A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer.
Liu, Joyce F; Tolaney, Sara M; Birrer, Michael; Fleming, Gini F; Buss, Mary K; Dahlberg, Suzanne E; Lee, Hang; Whalen, Christin; Tyburski, Karin; Winer, Eric; Ivy, Percy; Matulonis, Ursula A
Poly(ADP-ribose) polymerase (PARP)-inhibitors and anti-angiogenics have activity in recurrent ovarian and breast cancer; however, the effect of combined therapy against PARP and angiogenesis in this population has not been reported. We investigated the toxicities and recommended phase 2 dosing (RP2D) of the combination of cediranib, a multitargeted inhibitor of vascular endothelial growth factor receptor (VEGFR)-1/2/3 and olaparib, a PARP-inhibitor (NCT01116648). Cediranib tablets once daily and olaparib capsules twice daily were administered orally in a standard 3+3 dose escalation design. Patients with recurrent ovarian or metastatic triple-negative breast cancer were eligible. Patients had measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or met Gynecologic Cancer InterGroup (GCIG) CA125 criteria. No prior PARP-inhibitors or anti-angiogenics in the recurrent setting were allowed. 28 patients (20 ovarian, 8 breast) enrolled to 4 dose levels. 2 dose limiting toxicities (DLTs) (1 grade 4 neutropenia ≥ 4 days; 1 grade 4 thrombocytopenia) occurred at the highest dose level (cediranib 30 mg daily; olaparib 400 mg twice daily [BID]). The RP2D was cediranib 30 mg daily and olaparib 200 mg BID. Grade 3 or higher toxicities occurred in 75% of patients, and included grade 3 hypertension (25%) and grade 3 fatigue (18%). One grade 3 bowel obstruction occurred. The overall response rate (ORR) in the 18 RECIST-evaluable ovarian cancer patients was 44%, with a clinical benefit rate (ORR plus stable disease (SD) > 24 weeks) of 61%. None of the seven evaluable breast cancer patients achieved clinical response; two patients had stable disease for > 24 weeks. The combination of cediranib and olaparib has haematologic DLTs and anticipated class toxicities, with promising evidence of activity in ovarian cancer patients. Copyright © 2013 Elsevier Ltd. All rights reserved.
Liu, Joyce F.; Tolaney, Sara M.; Birrer, Michael; Fleming, Gini F.; Buss, Mary K.; Dahlberg, Suzanne E.; Lee, Hang; Whalen, Christin; Tyburski, Karin; Winer, Eric; Ivy, Percy; Matulonis, Ursula A.
Background PARP-inhibitors and anti-angiogenics have activity in recurrent ovarian and breast cancer; however, the effect of combined therapy against PARP and angiogenesis in this population has not been reported. We investigated the toxicities and recommended phase 2 dosing (RP2D) of the combination of cediranib, a multitargeted inhibitor of VEGFR-1/2/3, and olaparib, a PARP-inhibitor (NCT01116648). Methods Cediranib tablets once daily and olaparib capsules twice daily were administered orally in a standard 3+3 dose escalation design. Patients with recurrent ovarian or metastatic triple-negative breast cancer were eligible. Patients had measurable disease by RECIST 1.1 or met GCIG CA125 criteria. No prior PARP-inhibitors or anti-angiogenics in the recurrent setting were allowed. Results 28 patients (20 ovarian, 8 breast) enrolled to 4 dose levels. 2 DLTs (1 grade 4 neutropenia ≥4 days; 1 grade 4 thrombocytopenia) occurred at the highest dose level (cediranib 30mg daily; olaparib 400mg BID). The RP2D was cediranib 30mg daily and olaparib 200mg BID. Grade 3 or higher toxicities occurred in 75% of patients, and included grade 3 hypertension (25%) and grade 3 fatigue (18%). One grade 3 bowel obstruction occurred. The overall response rate (ORR) in the 18 RECIST-evaluable ovarian cancer patients was 44%, with a clinical benefit rate (ORR plus SD >24 weeks) of 61%. None of the 7 evaluable breast cancer patients achieved clinical response; 2 patients had stable disease for >24 weeks. Interpretation The combination of cediranib and olaparib has hematologic DLTs and anticipated class toxicities, with promising evidence of activity in ovarian cancer patients. PMID:23810467
Ivy, S Percy; Liu, Joyce F; Lee, Jung-Min; Matulonis, Ursula A; Kohn, Elise C
An estimated 22,000 women are diagnosed annually with ovarian cancer in the United States. Initially chemo-sensitive, recurrent disease ultimately becomes chemoresistant and may kill ~14,000 women annually. Molecularly targeted therapy with cediranib (AZD2171), a vascular endothelial growth factor receptor (VEGFR)-1, 2, and 3 signaling blocker, and olaparib (AZD2281), a poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor, administered orally in combination has shown anti-tumor activity in the treatment of high grade serous ovarian cancer (HGSOC). This combination has the potential to change the treatment of HGSOC. Preclinical and clinical studies of single agent cediranib and olaparib or their combination are reviewed. Data are presented from peer-reviewed published manuscripts, completed and ongoing early phase clinical trials registered in ClinicalTrials.gov, National Cancer Institute-sponsored clinical trials, and related recent abstracts. Advances in the treatment of HGSOC that improve progression-free and overall survival have proven elusive despite examination of molecularly targeted therapy. HGSOC patients with deleterious germline or somatic mutations in BRCA1 or BRCA2 (BRCAm) are most responsive to PARP inhibitors (PARPi). PARPi combined with angiogenesis inhibition improved anti-cancer response and duration in both BRCAm and BRCA wild type HGSOC patients, compared to olaparib single agent treatment, demonstrating therapeutic chemical and contextual synthetic lethality.
