tobias; Eiber, Matthias

    2018-01-01

    To investigate the value of 68 Ga-HBED-CC PSMA ( 68 Ga-PSMA) PET/CT for response assessment in metastatic castration-sensitive and castration-resistant prostate cancer (mCSPC and mCRPC) during docetaxel chemotherapy. 68 Ga-PSMA PET/CT was performed in seven mCSPC patients before and after six cycles of upfront docetaxel chemotherapy and in 16 mCRPC patients before and after three cycles of palliative docetaxel chemotherapy. Radiographic treatment response was evaluated separately on the 68 Ga-PSMA PET and CT datasets. Changes in 68 Ga-PSMA uptake (SUVmean) were assessed on a per-patient and a per-lesion basis using the PERCIST scoring system with slight modification. Treatment response was defined as absence of any PSMA uptake in all target lesions on posttreatment PET (complete response, CR) or a decrease in summed SUVmean of ≥30% (partial response, PR). The appearance of a new PET-positive lesion or an increase in summed SUVmean of ≥30% (progressive disease, PD) indicated nonresponse. A moderate change in summed SUVmean (between -30% and +30%) without a change in the number of target lesions was defined as stable disease (SD). For treatment response assessment on CT, RECIST1.1 criteria were used. Radiographic responses on 68 Ga-PSMA PET [RR(PET)] and on CT [RR(CT)] were compared and correlated with biochemical response (BR). A decrease in serum PSA level of ≥50% was defined as biochemical PR. Biochemical PR was found in six of seven patients with mCSPC (86%, 95% confidence interval 42% to 99.6%). The concordance rate was higher between BR and RR(PET) than between BR and RR(CT) (6/7 vs. 3/6 patients). 68 Ga-PSMA PET and CT were concordant in only three patients (50%, 12% to 88%). In mCRPC patients, biochemical PR was found in six of 16 patients (38%, 15% to 65%). Outcome prediction was concordant between BR and RR(PET) in nine of 16 patients (56%), and between BR and RR(CT) in only four of 12 patients (33%) with target lesions on CT. 68 Ga-PSMA PET and CT

  14. How MMPs Impact Bone Responses to Metastatic Prostate Cancer

    Science.gov (United States)

    2011-04-30

    bone metabolism. J Biol Chem 2006;281:33814–24. 28. Wilson TJ, Nannuru KC, Singh RK. Cathepsin G-mediated activation of pro-matrix metalloproteinase 9...male mice. Nat Genet 2003;35:252–7. [47] Lynch CC, Hikosaka A, Acuff HB, Martin MD, Kawai N, Singh RK, et al. MMP-7 promotes prostate cancer-induced...described (15). A luciferase tagged 4T1 mammary tumor cell line (16) was kindly provided by Dr. Swati Biswas of Vanderbilt Center for Bone Biology. All

  15. Management of elderly patients with prostate cancer without metastatic lesions

    International Nuclear Information System (INIS)

    Sakamoto, Naotaka; Akitake, Masakazu; Ikoma, Saya; Ri, Ken; Masuda, Katsuaki; Yoshikawa, Masahiro; Iguchi, Atsushi

    2010-01-01

    In order to assess the optimal management for elderly patients with localized and locally advanced prostate cancer (clinical stage: T1-T4N0M0), we reviewed the prognoses. From April 2000 to December 2008, we treated and followed up 175 patients aged 75 years, or older. In almost all of the patients above 79 years of age, endocrine therapy was selected. Among the 75 to 79-year-old patients, the proportion of radiation therapy, including external beam radiation therapy (EBRT) and high-dose-rate brachytherapy (HDR-brachytherapy), as well as radical prostatectomy increased. The follow-up period for all the patients was 0 to 106 months (median, 32 months). In the low- and intermediate-risk group, the actuarial biochemical control rate at 60 months for radical prostatectomy and endocrine therapy was 100% and 90%, respectively, and no patients with EBRT combined with endocrine therapy, and HDR-brachytherapy had biochemical failure at 34 and 46 months, respectively. In the high-risk group with 75 to 79-year-old patients, the actuarial biochemical control rate at 60 months for EBRT combined with endocrine therapy, radical prostatectomy and endocrine therapy was 71.4%, 69.0% and 55.7%, respectively, while the actuarial biochemical control rate at 48 months for HDR-brachytherapy was 40.9%. In the high-risk group with patients above 79 years of age, the actuarial biochemical control rate at 60 months for endocrine therapy was 64.5%. Prostate cancer death was recognized only in 1 patient within the high-risk group, treated by endocrine therapy. In all the patients, the overall survival rate at 60 months for EBRT combined with endocrine therapy, HDR-brachytherapy, radical prostatectomy and endocrine therapy was 100%, 100%, 76.4% and 89.5%, respectively. The actuarial biochemical control rate and overall survival rate were not significant among the management options in each risk group. However, the 75 to 79-year-old patients within the high-risk group, who were treated with

  16. Impact of Hypoxia on the Metastatic Potential of Human Prostate Cancer Cells

    International Nuclear Information System (INIS)

    Dai Yao; Bae, Kyungmi; Siemann, Dietmar W.

    2011-01-01

    Purpose: Intratumoral hypoxia is known to be associated with radioresistance and metastasis. The present study examined the effect of acute and chronic hypoxia on the metastatic potential of prostate cancer PC-3, DU145, and LNCaP cells. Methods and Materials: Cell proliferation and clonogenicity were tested by MTT assay and colony formation assay, respectively. 'Wound-healing' and Matrigel-based chamber assays were used to monitor cell motility and invasion. Hypoxia-inducible factor 1 alpha (HIF-1α) expression was tested by Western blot, and HIF-1-target gene expression was detected by real-time polymerase chain reaction. Secretion of matrix metalloproteinases (MMPs) was determined by gelatin zymography. Results: When PC-3 cells were exposed to 1% oxygen (hypoxia) for various periods of time, chronic hypoxia (≥24 h) decreased cell proliferation and induced cell death. In contrast, prostate cancer cells exposed to acute hypoxia (≤6 h) displayed increased motility, clonogenic survival, and invasive capacity. At the molecular level, both hypoxia and anoxia transiently stabilized HIF-1α. Exposure to hypoxia also induced the early expression of MMP-2, an invasiveness-related gene. Treatment with the HIF-1 inhibitor YC-1 attenuated the acute hypoxia-induced migration, invasion, and MMP-2 activity. Conclusions: The length of oxygen deprivation strongly affected the functional behavior of all three prostate cancer cell lines. Acute hypoxia in particular was found to promote a more aggressive metastatic phenotype.

  17. New serum biomarkers for prostate cancer diagnosis

    Science.gov (United States)

    Chadha, Kailash C.; Miller, Austin; Nair, Bindukumar B.; Schwartz, Stanley A.; Trump, Donald L.; Underwood, Willie

    2014-01-01

    Background Prostate-specific antigen (PSA) is currently used as a biomarker for diagnosis and management of prostate cancer (CaP). However, PSA typically lacks the sensitivity and specificity desired of a diagnostic marker. Objective The goal of this study was to identify an additional biomarker or a panel of biomarkers that is more sensitive and specific than PSA in differentiating benign versus malignant prostate disease and/or localized CaP versus metastatic CaP. Methods Concurrent measurements of circulating interleukin-8 (IL-8), Tumor necrosis factor-α (TNF-α) and soluble tumor necrosis factor-α receptors 1 (sTNFR1) were obtained from four groups of men: (1) Controls (2) with elevated prostate-specific antigen with a negative prostate biopsy (elPSA_negBx) (3) with clinically localized CaP and (4) with castration resistant prostate cancer. Results TNF-α Area under the receiver operating characteristic curve (AUC = 0.93) and sTNFR1 (AUC = 0.97) were strong predictors of elPSA_negBx (vs. CaP). The best predictor of elPSA_negBx vs CaP was sTNFR1 and IL-8 combined (AUC = 0.997). The strongest single predictors of localized versus metastatic CaP were TNF-α (AUC = 0.992) and PSA (AUC = 0.963) levels. Conclusions The specificity and sensitivity of a PSA-based CaP diagnosis can be significantly enhanced by concurrent serum measurements of IL-8, TNF-α and sTNFR1. In view of the concerns about the ability of PSA to distinguish clinically relevant CaP from indolent disease, assessment of these biomarkers in the larger cohort is warranted. PMID:25593898

  18. Alterations of global histone H4K20 methylation during prostate carcinogenesis

    Directory of Open Access Journals (Sweden)

    Behbahani Turang E

    2012-03-01

    Full Text Available Abstract Background Global histone modifications have been implicated in the progression of various tumour entities. Our study was designed to assess global methylation levels of histone 4 lysine 20 (H4K20me1-3 at different stages of prostate cancer (PCA carcinogenesis. Methods Global H4K20 methylation levels were evaluated using a tissue microarray in patients with clinically localized PCA (n = 113, non-malignant prostate disease (n = 27, metastatic hormone-naive PCA (mPCA, n = 30 and castration-resistant PCA (CRPC, n = 34. Immunohistochemistry was performed to assess global levels of H4K20 methylation levels. Results Similar proportions of the normal, PCA, and mPCA prostate tissues showed strong H4K20me3 staining. CRPC tissue analysis showed the weakest immunostaining levels of H4K20me1 and H4K20me2, compared to other prostate tissues. H4K20me2 methylation levels indicated significant differences in examined tissues except for normal prostate versus PCA tissue. H4K20me1 differentiates CRPC from other prostate tissues. H4K20me1 was significantly correlated with lymph node metastases, and H4K20me2 showed a significant correlation with the Gleason score. However, H4K20 methylation levels failed to predict PSA recurrence after radical prostatectomy. Conclusions H4K20 methylation levels constitute valuable markers for the dynamic process of prostate cancer carcinogenesis.

  19. A Paracrine Role for IL6 in Prostate Cancer Patients: Lack of Production by Primary or Metastatic Tumor Cells

    Science.gov (United States)

    Yu, Shu-Han; Zheng, Qizhi; Esopi, David; Macgregor-Das, Anne; Luo, Jun; Antonarakis, Emmanuel S.; Drake, Charles G.; Vessella, Robert; Morrissey, Colm; De Marzo, Angelo M.; Sfanos, Karen S.

    2015-01-01

    Correlative human studies suggest that the pleiotropic cytokine interleukin-6 (IL6) contributes to the development and/or progression of prostate cancer. However, the source of IL6 production in the prostate microenvironment in patients has yet to be determined. The cellular origin of IL6 in primary and metastatic prostate cancer was examined in formalin-fixed, paraffin-embedded (FFPE) tissues using a highly sensitive and specific chromogenic in situ hybridization (CISH) assay that underwent extensive analytical validation. Quantitative RT-PCR (q-RT-PCR) showed that benign prostate tissues often had higher expression of IL6 mRNA than matched tumor specimens. CISH analysis further indicated that both primary and metastatic prostate adenocarcinoma cells do not express IL6 mRNA. IL6 expression was highly heterogeneous across specimens and was nearly exclusively restricted to the prostate stromal compartment – including endothelial cells and macrophages among other cell types. The number of IL6-expressing cells correlated positively with the presence of acute inflammation. In metastatic disease, tumor cells were negative in all lesions examined and IL6 expression was restricted to endothelial cells within the vasculature of bone metastases. Finally, IL6 was not detected in any cells in soft tissue metastases. These data suggest that, in prostate cancer patients, paracrine rather than autocrine IL6 production is likely associated with any role for the cytokine in disease progression. PMID:26048576

  20. Impact of ethnicity on the outcome of men with metastatic, hormone-sensitive prostate cancer.

    Science.gov (United States)

    Bernard, Brandon; Muralidhar, Vinayak; Chen, Yu-Hui; Sridhar, Srikala S; Mitchell, Edith P; Pettaway, Curtis A; Carducci, Michael A; Nguyen, Paul L; Sweeney, Christopher J

    2017-05-01

    Prostate cancer (PCa) outcomes are impacted by socioeconomic and biologic factors. Ethnicity plays a role in the former, but little is known about the responsiveness of metastatic PCa to androgen-deprivation therapy (ADT) among races. The Surveillance, Epidemiology, and End Results (SEER) registry was used to identify men who were diagnosed with distant, de novo, metastatic PCa from 2004 to 2012. Patterns of presentation, overall survival (OS), and PCa-specific mortality (PCSM) were determined for each race. E3805 clinical trial data also were retrospectively reviewed to assess outcomes of ADT and ADT plus docetaxel by race. Of all PCa diagnoses in SEER, distant, de novo, metastatic disease was diagnosed in 4.2% of non-Hispanic whites, 5.8% of Hispanic whites, 5.7% of blacks, 5.5% of Asians/Pacific Islanders, and 8.8% of American Indians/Alaska Natives (P blacks, respectively. Few Asians participated in the E3805 trial. Asian men have superior median OS and PCSM for distant, de novo, metastatic PCa than men of other race. Non-Hispanic whites and blacks who receive treatment with ADT or chemohormonal therapy have comparable outcomes. Cancer 2017;123:1536-1544. © 2017 American Cancer Society. © 2017 American Cancer Society.

  1. Exaggerated venous mural hypertrophy in association with metastatic adenocarcinoma of the prostate

    International Nuclear Information System (INIS)

    Gerber, W.L.; Dellers, E.A.; Putong, P.B.

    1991-01-01

    A 61-year-old black man presented with metastases to the right groin 5 years after 125iodine treatment for a well differentiated primary prostatic adenocarcinoma. Medium sized veins within and immediately adjacent to the neoplasm showed marked mural thickening due to hypertrophy and hyperplasia of the inner circular and outer longitudinal muscles. There was no histological evidence of radiation effect in the stroma or in the tumor cells. We could find no report in the literature of such changes associated with metastatic carcinoma

  2. Rare incidence of tumor lysis syndrome in metastatic prostate cancer following treatment with docetaxel.

    Science.gov (United States)

    Bhardwaj, Sharonlin; Varma, Seema

    2018-03-01

    Tumor lysis syndrome is a serious and sometimes lethal complication of cancer treatment that is comprised of a set of metabolic disturbances along with clinical manifestations. Initiating chemotherapy in bulky, rapidly proliferating tumors causes rapid cell turnover that in turn releases metabolites into circulation that give rise to metabolic derangements that can be dangerous. This syndrome is usually seen in high-grade hematological malignancies. Less commonly, tumor lysis syndrome can present in solid tumors and even rarely in genitourinary tumors. In this report, the authors describe a specific case of tumor lysis syndrome in a patient with metastatic prostate cancer following treatment with docetaxel.

  3. Disseminated intravascular coagulation in a patient with metastatic prostate cancer: Fatal outcome following strontium-89 therapy

    Energy Technology Data Exchange (ETDEWEB)

    Leong, C.; McKenzie, R.; Coupland, D.B. [Univ. of British Columbia, (Canada)] [and others

    1994-10-01

    A patient with metastatic prostate cancer was found to have low-grade disseminated intravascular coagulation (DIC). He had significant bone pain despite external-beam radiotherapy and was given {sup 89}Sr with subsequent thrombocytopenia and epistaxis. The patient died from generalized hemorrhage 36 days postinjection. Although it is not possible to establish a causal relationship between {sup 89}Sr and DIC, practitioners should be alert to complications associated with the primary disorder which might occur at a time to raise concern about the intervention. 8 refs., 1 tab.

  4. Radiotherapy in the management of non-metastatic prostate cancer: Current standards and future opportunities

    International Nuclear Information System (INIS)

    Forman, Jeffrey D.

    1997-01-01

    Objectives: The intent of this course is to review issues involved in the management of non-metastatic prostate cancer and to clarify the role of external beam radiotherapy, the use of neo-adjuvant and adjuvant hormonal therapy in conjunction with the radiation, the management of patients with regional metastases and recurrent disease following surgery and radiation. At the end of this course, participants should be able to fluently discuss management issues and strategies across the entire spectrum of non-metastatic prostate cancer. - Pre-treatment prognostic factors including clinical stage, grade, and pre-treatment PSA, will be presented and their relative value in determining therapeutic strategies will be discussed. Strategies to be discussed include standard dose radiation, escalated dose radiation, particle radiation and the use of adjuvant and neo-adjuvant hormonal therapy. - The process of simulation and field design will be presented, the value of CT-based treatment planning, beams-eye view design and the relative value of three-dimensional treatment planning will be discussed. - The significance of prostate and patient movement and strategies for dealing with this will also be presented so that what constitutes an adequate simulation and margin of treatment can be clarified. - The management of newly diagnosed patients, covering the range of low stage/low grade to locally advanced prostate cancer will be discussed. - The relative value of increasing dose, the relative value of using neo-adjuvant and/or adjuvant hormone therapy and the indications for escalated dose will be presented. - Strategies for managing post-prostatectomy patients will be reviewed. Data on adjuvant and therapeutic irradiation for biochemical failure will be presented and a strategy for management will be discussed. - How to deal with patients with residual disease post radiation will be discussed and the relative value of cryotherapy, salvage prostatectomy or hormonal therapy will

  5. Current Stem Cell Biomarkers and Their Functional Mechanisms in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Kaile Zhang

    2016-07-01

    Full Text Available Currently there is little effective treatment available for castration resistant prostate cancer, which is responsible for the majority of prostate cancer related deaths. Emerging evidence suggested that cancer stem cells might play an important role in resistance to traditional cancer therapies, and the studies of cancer stem cells (including specific isolation and targeting on those cells might benefit the discovery of novel treatment of prostate cancer, especially castration resistant disease. In this review, we summarized major biomarkers for prostate cancer stem cells, as well as their functional mechanisms and potential application in clinical diagnosis and treatment of patients.