Kummar, Shivaani; Allen, Deborah; Monks, Anne; Polley, Eric C.; Hose, Curtis D.; Ivy, S. Percy; Turkbey, Ismail B.; Lawrence, Scott; Kinders, Robert J.; Choyke, Peter; Simon, Richard; Steinberg, Seth M.; Doroshow, James H.; Helman, Lee
Purpose Alveolar soft part sarcoma (ASPS) is a rare, highly vascular tumor, for which no effective standard systemic treatment exists for patients with unresectable disease. Cediranib is a potent, oral small-molecule inhibitor of all three vascular endothelial growth factor receptors (VEGFRs). Patients and Methods We conducted a phase II trial of once-daily cediranib (30 mg) given in 28-day cycles for patients with metastatic, unresectable ASPS to determine the objective response rate (ORR). We also compared gene expression profiles in pre- and post-treatment tumor biopsies and evaluated the effect of cediranib on tumor proliferation and angiogenesis using positron emission tomography and dynamic contrast-enhanced magnetic resonance imaging. Results Of 46 patients enrolled, 43 were evaluable for response at the time of analysis. The ORR was 35%, with 15 of 43 patients achieving a partial response. Twenty-six patients (60%) had stable disease as the best response, with a disease control rate (partial response + stable disease) at 24 weeks of 84%. Microarray analysis with validation by quantitative real-time polymerase chain reaction on paired tumor biopsies from eight patients demonstrated downregulation of genes related to vasculogenesis. Conclusion In this largest prospective trial to date of systemic therapy for metastatic ASPS, we observed that cediranib has substantial single-agent activity, producing an ORR of 35% and a disease control rate of 84% at 24 weeks. On the basis of these results, an open-label, multicenter, randomized phase II registration trial is currently being conducted for patients with metastatic ASPS comparing cediranib with another VEGFR inhibitor, sunitinib. PMID:23630200
Lassen, U; Miller, W H; Hotte, S
PURPOSE: To investigate any effect of a CYP3A4 inhibitor (ketoconazole) or inducer (rifampicin) on cediranib steady-state pharmacokinetics in patients with advanced solid tumours. METHODS: In two Phase I, open-label trials, patients received once-daily oral doses of cediranib alone [20 mg...... (ketoconazole study); 45 mg (rifampicin study)] for 7 days followed by cediranib at the same dose with ketoconazole 400 mg/day for 3 days or once-daily rifampicin 600 mg/day for 7 days, respectively. Patients then continued to receive once-daily cediranib. RESULTS: In the ketoconazole study, 46 patients were...... dosed; 38 were evaluable for C (ss,max), 36 for AUC(ss). gMean AUC(ss) and C (ss,max) for cediranib 20 mg increased by 21 % (94 % CI 9-35 %) and 26 % (94 % CI 10-43 %), respectively, in the presence of ketoconazole. In the rifampicin study, 64 patients were dosed; 44 were evaluable for C (ss,max) and 41...