  6. Activation of β-catenin signaling in androgen receptor-negative prostate cancer cells.

    Science.gov (United States)

    Wan, Xinhai; Liu, Jie; Lu, Jing-Fang; Tzelepi, Vassiliki; Yang, Jun; Starbuck, Michael W; Diao, Lixia; Wang, Jing; Efstathiou, Eleni; Vazquez, Elba S; Troncoso, Patricia; Maity, Sankar N; Navone, Nora M

    2012-02-01

    To study Wnt/β-catenin in castrate-resistant prostate cancer (CRPC) and understand its function independently of the β-catenin-androgen receptor (AR) interaction. We carried out β-catenin immunocytochemical analysis, evaluated TOP-flash reporter activity (a reporter of β-catenin-mediated transcription), and sequenced the β-catenin gene in MDA prostate cancer 118a, MDA prostate cancer 118b, MDA prostate cancer 2b, and PC-3 prostate cancer cells. We knocked down β-catenin in AR-negative MDA prostate cancer 118b cells and carried out comparative gene-array analysis. We also immunohistochemically analyzed β-catenin and AR in 27 bone metastases of human CRPCs. β-Catenin nuclear accumulation and TOP-flash reporter activity were high in MDA prostate cancer 118b but not in MDA prostate cancer 2b or PC-3 cells. MDA prostate cancer 118a and MDA prostate cancer 118b cells carry a mutated β-catenin at codon 32 (D32G). Ten genes were expressed differently (false discovery rate, 0.05) in MDA prostate cancer 118b cells with downregulated β-catenin. One such gene, hyaluronan synthase 2 (HAS2), synthesizes hyaluronan, a core component of the extracellular matrix. We confirmed HAS2 upregulation in PC-3 cells transfected with D32G-mutant β-catenin. Finally, we found nuclear localization of β-catenin in 10 of 27 human tissue specimens; this localization was inversely associated with AR expression (P = 0.056, Fisher's exact test), suggesting that reduced AR expression enables Wnt/β-catenin signaling. We identified a previously unknown downstream target of β-catenin, HAS2, in prostate cancer, and found that high β-catenin nuclear localization and low or no AR expression may define a subpopulation of men with bone metastatic prostate cancer. These findings may guide physicians in managing these patients.

  7. Increased survival with enzalutamide in prostate cancer after chemotherapy

    NARCIS (Netherlands)

    H.I. Scher (Howard I.); K. Fizazi (Karim); F. Saad (Fred); M.-E. Taplin (Mary-Ellen); C.N. Sternberg (Cora); K. Miller (Kurt); R. de Wit (Ronald); P.F.A. Mulders (P. F A); K.N. Chi (Kim Nguyen); N.D. Shore (Neal); A.J. Armstrong (Andrew); T.W. Flaig (Thomas); A. Flechon (Aude); P. Mainwaring (Paul); M. Fleming; J.D. Hainsworth (John); M. Hirmand (Mohammad); B. Selby (Bryan); L. Seely (Lynn); J.S. de Bono (Johann)

    2012-01-01

    textabstractBACKGROUND: Enzalutamide (formerly called MDV3100) targets multiple steps in the androgen-receptor-signaling pathway, the major driver of prostate-cancer growth. We aimed to evaluate whether enzalutamide prolongs survival in men with castration-resistant prostate cancer after

  8. Increased survival with enzalutamide in prostate cancer after chemotherapy

    NARCIS (Netherlands)

    Scher, H.I.; Fizazi, K.; Saad, F.; Taplin, M.E.; Sternberg, C.N.; Miller, K.; de Wit, R.; Mulders, P.F.A.; Chi, K.N.; Shore, N.D.; Armstrong, A.J.; Flaig, T.W.; Flechon, A.; Mainwaring, P.; Fleming, M.; Hainsworth, J.D.; Hirmand, M.; Selby, B.; Seely, L.; Bono, J. De; Investigators, A.

    2012-01-01

    BACKGROUND: Enzalutamide (formerly called MDV3100) targets multiple steps in the androgen-receptor-signaling pathway, the major driver of prostate-cancer growth. We aimed to evaluate whether enzalutamide prolongs survival in men with castration-resistant prostate cancer after chemotherapy. METHODS:

  9. Early growth inhibition is followed by increased metastatic disease with vitamin D (calcitriol treatment in the TRAMP model of prostate cancer.

    Directory of Open Access Journals (Sweden)

    Adebusola Alagbala Ajibade

    Full Text Available The active metabolite of vitamin D3, 1,25-dihydroxyvitamin D3 (calcitriol has antiproliferative effects in non-aggressive prostate cancer, however, its effects in more aggressive model systems are still unclear. In these studies, effects of calcitriol and a less-calcemic vitamin D analog, QW-1624F2-2 (QW, were tested in vivo, using the aggressive autochthonous transgenic adenocarcinoma of mouse prostate (TRAMP model. To study prevention of androgen-stimulated prostate cancer, vehicle, calcitriol (20 µg/kg, or QW (50 µg/kg were administered to 4 week-old TRAMP mice intraperitoneal (i.p. 3×/week on a MWF schedule for 14 weeks. Calcitriol and QW slowed progression of prostate cancer as indicated by reduced urogenital tract (p = 0.0022, calcitriol; p = 0.0009, QW and prostate weights (p = 0.0178, calcitriol; p = 0.0086, QW. However, only calcitriol increased expression of the pro-differentiation marker, cadherin 1 (p = 0.0086, and reduced tumor proliferation (p = 0.0467. By contrast, neither vitamin D analog had any effect on castration resistant prostate cancer in mice treated pre- or post-castration. Interestingly, although vitamin D showed inhibitory activity against primary tumors in hormone-intact mice, distant organ metastases seemed to be enhanced following treatment (p = 0.0823. Therefore, TRAMP mice were treated long-term with calcitriol to further examine effects on metastasis. Calcitriol significantly increased the number of distant organ metastases when mice were treated from 4 weeks-of-age until development of palpable tumors (20-25 weeks-of-age(p = 0.0003. Overall, data suggest that early intervention with vitamin D in TRAMP slowed androgen-stimulated tumor progression, but prolonged treatment resulted in development of a resistant and more aggressive disease associated with increased distant organ metastasis.

  10. Management of patients with advanced prostate cancer: recommendations of the St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) 2015

    NARCIS (Netherlands)

    Gillessen, S.; Omlin, A.; Attard, G.; Bono, J.S. de; Efstathiou, E.; Fizazi, K.; Halabi, S.; Nelson, P.S.; Sartor, O.; Smith, M.R.; Soule, H.R.; Akaza, H.; Beer, T.M.; Beltran, H.; Chinnaiyan, A.M.; Daugaard, G.; Davis, I.D.; Santis, M. de; Drake, C.G.; Eeles, R.A.; Fanti, S.; Gleave, M.E.; Heidenreich, A.; Hussain, M.; James, N.D.; Lecouvet, F.E.; Logothetis, C.J.; Mastris, K.; Nilsson, S.; Oh, W.K.; Olmos, D.; Padhani, A.R.; Parker, C.; Rubin, M.A.; Schalken, J.A.; Scher, H.I.; Sella, A.; Shore, N.D.; Small, E.J.; Sternberg, C.N.; Suzuki, H; Sweeney, C.J.; Tannock, I.F.; Tombal, B.

    2015-01-01

    The first St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) Expert Panel identified and reviewed the available evidence for the ten most important areas of controversy in advanced prostate cancer (APC) management. The successful registration of several drugs for castration-resistant

  11. Treatment Outcomes in Non-Metastatic Prostate Cancer Patients With Ultra-High Prostate-Specific Antigen

    International Nuclear Information System (INIS)

    Tai, Patricia; Tonita, Jon; Woitas, Carla; Zhu Tong; Joseph, Kurian; Skarsgard, David

    2012-01-01

    Purpose: It is commonly believed that prostate cancer patients with very high prostate-specific antigen (PSA) levels are unlikely to benefit from definitive local treatment, and patients with very high PSA are often underrepresented in, or excluded from, randomized clinical trials. Consequently, little is known about their optimal treatment or prognosis. We performed a registry-based analysis of management and outcome in this population of patients. Methods and Materials: Our provincial Cancer Registry was used to identify all men who were diagnosed with prostate cancer from 1990 to 2001. A retrospective chart review provided information on stage, Gleason score, PSA at diagnosis, and treatment. In this study, ultra-high PSA was defined as PSA of ≥50 ng/ml. For a more complete perspective, treatment outcomes of patients with PSA of 20 to 49.9 ng/ml were also studied. Results: Of the 8378 men diagnosed with prostate cancer during this period, 6,449 had no known nodal or distant metastatic disease. The median follow-up of this group was 67.2 months (range, 0–192 months). A total of 1534 patients had PSA of ≥20 ng/ml. Among the 995 patients with PSA 20 to 49.9 ng/ml, 85 had radical prostatectomy (RP), and their 5- and 10-year cause-specific survivals (CSS) were 95% and 84%, respectively. The 497 patients treated with radiotherapy (RT) had 5- and 10-year CSS of 92% and 71%. For the 332 patients with PSA 50–99.9 ng/ml, RT was associated with 5- and 10-year CSS of 81% and 55%. For the 207 patients with PSA of ≥100 ng/ml, RT was associated with 5- and 10-year CSS of 80% and 54%. Conclusions: This is the largest series in the world on non metastatic cancer patients with ultra-high PSA at diagnosis. Even in the setting of a very high presenting PSA level, prostatectomy and radiotherapy are often associated with prolonged survival.