Kim, Heisoog; Catana, Ciprian; Ratai, Eva-Maria; Andronesi, Ovidiu C.; Jennings, D.; Batchelor, Tracy T.; Jain, Rakesh K.; Sorensen, A. Gregory
Proton magnetic resonance spectroscopy (1H-MRS) is increasingly used in clinical studies of brain tumor to provide information about tissue metabolic profiles. In this study, we evaluated changes in the levels of metabolites predominant in recurrent glioblastoma (rGBM), to characterize the response of rGBM to anti-angiogenic therapy. We examined thirty-one rGBM patients treated with daily doses of cediranib, acquiring serial chemical shift imaging data at specific time points during the treatment regimen. We defined spectra from three regions of interest (ROIs)—enhancing tumor (ET), peritumoral tissue (PT), and normal tissue on the contralateral side (cNT)—in post-contrast T1-weighted images, and normalized the concentrations of N-acetylaspartate (NAA) and choline (Cho) in each ROI to the concentration of creatine in cNT (norCre). We analyzed the ratios of these normalized metabolites (i.e., NAA/Cho, NAA/norCre, and Cho/norCre) by averaging all patients and categorizing two different survival groups. Relative to pre-treatment values, NAA/Cho in ET was unchanged through day 28. However, after day 28, NAA/Cho significantly increased in relation to a significant increase in NAA/norCre and a decrease in Cho/norCre; interestingly, the observed trend was reversed after day 56, consistent with the clinical course of GBM recurrence. Notably, ROC analysis indicated that NAA/Cho in tumor shows a high prediction to 6-month overall survival. These metabolic changes in these rGBM patients strongly suggest a direct metabolic effect of cediranib, and might also reflect an anti-tumor response to anti-angiogenic treatment during the first two months of treatment. Further study is needed to confirm these findings. PMID:21507932
Matulonis, Ursula A; Berlin, Suzanne; Ivy, Percy; Tyburski, Karin; Krasner, Carolyn; Zarwan, Corrine; Berkenblit, Anna; Campos, Susana; Horowitz, Neil; Cannistra, Stephen A; Lee, Hang; Lee, Julie; Roche, Maria; Hill, Margaret; Whalen, Christin; Sullivan, Laura; Tran, Chau; Humphreys, Benjamin D; Penson, Richard T
Angiogenesis is important for epithelial ovarian cancer (EOC) growth, and blocking angiogenesis can lead to EOC regression. Cediranib is an oral tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptor (VEGFR) -1, VEGFR-2, VEGFR-3, and c-kit. We conducted a phase II study of cediranib for recurrent EOC or peritoneal or fallopian tube cancer; cediranib was administered as a daily oral dose, and the original dose was 45 mg daily. Because of toxicities observed in the first 11 patients, the dose was lowered to 30 mg. Eligibility included 16 weeks, or CA-125 nonprogression > 16 weeks), which was the primary end point, was 30%; eight patients (17%; 95% CI, 7.6% to 30.8%) had a PR, six patients (13%; 95% CI, 4.8% to 25.7%) had SD, and there were no CRs. Eleven patients (23%) were removed from study because of toxicities before two cycles. Grade 3 toxicities (> 20% of patients) included hypertension (46%), fatigue (24%), and diarrhea (13%). Grade 2 hypothyroidism occurred in 43% of patients. Grade 4 toxicities included CNS hemorrhage (n = 1), hypertriglyceridemia/hypercholesterolemia/elevated lipase (n = 1), and dehydration/elevated creatinine (n = 1). No bowel perforations or fistulas occurred. Median PFS was 5.2 months, and median OS has not been reached; median follow-up time is 10.7 months. Cediranib has activity in recurrent EOC, tubal cancer, and peritoneal cancer with predictable toxicities observed with other TKIs.
Liu, Joyce F.; Barry, William T.; Birrer, Michael; Lee, Jung-Min; Buckanovich, Ronald J.; Fleming, Gini F.; Rimel, BJ; Buss, Mary K.; Nattam, Sreenivasa; Hurteau, Jean; Luo, Weixiu; Quy, Philippa; Whalen, Christin; Obermayer, Lisa; Lee, Hang; Winer, Eric P.; Kohn, Elise C.; Ivy, S. Percy; Matulonis, Ursula A.
Background Olaparib is an oral poly(ADP-ribose) polymerase inhibitor and cediranib is an oral anti-angiogenic with activity against VEGFR-1, 2, and 3. Both agents have antitumor activity in women with recurrent ovarian cancer, and the combination of these agents was active and had manageable toxicities in a Phase 1 trial. We asked whether the combination of cediranib and olaparib could improve progression-free survival compared to olaparib monotherapy in women with recurrent platinum-sensitive ovarian cancer. Methods We conducted a randomized, open-label, phase 2 study to evaluate the activity of olaparib monotherapy compared with combination cediranib and olaparib in women with ovarian cancer with measurable platinum-sensitive, relapsed, high-grade serous or endometrioid disease or those with deleterious germline BRCA1/2 mutations (gBRCAm). Patients were randomized using permuted blocks within stratum defined by gBRCA status and prior anti-angiogenic therapy to receive olaparib capsules 400mg twice daily or the combination at the recommended phase 2 dose of cediranib 30mg daily and olaparib capsules 200mg twice daily. The primary endpoint was progression-free survival (PFS) analyzed under intention to treat. The trial is registered with ClinicalTrials.gov, NCT01116648. The Phase 2 portion of the trial reported here is no longer accruing patients. Findings Forty-six of 90 randomized patients received olaparib alone, and 44 received cediranib/olaparib. Median PFS was significantly longer with cediranib/olaparib (17.7 vs. 9.0 mos, HR 0.42; p = 0.005). Grade 3 and 4 adverse events were more common with cediranib/olaparib, including fatigue (12 vs. 5), diarrhea (10 vs. 0), and hypertension (18 vs. 0). Subset analysis within stratum defined by BRCA1/2 status demonstrated activity of cediranib/olaparib in both gBRCAm and gBRCAwt/u (wild-type/unknown) patients. Significant improvement in PFS occurred in gBRCAwt/u women receiving cediranib/olaparib (16.5 vs. 5.7 mos, p = 0