  12. Co-Targeting Prostate Cancer Epithelium and Bone Stroma by Human Osteonectin-Promoter-Mediated Suicide Gene Therapy Effectively Inhibits Androgen-Independent Prostate Cancer Growth.

    Directory of Open Access Journals (Sweden)

    Shian-Ying Sung

    Full Text Available Stromal-epithelial interaction has been shown to promote local tumor growth and distant metastasis. We sought to create a promising gene therapy approach that co-targets cancer and its supporting stromal cells for combating castration-resistant prostate tumors. Herein, we demonstrated that human osteonectin is overexpressed in the prostate cancer epithelium and tumor stroma in comparison with their normal counterpart. We designed a novel human osteonectin promoter (hON-522E containing positive transcriptional regulatory elements identified in both the promoter and exon 1 region of the human osteonectin gene. In vitro reporter assays revealed that the hON-522E promoter is highly active in androgen receptor negative and metastatic prostate cancer and bone stromal cells compared to androgen receptor-positive prostate cancer cells. Moreover, in vivo prostate-tumor-promoting activity of the hON-522E promoter was confirmed by intravenous administration of an adenoviral vector containing the hON-522E promoter-driven luciferase gene (Ad-522E-Luc into mice bearing orthotopic human prostate tumor xenografts. In addition, an adenoviral vector with the hON-522E-promoter-driven herpes simplex virus thymidine kinase gene (Ad-522E-TK was highly effective against the growth of androgen-independent human prostate cancer PC3M and bone stromal cell line in vitro and in pre-established PC3M tumors in vivo upon addition of the prodrug ganciclovir. Because of the heterogeneity of human prostate tumors, hON-522E promoter-mediated gene therapy has the potential for the treatment of hormone refractory and bone metastatic prostate cancers.

  13. TH-E-BRF-08: Subpopulations of Similarly-Responding Lesions in Metastatic Prostate Cancer

    International Nuclear Information System (INIS)

    Lin, C; Harmon, S; Perk, T; Jeraj, R

    2014-01-01

    Purpose: In patients with multiple lesions, resistance to cancer treatments and subsequent disease recurrence may be due to heterogeneity of response across lesions. This study aims to identify subpopulations of similarly-responding metastatic prostate cancer lesions in bone using quantitative PET metrics. Methods: Seven metastatic prostate cancer patients treated with AR-directed therapy received pre-treatment and mid-treatment [F-18]NaF PET/CT scans. Images were registered using an articulated CT registration algorithm and transformations were applied to PET segmentations. Midtreatment response was calculated on PET-based texture features. Hierarchical agglomerative clustering was used to form groups of similarly-responding lesions, with the number of natural clusters (K) determined by the inconsistency coefficient. Lesion clustering was performed within each patient, and for the pooled population. The cophenetic coefficient (C) quantified how well the data was clustered. The Jaccard Index (JI) assessed similarity of cluster assignments from patient clustering and from population clustering. Results: 188 lesions in seven patients were identified for analysis (between 6 to 53 lesions per patient). Lesion response was defined as percent change relative to pre-treatment for 23 uncorrelated PET-based feature identifiers. . High response heterogeneity was found across all lesions (i.e. range ΔSUVmax =−95.98% to 775.00%). For intra-patient clustering, K ranged from 1–20. Population-based clustering resulted in 75 clusters, of 1-6 lesions each. Intra-patient clustering resulted in higher quality clusters than population clustering (mean C=0.95, range=0.89 to 1.00). For all patients, cluster assignments from population clustering showed good agreement to intra-patient clustering (mean JI=0.87, range=0.68 to 1.00). Conclusion: Subpopulations of similarly-responding lesions were identified in patients with multiple metastatic lesions. Good agreement was found between

  14. Dual-Targeting of AR and Akt Pathways by Berberine in Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2016-10-01

    more effective treatments. Preliminary studies conducted in our lab have shown that a berberine (BBR), a plant -derived isoquinoline alkaloid...mice was measured weekly. At the end of experiment, animals were sacrificed by CO2 inhalation. The genitourinary bloc (GU bloc), consisting of the...phosphorylation by PDK1 and mTORC2 (7), in the Pten-null model. The experimental design is similar to that described above. Vehicle (10% 1- methyl

  15. Epithelial Plasticity in Castration-Resistant Prostate Cancer: Biology of the Lethal Phenotype

    Science.gov (United States)

    2011-07-01

    647, cytokeratin (AbD Serotec #MCA 1907HT) labeled with Alexa 555, and Vimentin (BD Biosciences, San Jose , CA #550513) labeled with Alexa 488. Nuclear...importance of the transitional phenotypic state to lethal cancer biology. In: Proceedings of the Genitourinary Cancers Symposium; 5–7 March 2010; San ...resulting gene list was used to determine the significantly differentially expressed genes between AT3-M and AT3-T using the "Filtering on Volcano

  16. Dual-Targeting of AR and Akt Pathways by Berberine in Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2014-08-01

    underlying the downregulation of full-length and splice variants of AR by the phytochemical berberine (BBR). We concluded that BBR inhibits the...46-54. [34] Narizhneva NV, Tararova ND, Ryabokon P, Shy- shynova I, Prokvolit A, Komarov PG, Purmal AA, Gudkov AV, Gurova KV. Small molecule screen

  17. Biomarkers for Taxane Sensitivity and Hormonal Resistance in Patients with Castration Resistant Prostate Cancer

    Science.gov (United States)

    2016-04-01

    were treated in the same manner as described in Fig. 2A except for pre-treatment with 10 µM enzalutamide (DMSO as a vehicle control) 2 h prior to DHT ...vectors for FLAG- tagged AR-FL or AR-V. The cells were treated 24 h later with DHT (1 nM), LMB (10 ng/ml), or vehicle control for 4 h. A. The

  18. MiR-146-SIAH2-AR Signaling in Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2015-09-01

    determined whether miR-146a inhibitor promotes CRPC phenotype by upregulating SIAH2 in LNCaP and MDAPCa2b cells. First we determined the effect of DHT (5α...dihydrotestosterone) on proliferation of these cells grown in the presence of charcoal stripped calf serum. The results indicated that DHT increased...proliferation of both parental LNCaP and MDAPCa2b cells but DHT did not increase proliferation of miR-146a inhibitor expressing cell lines (Fig. 6

  19. Interdisciplinary critique of sipuleucel-T as immunotherapy in castration-resistant prostate cancer

    DEFF Research Database (Denmark)

    Huber, Marie L; Haynes, Laura; Parker, Chris

    2012-01-01

    -thirds of the cells harvested from placebo patients, but not from the sipuleucel-T arm, were frozen and not reinfused, a detrimental effect of this large repeated cell loss provides a potential alternative explanation for the survival "benefit." Patient safety depends on adequately addressing this alternative...

  20. Effects of Phthalates on Androgen Receptor Regulation Associated with Castration-Resistant Prostate Cancer Development

    Science.gov (United States)

    2017-07-01

    Flaws, J. A. Monohaloacetic acid drinking water disinfection by-products inhibit follicle growth and steroidogenesis in mouse ovarian antral follicles...Occurrence and Toxicity of Disinfection Byproducts in European Drinking Waters in Relation with the HIWATE Epidemiology Study, US-Korea Annual...by-products in drinking water , J. Environ. Sci. 2017, (in press) 2. Jeong, C. H., Gao, G., Dettro, T., Wagner, E. D., Ricke, E. A., Plewa, M. J

  1. Uncarboxylated Osteocalcin and Gprc6a Axis Produce Intratumoral Androgens in Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2016-05-01

    with bone extracellular matrix associated calcium and hydroxyapatite and deposited in the bone matrix. Some Osteocalcin is released into circulation...RFP (red fluorescence protein as control) Osteocalcin and mutant Osteocalcin using lentivirus mediated stable infections. 2. Determined the gene...in bone tumors Expression of Osteocalcin forms in VCaP cells: We used a lentiviral system for expressing Osteocalcin and mutated Osteocalcin

  2. CpG-STAT3siRNA for Castration-Resistant Prostate Cancer Therapy

    Science.gov (United States)

    2015-12-01

    preliminary studies (Supplementary Fig. S2). Then selected myeloid cell populations were isolated using high- speed cell sorting using FACS-Aria (BD...experimental conditions, we analyzed IFNg and granzyme B production by CD8þ T cells. Both IFNg (Fig. 5G ) and granzyme B (Fig. 5H) expression levels were

  3. Novel Therapeutic Targets to Inhibit Tumor Microenvironment-Induced Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2014-10-01

    proposed studies at the conclusion of this award. 15. SUBJECT TERMS 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a...MAPK4. J Biol Chem 281, 35499-510 (2006). 5. Kant , S. et al. Characterization of the atypical MAPK ERK4 and its activation of the MAPK-activated

  4. Understanding the Role of MDSCs in Castration-Resistant Prostate Cancer and Metastasis

    Science.gov (United States)