Liu, Joyce F; Barry, William T; Birrer, Michael; Lee, Jung-Min; Buckanovich, Ronald J; Fleming, Gini F; Rimel, Bj; Buss, Mary K; Nattam, Sreenivasa; Hurteau, Jean; Luo, Weixiu; Quy, Philippa; Whalen, Christin; Obermayer, Lisa; Lee, Hang; Winer, Eric P; Kohn, Elise C; Ivy, S Percy; Matulonis, Ursula A
Olaparib is a poly(ADP-ribose) polymerase inhibitor and cediranib is an anti-angiogenic agent with activity against VEGF receptor (VEGFR) 1, VEGFR2, and VEGFR3. Both oral agents have antitumour activity in women with recurrent ovarian cancer, and their combination was active and had manageable toxicities in a phase 1 trial. We investigated whether this combination could improve progression-free survival (PFS) compared with olaparib monotherapy in women with recurrent platinum-sensitive ovarian cancer. In our randomised, open-label, phase 2 study, we recruited women (aged ≥18 years) who had measurable platinum-sensitive, relapsed, high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer, or those with deleterious germline BRCA1/2 mutations from nine participating US academic medical centres. We randomly allocated participants (1:1) according to permuted blocks, stratified by germline BRCA status and previous anti-angiogenic therapy, to receive olaparib capsules 400 mg twice daily or the combination at the recommended phase 2 dose of cediranib 30 mg daily and olaparib capsules 200 mg twice daily. The primary endpoint was progression-free survival analysed in the intention-to-treat population. The phase 2 trial is no longer accruing patients. An interim analysis was conducted in November, 2013, after 50% of expected events had occurred and efficacy results were unmasked. The primary analysis was performed on March 31, 2014, after 47 events (66% of those expected). The trial is registered with ClinicalTrials.gov, number NCT01116648. Between Oct 26, 2011, and June 3, 2013, we randomly allocated 46 women to receive olaparib alone and 44 to receive the combination of olaparib and cediranib. Median PFS was 17·7 months (95% CI 14·7-not reached) for the women treated with cediranib plus olaparib compared with 9·0 months (95% CI 5·7-16·5) for those treated with olaparib monotherapy (hazard ratio 0·42, 95% CI 0·23-0·76; p=0·005). Grade
Dy, Grace K; Mandrekar, Sumithra J; Nelson, Garth D; Meyers, Jeffrey P; Adjei, Araba A; Ross, Helen J; Ansari, Rafat H; Lyss, Alan P; Stella, Philip J; Schild, Steven E; Molina, Julian R; Adjei, Alex A
The purpose of this study was to assess the safety and efficacy of gemcitabine and carboplatin with (arm A) or without (arm B) daily oral cediranib as first-line therapy for advanced non-small-cell lung cancer. A lead-in phase to determine the tolerability of gemcitabine 1000 mg/m on days 1 and 8, and carboplatin on day 1 at area under curve 5 administered every 21 days with cediranib 45 mg once daily was followed by a 2 (A):1 (B) randomized phase II study. The primary end point was confirmed overall response rate (ORR) with 6-month progression-free survival (PFS6) rate in arm A as secondary end point. Polymorphisms in genes encoding cediranib targets and transport were correlated with treatment outcome. On the basis of the safety assessment, cediranib 30 mg daily was used in the phase II portion. A total of 58 and 29 evaluable patients were accrued to arms A and B. Patients in A experienced more grade 3+ nonhematologic adverse events, 71% versus 45% (p = 0.01). The ORR was 19% (A) versus 20% (B) (p = 1.0). PFS6 in A was 48% (95% confidence interval: 35%-62%), thus meeting the protocol-specified threshold of at least 40%. The median overall survival was 12.0 versus 9.9 months (p = 0.10). FGFR1 rs7012413, FGFR2 rs2912791, and VEGFR3 rs11748431 polymorphisms were significantly associated with decreased overall survival (hazard ratio 2.78-5.01, p = 0.0002-0.0095). The trial did not meet its primary end point of ORR but met its secondary end point of PFS6. The combination with cediranib 30 mg daily resulted in increased toxicity. Pharmacogenetic analysis revealed an association of FGFR and VEGFR variants with survival.
Kamoun, Walid S; Ley, Carsten D; Farrar, Christian T
anti-VEGF agents may decrease tumor contrast-enhancement, vascularity, and edema, the mechanisms leading to improved survival in patients remain incompletely understood. Our goal was to determine whether alleviation of edema by anti-VEGF agents alone could increase survival in mice. METHODS: We treated...... mice bearing three different orthotopic models of glioblastoma with a VEGF-targeted kinase inhibitor, cediranib. Using intravital microscopy, molecular techniques, and magnetic resonance imaging (MRI), we measured survival, tumor growth, edema, vascular morphology and function, cancer cell apoptosis...... by an increase in plasma collagen IV. These rapid changes in tumor vascular morphology and function led to edema alleviation -- as measured by MRI and by dry/wet weight measurement of water content -- but did not affect tumor growth. By immunohistochemistry, we found a transient decrease in macrophage...
CECs and IL-8 Have Prognostic and Predictive Utility in Patients with Recurrent Platinum-Sensitive Ovarian Cancer: Biomarker Correlates from the Randomized Phase-2 Trial of Olaparib and Cediranib Compared with Olaparib in Recurrent Platinum-Sensitive Ovarian Cancer.
Lee, Jung-Min; Trepel, Jane B; Choyke, Peter; Cao, Liang; Sissung, Tristan; Houston, Nicole; Yu, Minshu; Figg, William D; Turkbey, Ismail Baris; Steinberg, Seth M; Lee, Min-Jung; Ivy, S Percy; Liu, Joyce F; Matulonis, Ursula A; Kohn, Elise C
Olaparib (O), a polyADPribose polymerase (PARP) inhibitor, and cediranib (C), a VEGF receptor (VEGFR)1-3 inhibitor together had greater activity than O alone in women with recurrent platinum-sensitive ovarian cancer (OvCa). The objective of this study is to identify potential lead biomarker candidates for response to O + C in the setting of a multi-institutional phase II study of O with and without C in recurrent platinum-sensitive OvCa. A self-selected group of patients participated in a prospectively planned exploratory biomarker substudy of the randomized phase II study of O versus O + C. Whole blood for peripheral blood mononuclear cell (PBMC) and plasma isolation was collected prior to and on day 3 of treatment. Quantitation of circulating endothelial cells (CEC), IL-6, IL-8, VEGF, and soluble VEGFR-2 plasma concentrations, and polyADPribose (PAR) incorporation were performed. Single nucleotide polymorphism analysis of XRCC1 280H, R194W, and Q399R was done. Dynamic contrast-enhanced-magnetic resonance imaging (DCE-MRI) was performed at baseline and day 3 of treatment. Parameter changes were compared between the two arms using an exact Wilcoxon rank sum test. Kaplan-Meier and log-rank tests were used to examine survival outcome. Thirteen patients elected to participate in the translational substudy, seven patients on O and six patients on O + C. Patients on O + C had a greater decrease in IL-8 concentration and larger CEC fold increase compared with those on O alone (p = 0.026, p = 0.032). The fold increase in CEC on day 3 was associated with duration of progression-free survival (PFS) (R (2) = 0.77, 95% CI 0.55-0.97, p < 0.001). IL-8 post-pretreatment changes correlate with PFS (p = 0.028). XRCC1 DNA polymorphisms were not related to PFS. All patients had reduction in PAR incorporation, and all except one had reduction in vascular flow on DCE-MRI. Our exploratory correlative studies indicate that CEC and IL-8 changes may be
Hormigo, Adília; Gutin, Philip H.; Rafii, Shahin
Clinical assessment of the response to antiangiogenic therapy has been cumbersome. A study in this issue of Cancer Cell demonstrates that a combination of magnetic resonance imaging (MRI) for quantification of normalized vessels with measurements of circulating levels of proangiogenic factors, including FGF2, SDF1, and viable circulating endothelial cells, provides an effective means to evaluate the response of recurrent glioblastoma to a prototypical pan-VEGF receptor tyrosine kinase inhibitor, AZD2171. PMID:17222788
5, 6- dicyano -1, 4 - benzoquinone (DDQ) and employment of the reaction as a basis for the development of a ... association constant of the complex was 0.5 × 103 L mol−1 in 2-propanol. ..... some substituted naphthoquinones. Bull Chem Soc.
Christian T Farrar
Full Text Available MRI biomarkers of tumor edema, vascular permeability, blood volume, and average vessel caliber are increasingly being employed to assess the efficacy of tumor therapies. However, the dependence of these biomarkers on a number of physiological factors can compromise their sensitivity and complicate the assessment of therapeutic efficacy. Here we examine the response of these MRI tumor biomarkers to cediranib, a potent vascular endothelial growth factor receptor (VEGFR inhibitor, in an orthotopic mouse glioma model. A significant increase in the tumor volume and relative vessel caliber index (rVCI and a slight decrease in the water apparent diffusion coefficient (ADC were observed for both control and cediranib treated animals. This contrasts with a clinical study that observed a significant decrease in tumor rVCI, ADC and volume with cediranib therapy. While the lack of a difference between control and cediranib treated animals in these biomarker responses might suggest that cediranib has no therapeutic benefit, cediranib treated mice had a significantly increased survival. The increased survival benefit of cediranib treated animals is consistent with the significant decrease observed for cediranib treated animals in the relative cerebral blood volume (rCBV, relative microvascular blood volume (rMBV, transverse relaxation time (T2, blood vessel permeability (K(trans, and extravascular-extracellular space (ν(e. The differential response of pre-clinical and clinical tumors to cediranib therapy, along with the lack of a positive response for some biomarkers, indicates the importance of evaluating the whole spectrum of different tumor biomarkers to properly assess the therapeutic response and identify and interpret the therapy-induced changes in the tumor physiology.