    2016-12-01

    MRI  analysis   (data  not   shown).  There   is  no  noticeable   normal   epithelium   in   the   castrated   Ptenpc...recruitment  of  MDSCs  to  the  TME  of   Ptenpc-­‐/-­‐Smad4pc-­‐/-­‐  tumors,  we  assessed  the  impact  of   pharmacologic ...B 9 Methodology:   We   used   pharmacological   approach   to   inhibit   CXCL5   and

  5. Deregulation of MiR-34b/Sox2 Predicts Prostate Cancer Progression.

    Directory of Open Access Journals (Sweden)

    Irene Forno

    Full Text Available Most men diagnosed with prostate cancer will have an indolent and curable disease, whereas approximately 15% of these patients will rapidly progress to a castrate-resistant and metastatic stage with high morbidity and mortality. Therefore, the identification of molecular signature(s that detect men at risk of progressing disease remains a pressing and still unmet need for these patients. Here, we used an integrated discovery platform combining prostate cancer cell lines, a Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP model and clinically-annotated human tissue samples to identify loss of expression of microRNA-34b as consistently associated with prostate cancer relapse. Mechanistically, this was associated with epigenetics silencing of the MIR34B/C locus and increased DNA copy number loss, selectively in androgen-dependent prostate cancer. In turn, loss of miR-34b resulted in downstream deregulation and overexpression of the "stemness" marker, Sox2. These findings identify loss of miR-34b as a robust biomarker for prostate cancer progression in androgen-sensitive tumors, and anticipate a potential role of progenitor/stem cell signaling in this stage of disease.

  6. Deregulation of MiR-34b/Sox2 Predicts Prostate Cancer Progression.

    Science.gov (United States)

    Forno, Irene; Ferrero, Stefano; Russo, Maria Veronica; Gazzano, Giacomo; Giangiobbe, Sara; Montanari, Emanuele; Del Nero, Alberto; Rocco, Bernardo; Albo, Giancarlo; Languino, Lucia R; Altieri, Dario C; Vaira, Valentina; Bosari, Silvano

    2015-01-01

    Most men diagnosed with prostate cancer will have an indolent and curable disease, whereas approximately 15% of these patients will rapidly progress to a castrate-resistant and metastatic stage with high morbidity and mortality. Therefore, the identification of molecular signature(s) that detect men at risk of progressing disease remains a pressing and still unmet need for these patients. Here, we used an integrated discovery platform combining prostate cancer cell lines, a Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model and clinically-annotated human tissue samples to identify loss of expression of microRNA-34b as consistently associated with prostate cancer relapse. Mechanistically, this was associated with epigenetics silencing of the MIR34B/C locus and increased DNA copy number loss, selectively in androgen-dependent prostate cancer. In turn, loss of miR-34b resulted in downstream deregulation and overexpression of the "stemness" marker, Sox2. These findings identify loss of miR-34b as a robust biomarker for prostate cancer progression in androgen-sensitive tumors, and anticipate a potential role of progenitor/stem cell signaling in this stage of disease.

  7. Local Treatment of Metastatic Prostate Cancer: What is the Evidence So Far?

    Directory of Open Access Journals (Sweden)

    Pedro Leonel Almeida

    2018-01-01

    Full Text Available Background. Advances in technological, laboratorial, and imaging studies and new treatments available in the last decades significantly improved prostate cancer survival rates. However, this did not occur in metastatic prostate cancer (mPCa at diagnosis which, in young and fit patients, will become invariably resistant to the established treatments. Progression will lead to an impairment in patients’ quality of life and disease-related death. Methods. The authors intend to perform a literature review of the advantages of primary treatment of mPCa. Articles were retrieved and filtered for relevance from PubMed, SciELO, and ScienceDirect until March 2017. Results. Primary treatment is currently indicated only in cases of nonmetastatic PCa. Nonetheless, there might be some benefits in doing local treatment in mPCa in order to control local disease, prevent new metastasis, and improve the efficacy of chemotherapy and hormonotherapy with similar complications rate when compared to locally confined cancer. Independent factors that have a negative influence are age above 70 years, cT4 stage or high-grade disease, PSA≥20 ng/ml, and pelvic lymphadenopathies. The presence of 3 or more of these factors conditions CSS and OS is the same between patients who performed local treatment and those who did not. Metastasis degree and location number can also influence outcome. Meanwhile, patients with visceral metastases have worse results. Conclusions. There is growing evidence supporting local treatment in cases of metastatic prostate cancer at diagnosis in the context of a multimodal approach. However, it should be kept in mind that most of the existing studies are retrospective and it would be important to make consistent prospective studies with well-defined patient selection criteria in order to sustain the existing data and understand the main indications to select patients and perform primary treatment in mPCa.

  8. Local Treatment of Metastatic Prostate Cancer: What is the Evidence So Far?

    Science.gov (United States)

    Leonel Almeida, Pedro; Jorge Pereira, Bruno

    2018-01-01

    Advances in technological, laboratorial, and imaging studies and new treatments available in the last decades significantly improved prostate cancer survival rates. However, this did not occur in metastatic prostate cancer (mPCa) at diagnosis which, in young and fit patients, will become invariably resistant to the established treatments. Progression will lead to an impairment in patients' quality of life and disease-related death. The authors intend to perform a literature review of the advantages of primary treatment of mPCa. Articles were retrieved and filtered for relevance from PubMed, SciELO, and ScienceDirect until March 2017. Primary treatment is currently indicated only in cases of nonmetastatic PCa. Nonetheless, there might be some benefits in doing local treatment in mPCa in order to control local disease, prevent new metastasis, and improve the efficacy of chemotherapy and hormonotherapy with similar complications rate when compared to locally confined cancer. Independent factors that have a negative influence are age above 70 years, cT4 stage or high-grade disease, PSA ≥ 20 ng/ml, and pelvic lymphadenopathies. The presence of 3 or more of these factors conditions CSS and OS is the same between patients who performed local treatment and those who did not. Metastasis degree and location number can also influence outcome. Meanwhile, patients with visceral metastases have worse results. There is growing evidence supporting local treatment in cases of metastatic prostate cancer at diagnosis in the context of a multimodal approach. However, it should be kept in mind that most of the existing studies are retrospective and it would be important to make consistent prospective studies with well-defined patient selection criteria in order to sustain the existing data and understand the main indications to select patients and perform primary treatment in mPCa.

  9. Prognostic Factors for Hormone Sensitive Metastatic Prostate Cancer: Impact of Disease Volume

    Science.gov (United States)

    Alhanafy, Alshimaa Mahmoud; Zanaty, Fouad; Ibrahem, Reda; Omar, Suzan

    2018-04-27

    Background and Aim: The optimal management of metastatic hormone-sensitive prostate cancer has been controversial in recent years with introduction of upfront chemohormonal treatment based on results of several Western studies. This changing landscape has renewed interest in the concept “disease volume”, the focus of the present study is the Egyptian patients. Methods: Patients with hormone sensitive metastatic prostate cancer presenting at Menoufia University Hospital, Egypt, during the period from June 2013 to May 2016, were enrolled. All received hormonal treatment. Radiologic images were evaluated and patients were stratified according to their disease volume into high or low, other clinical and pathological data that could affect survival also being collected and analyzed. Results: A total of 128 patients were included, with a median age of 70 years (53.9% ≥70). About 46% had co-morbidities, 62% having high volume disease. During the median follow up period of 28 months about half of the patients progressed and one third received chemotherapy. On univariate analysis, disease volume, performance status (PS), prostate specific antigen level (PSA) and presence of pain at presentation were identified as factors influencing overall survival. Multivariate analysis revealed the independent predictor factors for survival to be PS, PSA and disease volume. The median overall survival with 27 months was high volume versus 49 with low volume disease (hazard ratio 2.1; 95% CI 1.2 - 4.4; P=0.02). Median progression free survival was 19 months in the high volume, as compared with 48 months in the low volume disease patients (hazard ratio, 2.44; 95% CI, 1.42 – 7.4; P=0.009). Conclusions: Disease volume is a reliable predictor of survival which should be incorporated with other important factors as; patient performance status and comorbidities in treatment decision-making. Creative Commons Attribution License

  10. Tissue polypeptide-specific antigen (TPS) determinations before and during intermittent maximal androgen blockade in patients with metastatic prostatic carcinoma

    NARCIS (Netherlands)

    Kil, P. J. M.; Goldschmidt, H. M. J.; Wieggers, B. J. A.; Kariakine, O. B.; Studer, U. E.; Whelan, P.; Hetherington, J.; de Reijke, Th M.; Hoekstra, J. W.; Collette, L.