Peterson, Teresa E.; Kirkpatrick, Nathaniel D.; Huang, Yuhui; Farrar, Christian T.; Marijt, Koen A.; Kloepper, Jonas; Datta, Meenal; Amoozgar, Zohreh; Seano, Giorgio; Jung, Keehoon; Kamoun, Walid S.; Vardam, Trupti; Snuderl, Matija; Goveia, Jermaine; Chatterjee, Sampurna; Batista, Ana; Muzikansky, Alona; Leow, Ching Ching; Xu, Lei; Batchelor, Tracy T.; Duda, Dan G.; Fukumura, Dai; Jain, Rakesh K.
Glioblastomas (GBMs) rapidly become refractory to anti-VEGF therapies. We previously demonstrated that ectopic overexpression of angiopoietin-2 (Ang-2) compromises the benefits of anti-VEGF receptor (VEGFR) treatment in murine GBM models and that circulating Ang-2 levels in GBM patients rebound after an initial decrease following cediranib (a pan-VEGFR tyrosine kinase inhibitor) administration. Here we tested whether dual inhibition of VEGFR/Ang-2 could improve survival in two orthotopic models of GBM, Gl261 and U87. Dual therapy using cediranib and MEDI3617 (an anti–Ang-2–neutralizing antibody) improved survival over each therapy alone by delaying Gl261 growth and increasing U87 necrosis, effectively reducing viable tumor burden. Consistent with their vascular-modulating function, the dual therapies enhanced morphological normalization of vessels. Dual therapy also led to changes in tumor-associated macrophages (TAMs). Inhibition of TAM recruitment using an anti–colony-stimulating factor-1 antibody compromised the survival benefit of dual therapy. Thus, dual inhibition of VEGFR/Ang-2 prolongs survival in preclinical GBM models by reducing tumor burden, improving normalization, and altering TAMs. This approach may represent a potential therapeutic strategy to overcome the limitations of anti-VEGFR monotherapy in GBM patients by integrating the complementary effects of anti-Ang2 treatment on vessels and immune cells. PMID:27044097
Mir, Olivier; Boudou-Rouquette, Pascaline; Larousserie, Frédérique; Blanchet, Benoit; Babinet, Antoine; Anract, Philippe; Goldwasser, François
Alveolar soft part sarcoma is a rare malignancy usually considered resistant to conventional chemotherapy, but recent data suggest that the multikinase inhibitors sunitinib and cediranib could be active in this setting. A 90-year-old lady with alveolar soft part sarcoma of the leg and lung metastases was started on sunitinib 37.5 mg daily. The treatment was poorly tolerated with grade 3 hypertension and grade 3 thrombocytopenia, which persisted after dose reduction to 25 mg daily. The patient was subsequently started on bevacizumab 10 mg/kg every 2 weeks, resulting in a marked improvement in pain and a partial response on lung metastases for 16 months and ongoing. Agents targeting the vascular endothelial growth factor-signalling pathway seem to exert clinically relevant and prolonged activity against alveolar soft part sarcoma and deserve further evaluation in the treatment of this rare soft tissue sarcoma.
Adam A Friedman
Full Text Available A newer generation of anti-cancer drugs targeting underlying somatic genetic driver events have resulted in high single-agent or single-pathway response rates in selected patients, but few patients achieve complete responses and a sizeable fraction of patients relapse within a year. Thus, there is a pressing need for identification of combinations of targeted agents which induce more complete responses and prevent disease progression. We describe the results of a combination screen of an unprecedented scale in mammalian cells performed using a collection of targeted, clinically tractable agents across a large panel of melanoma cell lines. We find that even the most synergistic drug pairs are effective only in a discrete number of cell lines, underlying a strong context dependency for synergy, with strong, widespread synergies often corresponding to non-specific or off-target drug effects such as multidrug resistance protein 1 (MDR1 transporter inhibition. We identified drugs sensitizing cell lines that are BRAFV600E mutant but intrinsically resistant to BRAF inhibitor PLX4720, including the vascular endothelial growth factor receptor/kinase insert domain receptor (VEGFR/KDR and platelet derived growth factor receptor (PDGFR family inhibitor cediranib. The combination of cediranib and PLX4720 induced apoptosis in vitro and tumor regression in animal models. This synergistic interaction is likely due to engagement of multiple receptor tyrosine kinases (RTKs, demonstrating the potential of drug- rather than gene-specific combination discovery approaches. Patients with elevated biopsy KDR expression showed decreased progression free survival in trials of mitogen-activated protein kinase (MAPK kinase pathway inhibitors. Thus, high-throughput unbiased screening of targeted drug combinations, with appropriate library selection and mechanistic follow-up, can yield clinically-actionable drug combinations.
Gilbert, Ashley N; Anderson, Joshua C; Duarte, Christine W; Shevin, Rachael S; Langford, Catherine P; Singh, Raj; Gillespie, G Yancey; Willey, Christopher D
Glioblastoma multiforme (GBM), the most common form of primary malignant brain cancer in adults, is a devastating disease for which effective treatment has remained elusive for over 75 years. One reason for the minimal progress during this time is the lack of accurate preclinical models to represent the patient's tumor's in vivo environment, causing a disconnect in drug therapy effectiveness between the laboratory and clinic. While patient-derived xenografts (PDX's or xenolines) are excellent human tumor representations, they are not amenable to high throughput testing. Therefore, we developed a miniaturized xenoline system (microtumors) for drug testing. Nineteen GBM xenolines were profiled for global kinase (kinomic) activity revealing actionable kinase targets associated with intracranial tumor growth rate. Kinase inhibitors for these targets (WP1066, selumetinib, crizotinib, and cediranib) were selected for single and combination therapy using a fully human-derived three-dimensional (3D) microtumor model of GBM xenoline cells embedded in HuBiogel for subsequent molecular and phenotype assays. GBM microtumors closely resembled orthotopically-implanted tumors based on immunohistochemical analysis and displayed kinomic and morphological diversity. Drug response testing could be reproducibly performed in a 96-well format identifying several synergistic combinations. Our findings indicate that 3D microtumors can provide a suitable high-throughput model for combination drug testing.
Full Text Available Judith Meza-Junco, Michael B SawyerDepartment of Oncology, Cross Cancer Institute, Edmonton, Alberta, CanadaAbstract: Gastric cancer (GC is currently the second leading cause of cancer death worldwide; unfortunately, most patients will present with locally advanced or metastatic disease. Despite recent progress in diagnosis, surgery, chemotherapy, and radiotherapy, prognosis remains poor. A better understanding of GC biology and signaling pathways is expected to improve GC therapy, and the integration of targeted therapies has recently become possible and appears to be promising. This article focuses on anti-Her-2 therapy, specifically trastuzumab, as well as other epidermal growth factor receptor antagonists such as cetuximab, panitumub, matuzumab, nimotzumab, gefitinib, and erlotinib. Additionally, drugs that target angiogenesis pathways are also under investigation, particulary bevacizumab, ramucirumab, sorafenib, sunitinib, and cediranib. Other targeted agents in preclinical or early clinical development include mTOR inhibitors, anti c-MET, polo-like kinase 1 inhibitors, anti-insulin-like growth factor, anti-heat shock proteins, and small molecules targeting Hedgehog signaling.Keywords: gastric cancer, targeted therapy, antiangiogenesis drugs, anti-EGFR drugs
Suh, Dong Hoon; Kim, Miseon; Kim, Kidong; Kim, Hak Jae; Lee, Kyung Hun; Kim, Jae Weon
In 2016, 13 topics were selected as major research advances in gynecologic oncology. For ovarian cancer, study results supporting previous ones regarding surgical preventive strategies were reported. There were several targeted agents that showed comparable responses in phase III trials, including niraparib, cediranib, and nintedanib. On the contrary to our expectations, dose-dense weekly chemotherapy regimen failed to prove superior survival outcomes compared with conventional triweekly regimen. Single-agent non-platinum treatment to prolong platinum-free-interval in patients with recurrent, partially platinum-sensitive ovarian cancer did not improve and even worsened overall survival (OS). For cervical cancer, we reviewed robust evidences of larger-scaled population-based study and cost-effectiveness of nonavalent vaccine for expanding human papillomavirus (HPV) vaccine coverage. Standard of care treatment of locally advanced cervical cancer (LACC) was briefly reviewed. For uterine corpus cancer, new findings about appropriate surgical wait time from diagnosis to surgery were reported. Advantages of minimally invasive surgery over conventional laparotomy were reconfirmed. There were 5 new gene regions that increase the risk of developing endometrial cancer. Regarding radiation therapy, Post-Operative Radiation Therapy in Endometrial Cancer (PORTEC)-3 quality of life (QOL) data were released and higher local control rate of image-guided adaptive brachytherapy was reported in LACC. In addition, 4 general oncology topics followed: chemotherapy at the end-of-life, immunotherapy with reengineering T-cells, actualization of precision medicine, and artificial intelligence (AI) to make personalized cancer therapy real. For breast cancer, adaptively randomized trials, extending aromatase inhibitor therapy, and ribociclib and palbociclib were introduced. Copyright © 2017. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology.