    2003-01-01

    To evaluate the prognostic significance of serially measured tissue polypeptide-specific antigen (TPS) levels in patients with metastatic prostatic carcinoma treated with intermittent maximal androgen blockade (MAB). To determine its value with respect to predicting response to treatment and time to

  11. Metastatic adenocarcinoma of prostate in a 28-year-old male: The outcome is poor in young patients?

    Directory of Open Access Journals (Sweden)

    Renu Madan

    2015-01-01

    Full Text Available Prostate cancer is common in older patients. Rarity in younger population limits the study of natural history and prognosis in this population. Most of the published data has reported poor outcome in younger patients with metastatic prostate cancer. Here, we report a case of prostate cancer in 28-year-old male who presented with bone metastasis. After bilateral inguinal orchidectomy, he was started on anti-androgen therapy and received palliative radiotherapy for bone metastasis. There was only a slight decrease in prostate-specific antigen (PSA level and pelvic disease post treatment. Subsequently, he was started on opioid analgesics (by World Health Organization, WHO, step ladder in view of persistent pain. The index case is being presented for its rarity and probable poor outcome in young patients and to stress on the fact that the possibility of primary prostatic adenocarcinoma should be investigated in a male presenting with bone metastasis irrespective of the age.

  12. Paucity of PD-L1 expression in prostate cancer: innate and adaptive immune resistance.

    Science.gov (United States)

    Martin, A M; Nirschl, T R; Nirschl, C J; Francica, B J; Kochel, C M; van Bokhoven, A; Meeker, A K; Lucia, M S; Anders, R A; DeMarzo, A M; Drake, C G

    2015-12-01

    Primary prostate cancers are infiltrated with programmed death-1 (PD-1) expressing CD8+ T-cells. However, in early clinical trials, men with metastatic castrate-resistant prostate cancer did not respond to PD-1 blockade as a monotherapy. One explanation for this unresponsiveness could be that prostate tumors generally do not express programmed death ligand-1 (PD-L1), the primary ligand for PD-1. However, lack of PD-L1 expression in prostate cancer would be surprising, given that phosphatase and tensin homolog (PTEN) loss is relatively common in prostate cancer and several studies have shown that PTEN loss correlates with PD-L1 upregulation--constituting a mechanism of innate immune resistance. This study tested whether prostate cancer cells were capable of expressing PD-L1, and whether the rare PD-L1 expression that occurs in human specimens correlates with PTEN loss. Human prostate cancer cell lines were evaluated for PD-L1 expression and loss of PTEN by flow cytometry and western blotting, respectively. Immunohistochemical (IHC) staining for PTEN was correlated with PD-L1 IHC using a series of resected human prostate cancer samples. In vitro, many prostate cancer cell lines upregulated PD-L1 expression in response to inflammatory cytokines, consistent with adaptive immune resistance. In these cell lines, no association between PTEN loss and PD-L1 expression was apparent. In primary prostate tumors, PD-L1 expression was rare, and was not associated with PTEN loss. These studies show that some prostate cancer cell lines are capable of expressing PD-L1. However, in human prostate cancer, PTEN loss is not associated with PD-L1 expression, arguing against innate immune resistance as a mechanism that mitigates antitumor immune responses in this disease.

  13. Slug/SNAI2 regulates cell proliferation and invasiveness of metastatic prostate cancer cell lines.

    Science.gov (United States)

    Emadi Baygi, Modjtaba; Soheili, Zahra-Soheila; Essmann, Frank; Deezagi, Abdolkhaleg; Engers, Rainer; Goering, Wolfgang; Schulz, Wolfgang A

    2010-08-01

    Many metastatic cancers recapitulate the epithelial-to-mesenchymal transition (EMT) resulting in enhanced cell motility and invasiveness. The EMT is regulated by several transcription factors, including the zinc finger protein SNAI2, also named Slug, which appears to exert additional functions during development and cancer progression. We have studied the function of SNAI2 in prostate cancer cells. Quantitative RT-PCR analysis showed strong SNAI2 expression particularly in the PC-3 and PC3-16 prostate carcinoma cell lines. Knockdown of SNAI2 by specific siRNA induced changes in EMT markers and inhibited invasion of both cell lines into a matrigel matrix. SNAI2 siRNA-treated cells did not tolerate detachment from the culture plates, likely at least in part due to downregulation of integrin alpha6beta4. SNAI2 knockdown disturbed the microtubular and actin cytoskeletons, especially severely in PC-3 cells, resulting in grossly enlarged, flattened, and sometimes multinuclear cells. Knockdown also decreased cell proliferation, with a prominent G0/G1 arrest in PC3-16. Together, our data imply that SNAI2 exerts strong effects on the cytoskeleton and adhesion of those prostate cancer cells that express it and is necessary for their proliferation and invasiveness.

  14. Clinical Implications of Hedgehog Pathway Signaling in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Daniel L. Suzman

    2015-09-01

    Full Text Available Activity in the Hedgehog pathway, which regulates GLI-mediated transcription, is important in organogenesis and stem cell regulation in self-renewing organs, but is pathologically elevated in many human malignancies. Mutations leading to constitutive activation of the pathway have been implicated in medulloblastoma and basal cell carcinoma, and inhibition of the pathway has demonstrated clinical responses leading to the approval of the Smoothened inhibitor, vismodegib, for the treatment of advanced basal cell carcinoma. Aberrant Hedgehog pathway signaling has also been noted in prostate cancer with evidence suggesting that it may render prostate epithelial cells tumorigenic, drive the epithelial-to-mesenchymal transition, and contribute towards the development of castration-resistance through autocrine and paracrine signaling within the tumor microenvironment and cross-talk with the androgen pathway. In addition, there are emerging clinical data suggesting that inhibition of the Hedgehog pathway may be effective in the treatment of recurrent and metastatic prostate cancer. Here we will review these data and highlight areas of active clinical research as they relate to Hedgehog pathway inhibition in prostate cancer.

  15. Identification of novel androgen receptor target genes in prostate cancer

    Directory of Open Access Journals (Sweden)

    Gerald William L

    2007-06-01

    Full Text Available Abstract Background The androgen receptor (AR plays critical roles in both androgen-dependent and castrate-resistant prostate cancer (PCa. However, little is known about AR target genes that mediate the receptor's roles in disease progression. Results Using Chromatin Immunoprecipitation (ChIP Display, we discovered 19 novel loci occupied by the AR in castrate resistant C4-2B PCa cells. Only four of the 19 AR-occupied regions were within 10-kb 5'-flanking regulatory sequences. Three were located up to 4-kb 3' of the nearest gene, eight were intragenic and four were in gene deserts. Whereas the AR occupied the same loci in C4-2B (castrate resistant and LNCaP (androgen-dependent PCa cells, differences between the two cell lines were observed in the response of nearby genes to androgens. Among the genes strongly stimulated by DHT in C4-2B cells – D-dopachrome tautomerase (DDT, Protein kinase C delta (PRKCD, Glutathione S- transferase theta 2 (GSTT2, Transient receptor potential cation channel subfamily V member 3 (TRPV3, and Pyrroline-5-carboxylate reductase 1 (PYCR1 – most were less strongly or hardly stimulated in LNCaP cells. Another AR target gene, ornithine aminotransferase (OAT, was AR-stimulated in a ligand-independent manner, since it was repressed by AR siRNA knockdown, but not stimulated by DHT. We also present evidence for in vivo AR-mediated regulation of several genes identified by ChIP Display. For example, PRKCD and PYCR1, which may contribute to PCa cell growth and survival, are expressed in PCa biopsies from primary tumors before and after ablation and in metastatic lesions in a manner consistent with AR-mediated stimulation. Conclusion AR genomic occupancy is similar between LNCaP and C4-2B cells and is not biased towards 5' gene flanking sequences. The AR transcriptionally regulates less than half the genes nearby AR-occupied regions, usually but not always, in a ligand-dependent manner. Most are stimulated and a few are

  16. Clinical roundtable monograph: new and emerging treatments for advanced prostate cancer.

    Science.gov (United States)

    George, Daniel J; Kantoff, Philip W; Lin, Daniel W

    2011-06-01

    Historically, the treatment of metastatic castration-resistant prostate cancer (CRPC) has been limited to chemotherapeutic regimens that did not improve patient survival. In 2004, clinical studies began to demonstrate significant improvements in patient outcomes, including overall survival, with docetaxel versus mitoxantrone chemotherapy. Since these pivotal trials, the combination of docetaxel plus prednisone has become a standard of care for patients with metastatic CRPC. However, the limited survival benefit achieved with this regimen prompted several investigations into the development of alternative therapeutic options. Recent advances have now led to an unprecedented number of new drug approvals within the past year, providing many new treatment options for patients with metastatic CRPC. Sipuleucel-T, considered a new paradigm in cancer treatment, is the first such immunotherapeutic agent approved by the US Food and Drug Administration. Other successes include abiraterone acetate, the first androgen biosynthesis inhibitor, and cabazitaxel, a novel microtubule inhibitor, both of which have demonstrated improved survival following docetaxel failure. The bone-targeting agent denosumab, also recently approved in this setting, offers these patients significant improvement in the prevention of skeletal-related events. The data supporting the approval of each of these agents are described in this monograph, as are current approaches in the treatment of metastatic CRPC and ongoing clinical trials of novel treatments and strategies. The experts also discuss several of the issues regarding the introduction of these novel agents into clinical practice for metastatic CRPC patients.