Bayés, M; Rabasseda, X; Prous, J R
Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Trials Knowledge Area of Prous Science Intergrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: 249553, 2-Methoxyestradiol; Abatacept, Adalimumab, Adefovir dipivoxil, Agalsidase beta, Albinterferon alfa-2b, Aliskiren fumarate, Alovudine, Amdoxovir, Amlodipine besylate/atorvastatin calcium, Amrubicin hydrochloride, Anakinra, AQ-13, Aripiprazole, AS-1404, Asoprisnil, Atacicept, Atrasentan; Belimumab, Bevacizumab, Bortezomib, Bosentan, Botulinum toxin type B, Brivaracetam; Catumaxomab, Cediranib, Cetuximab, cG250, Ciclesonide, Cinacalcet hydrochloride, Curcumin, Cypher; Darbepoetin alfa, Denosumab, Dihydrexidine; Eicosapentaenoic acid/docosahexaenoic acid, Entecavir, Erlotinib hydrochloride, Escitalopram oxalate, Etoricoxib, Everolimus, Ezetimibe; Febuxostat, Fenspiride hydrochloride, Fondaparinux sodium; Gefitinib, Ghrelin (human), GSK-1562902A; HSV-tk/GCV; Iclaprim, Imatinib mesylate, Imexon, Indacaterol, Insulinotropin, ISIS-112989; L-Alanosine, Lapatinib ditosylate, Laropiprant; Methoxy polyethylene glycol-epoetin-beta, Mipomersen sodium, Motexafin gadolinium; Natalizumab, Nimotuzumab; OSC, Ozarelix; PACAP-38, Paclitaxel nanoparticles, Parathyroid Hormone-Related Protein-(1-36), Pasireotide, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Pemetrexed disodium, Pertuzumab, Picoplatin, Pimecrolimus, Pitavastatin calcium, Plitidepsin; Ranelic acid distrontium salt, Ranolazine, Recombinant human relaxin H2, Regadenoson, RFB4(dsFv)-PE38, RO-3300074, Rosuvastatin calcium; SIR-Spheres, Solifenacin succinate, Sorafenib, Sunitinib malate; Tadalafil, Talabostat, Taribavirin hydrochloride, Taxus, Temsirolimus, Teriparatide, Tiotropium bromide, Tipifarnib, Tirapazamine, Tocilizumab; UCN-01, Ularitide
Tomillero, A; Moral, M A
(-)-Epigallocatechin gallate, Abafungin, ACE-031, Adapalene/benzoyl peroxide, AE-37, Aflibercept, AGS-003, Albiglutide, Alemtuzumab, Aliskiren fumarate, ALT-801, AN-2728, Anacetrapib, API, Aprepitant, ARQ-197, Ascorbic acid, Atazanavir sulfate, ATN-224, AVI-4658, Azacitidine, Azelnidipine; Belinostat, Bevacizumab, BI-2536, Biphasic insulin aspart, Bortezomib, Bovine lactoferrin, Bryostatin 1, Budesonide/formoterol fumarate; cAC10, Canfosfamide hydrochloride, Cediranib, Clofarabine, Cocaine conjugate vaccine; Darbepoetin alfa, Dasatinib, Denosumab, Disomotide, Doripenem, Dovitinib Lactate, Dronedarone hydrochloride, Drospirenone/estradiol, Dutasteride; Ecogramostim, Entinostat, Enzastaurin hydrochloride, Erlotinib hydrochloride, Everolimus, Exenatide, Ezetimibe, Ezetimibe/simvastatin; Fampridine, Fenretinide LXS, FFR-factor VIIa, Fingolimod hydrochloride, Frovatriptan; Gefitinib, Gimatecan, GP-2/GM-CSF; Iloperidone, Imatinib mesylate, Indibulin, Ipilimumab, Ivabradine hydrochloride; Lactobacillus rhamnosus, Lapatinib ditosylate, LC-07, Lenalidomide, Linifanib, Liposomal doxorubicin, Liposomal vincristine, Litenimod, Lutein; M-118, MDX-1401, MEDI-528, Midostaurin, Miglustat, MK-0657; Natalizumab, Nesiritide, NGR-TNF, Niacin/simvastatin; Obatoclax mesylate, Olaparib, Omacetaxine mepesuccinate; Paclitaxel nanoparticles, Paclitaxel-eluting stent, Palonosetron hydrochloride, Pazopanib hydrochloride, Pegfilgrastim, Pemetrexed disodium, PER.C-flu, Perifosine, PF-02341066, Pimecrolimus, Pitrakinra, Plerixafor hydrochloride, Posaconazole; Rasburicase, Recombinant human relaxin H2, ReoT3D, Retaspimycin hydrochloride, Riferminogene pecaplasmid, Rindopepimut, Romiplostim, Ronacaleret hydrochloride, Rosuvastatin calcium, Rotigotine; Sagopilone, sALP-FcD10, SAR-245409, SCH-697243, Selumetinib, Sirolimus-eluting stent, SIR-Spheres, Sitagliptin phosphate monohydrate, Sitaxentan sodium, Sorafenib, Sunitinib malate; Tadalafil, Tandutinib, Tasimelteon, Temsirolimus, Teriparatide