  17. Imaging yield from 133 consecutive patients with prostate cancer and low trigger PSA from a single institution

    International Nuclear Information System (INIS)

    Shinagare, A.B.; Keraliya, A.; Somarouthu, B.; Tirumani, S.H.; Ramaiya, N.H.; Kantoff, P.W.

    2016-01-01

    Aim: To investigate the yield of imaging in patients with relapsed prostate cancer (PC) with a low trigger prostate-specific antigen (PSA). Materials and methods: This institutional review board (IRB)-approved, Health Insurance Portability and Accountability Act (HIPAA)-compliant retrospective study included all 133 patients (mean age 68 years; range 45–88; median 69 months since original diagnosis; interquartile range [IQR]: 32–139) with hormone-sensitive PC (HSPC, n=28) or castration-resistant PC (CRPC, n=105) and trigger PSA 0.05 for all). Fifty-seven of the 133 (43%) patients had findings seen only at CT, of which 37 had new extra-osseous findings. Only 2/133 (2%) had findings at bone scintigraphy not seen at CT, both in areas not covered on CT. Conclusion: Imaging frequently demonstrated new metastatic and non-metastatic findings in patients with a low trigger PSA. CT is valuable in these patients because extra-osseous findings not visible at bone scintigraphy are frequently seen. - Highlights: • New and existing metastases common in prostate cancer with low trigger PSA. • Previous reports of threshold PSA levels may not apply in follow-up setting. • No difference in metastatic pattern between hormone sensitive and resistant disease. • CT showed extra-osseous findings not seen on bone scan in 44% patients. • Bone scan rarely showed findings not visible on concurrent CT.

  18. Hormonal therapy with external radiation therapy for metastatic spinal cord compression from newly diagnosed prostate cancer

    International Nuclear Information System (INIS)

    Kato, So; Hozumi, Takahiro; Yamakawa, Kiyofumi; Higashikawa, Akiro; Goto, Takahiro; Shinohara, Mitsuru; Kondo, Taiji

    2013-01-01

    Although hormonal therapy is effective for treatment of prostate cancer, its effect in the treatment of metastatic spinal cord compression (MSCC) has not been established. The objective of this study was to clarify the efficacy of conservative treatment of MSCC-induced paralysis resulting from prostate cancer for patients without a previous treatment history. We reviewed data from 38 patients with MSCC-induced paralysis from newly diagnosed prostate cancer who presented to our service between 1984 and 2010. Conservative treatment consisted of hormonal therapy with external radiation therapy (ERT). Patient demographic data, treatment details, involved spine MRI images, complications, and the course of neurologic recovery were investigated. Twenty-five patients were treated conservatively. Mean follow-up period was 36.8 months. Sixteen patients (two with Frankel B, 14 with Frankel C) were unable to walk at initial presentation. After initiating conservative treatment, 75% (12 of 16) of these patients regained the ability to walk within 1 month, 88% (14 in 16) did so within 3 months, and all non-ambulatory patients did so within 6 months. No one had morbid complications. Four patients who did not regain the ability to walk at 1 month were found to have progressed to paraplegia rapidly, and tended to have severe compression as visualized on MRI, with a delay in the start of treatment in comparison with those who did so within 1 month (21.0 vs. 7.8 days). Hormonal therapy associated with ERT is an important option for treatment of MSCC resulting from newly diagnosed prostate cancer. (author)

  19. Robotic Image-Guided Stereotactic Radiotherapy, for Isolated Recurrent Primary, Lymph Node or Metastatic Prostate Cancer

    International Nuclear Information System (INIS)

    Jereczek-Fossa, Barbara Alicja; Beltramo, Giancarlo; Fariselli, Laura; Fodor, Cristiana; Santoro, Luigi; Vavassori, Andrea; Zerini, Dario; Gherardi, Federica; Ascione, Carmen; Bossi-Zanetti, Isa; Mauro, Roberta; Bregantin, Achille; Bianchi, Livia Corinna; De Cobelli, Ottavio; Orecchia, Roberto

    2012-01-01

    Purpose: To evaluate the outcome of robotic CyberKnife (Accuray, Sunnyvale, CA)–based stereotactic radiotherapy (CBK-SRT) for isolated recurrent primary, lymph node, or metastatic prostate cancer. Methods and Materials: Between May 2007 and December 2009, 34 consecutive patients/38 lesions were treated (15 patients reirradiated for local recurrence [P], 4 patients reirradiated for anastomosis recurrence [A], 16 patients treated for single lymph node recurrence [LN], and 3 patients treated for single metastasis [M]). In all but 4 patients, [ 11 C]choline positron emission tomography/computed tomography was performed. CBK-SRT consisted of reirradiation and first radiotherapy in 27 and 11 lesions, respectively. The median CBK-SRT dose was 30 Gy in 4.5 fractions (P, 30 Gy in 5 fractions; A, 30 Gy in 5 fractions; LN, 33 Gy in 3 fractions; and M, 36 Gy in 3 fractions). In 18 patients (21 lesions) androgen deprivation was added to CBK-SRT (median duration, 16.6 months). Results: The median follow-up was 16.9 months. Acute toxicity included urinary events (3 Grade 1, 2 Grade 2, and 2 Grade 3 events) and rectal events (1 Grade 1 event). Late toxicity included urinary events (3 Grade 1, 2 Grade 2, and 2 Grade 3 events) and rectal events (1 Grade 1 event and 1 Grade 2 event). Biochemical response was observed in 32 of 38 evaluable lesions. Prostate-specific antigen stabilization was seen for 4 lesions, and in 2 cases prostate-specific antigen progression was reported. The 30-month progression-free survival rate was 42.6%. Disease progression was observed for 14 lesions (5, 2, 5, and 2 in Groups P, A, LN, and M respectively). In only 3 cases, in-field progression was seen. At the time of analysis (May 2010), 19 patients are alive with no evidence of disease and 15 are alive with disease. Conclusions: CyberKnife-based stereotactic radiotherapy is a feasible approach for isolated recurrent primary, lymph node, or metastatic prostate cancer, offering excellent in-field tumor

  20. Estrogen receptor signaling in prostate cancer: Implications for carcinogenesis and tumor progression.

    Science.gov (United States)

    Bonkhoff, Helmut

    2018-01-01

    The androgen receptor (AR) is the classical target for prostate cancer prevention and treatment, but more recently estrogens and their receptors have also been implicated in prostate cancer development and tumor progression. Recent experimental and clinical data were reviewed to elucidate pathogenetic mechanisms how estrogens and their receptors may affect prostate carcinogenesis and tumor progression. The estrogen receptor beta (ERβ) is the most prevalent ER in the human prostate, while the estrogen receptor alpha (ERα) is restricted to basal cells of the prostatic epithelium and stromal cells. In high grade prostatic intraepithelial neoplasia (HGPIN), the ERα is up-regulated and most likely mediates carcinogenic effects of estradiol as demonstrated in animal models. The partial loss of the ERβ in HGPIN indicates that the ERβ acts as a tumor suppressor. The tumor promoting function of the TMPRSS2-ERG fusion, a major driver of prostate carcinogenesis, is triggered by the ERα and repressed by the ERβ. The ERβ is generally retained in hormone naïve and metastatic prostate cancer, but is partially lost in castration resistant disease. The progressive emergence of the ERα and ERα-regulated genes (eg, progesterone receptor (PR), PS2, TMPRSS2-ERG fusion, and NEAT1) during prostate cancer progression and hormone refractory disease suggests that these tumors can bypass the AR by using estrogens and progestins for their growth. In addition, nongenomic estrogen signaling pathways mediated by orphan receptors (eg, GPR30 and ERRα) has also been implicated in prostate cancer progression. Increasing evidences demonstrate that local estrogen signaling mechanisms are required for prostate carcinogenesis and tumor progression. Despite the recent progress in this research topic, the translation of the current information into potential therapeutic applications remains highly challenging and clearly warrants further investigation. © 2017 Wiley Periodicals, Inc.

  1. PCA3 Silencing Sensitizes Prostate Cancer Cells to Enzalutamide-mediated Androgen Receptor Blockade.

    Science.gov (United States)

    Özgür, Emre; Celik, Ayca Iribas; Darendeliler, Emin; Gezer, Ugur

    2017-07-01

    Prostate cancer (PCa) is an androgen-dependent disease. Novel anti-androgens (i.e. enzalutamide) have recently been developed for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC). Evidence is accumulating that prostate cancer antigen 3 (PCA3) is involved in androgen receptor (AR) signaling. Here, in combination with enzalutamide-mediated AR blockade, we investigated the effect of PCA3 targeting on the viability of PCa cells. In hormone-sensitive LNCaP cells, AR-overexpressing LNCaP-AR + cells and VCaP cells (representing CRPC), PCA3 was silenced using siRNA oligonucleotides. Gene expression and cell viability was assessed in PCA3-silenced and/or AR-blocked cells. PCA3 targeting reduced the expression of AR-related genes (i.e. prostate-specific antigen (PSA) and prostate-specific transcript 1 (non-protein coding) (PCGEM1)) and potentiated the effect of enzalutamide. Proliferation of PCa cells was suppressed upon PCA3 silencing with a greater effect in LNCaP-AR + cells. Furthermore, PCA3 silencing sensitized PCa cells to enzalutamide-induced loss of cell growth. PCA3, as a therapeutic target in PCa, might be used to potentiate AR antagonists. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  2. Docetaxel-related fatigue in men with metastatic prostate cancer: a descriptive analysis.

    Science.gov (United States)

    Bergin, A R T; Hovey, E; Lloyd, A; Marx, G; Parente, P; Rapke, T; de Souza, P

    2017-09-01

    Fatigue is a prevalent and debilitating side effect of docetaxel chemotherapy in metastatic prostate cancer. A better understanding of the kinetics and nature of docetaxel-related fatigue may provide a framework for intervention. This secondary analysis was performed using the MOTIF database, from a phase III, randomised, double-blind, placebo-controlled study of modafinil (200 mg/day for 15 days) for docetaxel-related fatigue in men with metastatic prostate cancer [1]. The pattern of fatigue was analysed using the MDASI (MD Anderson Symptom Inventory) score. The impact of modafinil, cumulative docetaxel exposure, age and smoking status on fatigue kinetics were explored. Fatigue-related symptoms were assessed using the SOMA6 (fatigue and related symptoms) subset of the SPHERE (Somatic and Psychological Health Report). Mood was tracked using the short form 36 health survey questionnaire (SF-36). Across four docetaxel cycles, fatigue scores were higher in the first week and decreased over weeks two and three. Whilst men randomised to modafinil had reduced fatigue scores, cumulative docetaxel had little impact. Younger men (55-68 years) had significantly reduced fatigue scores, whereas current and ex-smokers had higher scores. There was no significant change in mood status or haemoglobin across treatment cycles. Men described both 'somnolence' and 'muscle fatigue' contributing significantly to their symptom complex. Assessment and management of docetaxel-related fatigue remains an important challenge. Given the complex, multifactorial nature of fatigue, identification through structured interview and interventions targeted to specific 'at risk' groups may be the most beneficial. Understanding the temporal pattern (kinetics) and nature of fatigue is critical to guide this process.

  3. Identification of the epigenetic reader CBX2 as a potential drug target in advanced prostate cancer.

    Science.gov (United States)

    Clermont, Pier-Luc; Crea, Francesco; Chiang, Yan Ting; Lin, Dong; Zhang, Amy; Wang, James Z L; Parolia, Abhijit; Wu, Rebecca; Xue, Hui; Wang, Yuwei; Ding, Jiarui; Thu, Kelsie L; Lam, Wan L; Shah, Sohrab P; Collins, Colin C; Wang, Yuzhuo; Helgason, Cheryl D

    2016-01-01

    While localized prostate cancer (PCa) can be effectively cured, metastatic disease inevitably progresses to a lethal state called castration-resistant prostate cancer (CRPC). Emerging evidence suggests that aberrant epigenetic repression by the polycomb group (PcG) complexes fuels PCa progression, providing novel therapeutic opportunities. In the search for potential epigenetic drivers of CRPC, we analyzed the molecular profile of PcG members in patient-derived xenografts and clinical samples. Overall, our results identify the PcG protein and methyl-lysine reader CBX2 as a potential therapeutic target in advanced PCa. We report that CBX2 was recurrently up-regulated in metastatic CRPC and that elevated CBX2 expression was correlated with poor clinical outcome in PCa cohorts. Furthermore, CBX2 depletion abrogated cell viability and induced caspase 3-mediated apoptosis in metastatic PCa cell lines. Mechanistically explaining this phenotype, microarray analysis in CBX2-depleted cells revealed that CBX2 controls the expression of many key regulators of cell proliferation and metastasis. Taken together, this study provides the first evidence that CBX2 inhibition induces cancer cell death, positioning CBX2 as an attractive drug target in lethal CRPC.

  4. Effects of occupational therapy on quality of life of patients with metastatic prostate cancer

    Science.gov (United States)

    Huri, Meral; Huri, Emre; Kayihan, Hulya; Altuntas, Onur

    2015-01-01

    Objectives: To evaluate the efficiency of occupational therapy relative to a home program in improving quality of life (QoL) among men who were treated for metastatic prostate cancer (MPC). Methods: Fifty-five men were assigned randomly to either the 12-week cognitive behavioral therapy based occupational therapy (OT-CBSM) intervention (treatment group) or a home program (control group) between March 2012 and August 2014 in the Department of Occupational Therapy, Faculty of Health Sciences, Hacettepe University, Ankara, Turkey. The Canadian Occupational Performance Measure (COPM) was used to measure the occupational performance and identify difficulties in daily living activities. The QoL and symptom status were measured by The European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire C30 and its Prostate Cancer Module. A 12-week OT-CBSM intervention including client-centered training of daily living activities, recreational group activities, and cognitive behavioral stress management intervention were applied. Results: The COPM performance and satisfaction scores, which indicate occupational participation and QoL increased statistically in the treatment group in relation to men who were included in the home-program (p≤0.05). Conclusion: A 12-week OT-CBSM intervention was effective in improving QoL in men treated for MPC, and these changes were associated significantly with occupational performance. PMID:26219446

  5. Dimensions of quality of life expressed by men treated for metastatic prostate cancer.

    Science.gov (United States)

    Clark, J A; Wray, N; Brody, B; Ashton, C; Giesler, B; Watkins, H

    1997-10-01

    Men who pursue active treatment for metastatic prostate cancer face a choice between medical or surgical castration. While both alternatives have documented side-effects (e.g. loss of libido, breast enlargement and tenderness, hot flashes, and nausea), their psychosocial impacts are not well understood. As part of a study of patients' treatment decision making, we have sought to construct a patient-based measure of the salient disease and treatment-related qualities of life experienced by these men subsequent to treatment. Focus groups (15 with patients, two with wives) were used to develop candidate Likert scale questionnaire items representing quality of life issues that patients said were important. These items were combined with assessments of symptoms, comorbidity, and generic measures of functional status and well-being in a mail survey of patients treated at the Houston VAMC and two other Houston hospitals (n = 201, response rate = 63%). Psychometric analyses (principal components and multitrait scaling) were used to identify distinct dimensions of life quality; correlations with generic measures, and symptom reports were used in validation analyses. Qualitative analyses of focus group data identified three major domains of life quality: self-perceptions, anxiety about the effects of treatment, and concern with the process of decision making and treatment. Psychometric analyses identified nine reliable and valid indicators of prostate cancer-related quality of life: body image, sexual problems, spouse affection, spouse worry, masculinity, cancer-related self-image, cancer distress, cancer acceptance, and regret of treatment decision. Internal consistency (alpha) ranged form 0.71 to 0.90. Correlations with reference scales (e.g. MOS Mental Health Index, Profile of Mood States) and symptom status supported concurrent validity. Prostate cancer patients perceive a number of important psychosocial consequences of their treatment. These consequences are

  6. Incidental detection of prostate-specific antigen-negative metastatic prostate cancer initially presented with solitary pulmonary nodule on fluorodeoxyglucose positron emission tomography/computed tomography

    International Nuclear Information System (INIS)

    Erdogan, Ezgi Basak; Buyukpinarbasili, Nur; Ziyade, Sedat; Akman, Tolga; Turk, Haci Mehmet; Aydin, Mehmet

    2005-01-01

    A 71-year-old male patient with solitary pulmonary nodule underwent fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) showing slightly increased FDG uptake in this nodule. In addition, PET/CT detected hypermetabolic sclerotic bone lesions in the right second rib and 7 th thoracic vertebrae, which were interpreted as possible metastases, and mildly increased FDG uptake in the prostate gland highly suspicious of malignancy. The patient's prostate-specific antigen (PSA) level was within normal range (3.8 ng/dL). The histopathological examination of the lung nodule and right second rib lesion proved metastases from prostate cancer, then the prostate biopsy-confirmed prostate adenocarcinoma. The unique feature of this case is to emphasize the importance of performing PET/CT for solitary pulmonary nodule in detecting PSA-negative metastatic prostate cancer. This case indicated that it should be kept in mind that, even if the PSA is negative, a lung metastasis of prostate cancer may be an underlying cause in patients evaluated for solitary pulmonary nodule by FDG PET/CT

  7. Treatment of Hormone Resistance with Docetaxel in Metastatic Prostate Cancer Patients: Results of a Clinical Experience at Omid Hospital, Isfahan, Iran

    Directory of Open Access Journals (Sweden)

    Mina Tajvidi

    2017-01-01

    Full Text Available Background: Metastatic prostate cancer is one of the most important cancers among men worldwide. Androgen ablation therapy can be used in treatment of these patients; however, most will progress to metastatic hormone-refractory prostate cancer. In this regard, docetaxel has been approved to treat metastatic hormone-refractory prostate cancer in the United States. In this study, we aimed to investigate the results of this treatment modality in metastatic prostate cancer patients from Iran. Methods:We evaluated PSA response and bone pain relief in 18 metastatic prostate cancer patients who underwent treatment with docetaxel at a dose of 75 mg/m2