Growing evidence from clinical trials of the next-generation androgen receptor (AR) pathway inhibitors abiraterone acetate (AA) and MDV3100 suggests that both compounds are likely to transform the care of patients with castration-resistant prostate cancer (CRPC), and drug approvals are anticipated in the next 1 to 2 years. However, not all patients benefit from these drugs, and the durability of response in those who do respond can be short. We are focusing on two parallel strategies to achieve better clinical results: 1) developing more potent AR inhibitors, and 2) defining mechanisms of drug resistance that will guide the rational selection of combination therapies. During the current funding cycle of this project (formerly RP-6, 2008-2010), we discovered the novel antiandrogen A52, which has superior activity to MDV3100 in side-by-side comparison. We then advanced the compound (now called ARN-509) to a phase 1 clinical trial in patients with CRPC, in collaboration with a corporate partner (Aragon Pharmaceuticals). In other work, we discovered that PTEN loss (found in -40% of primary prostate cancers) confers resistance to both MDV3100 and ARN-509 in preclinical prostate cancer models, but that this resistance can be overcome by combination therapy with a dual P13K/mTOR inhibitor, BEZ235. In the proposed funding period we will conduct clinical trials that directly address 1) the role of PTEN loss as a biomarker of resistance, and 2) whether combined PI3K + next-generation AR inhibition is more active than next-generation AR inhibition alone. We will also conduct pilot studies to evaluate ARN-509 in presurgical (ie, noncastrate) patients with prostate cancer.
Aim 1 : To determine if PTEN loss confers resistance to the next-generation AR antagonist ARN-509 in an expansion cohort of patients with metastatic CRPC treated in an ongoing phase 1 clinical trial.
Aim 2 : To evaluate the activity of the dual PI3K/mT0R inhibitor BEZ235 in patients with CRPC, first alone, then in combination with abiraterone.
Aim 3 : To evaluate the effects of ARN-509 in localized, hormone-nave disease in presurgical trials
Drug development in prostate cancer has moved from the evaluation of cytotoxic agents with activity in other tumor types to the rational development of targeted approaches based on a fundamental understanding of disease biology. This approach is validated by reported results with AR signaling inhibitors targeting oncogenic changes identified in molecular profiling studies of CRPC.
|Loeb, Stacy; Lilja, Hans; Vickers, Andrew (2016) Beyond prostate-specific antigen: utilizing novel strategies to screen men for prostate cancer. Curr Opin Urol 26:459-65|
|Fleshner, Katherine; Assel, Melissa; Benfante, Nicole et al. (2016) Clinical Findings and Treatment Outcomes in Patients with Extraprostatic Extension Identified on Prostate Biopsy. J Urol 196:703-8|
|Carlsson, Sigrid V; de Carvalho, Tiago M; Roobol, Monique J et al. (2016) Estimating the harms and benefits of prostate cancer screening as used in common practice versus recommended good practice: A microsimulation screening analysis. Cancer 122:3386-3393|
|Zelefsky, Michael J; Poon, Bing Ying; Eastham, James et al. (2016) Longitudinal assessment of quality of life after surgery, conformal brachytherapy, and intensity-modulated radiation therapy for prostate cancer. Radiother Oncol 118:85-91|
|Kent, Matthew; Penson, David F; Albertsen, Peter C et al. (2016) Successful external validation of a model to predict other cause mortality in localized prostate cancer. BMC Med 14:25|
|Scher, Howard I; Lu, David; Schreiber, Nicole A et al. (2016) Association of AR-V7 on Circulating Tumor Cells as a Treatment-Specific Biomarker With Outcomes and Survival in Castration-Resistant Prostate Cancer. JAMA Oncol 2:1441-1449|
|Sood, Anup; Miller, Alexandra M; Brogi, Edi et al. (2016) Multiplexed immunofluorescence delineates proteomic cancer cell states associated with metabolism. JCI Insight 1:|
|Danila, Daniel C; Samoila, Aliaksandra; Patel, Chintan et al. (2016) Clinical Validity of Detecting Circulating Tumor Cells by AdnaTest Assay Compared With Direct Detection of Tumor mRNA in Stabilized Whole Blood, as a Biomarker Predicting Overall Survival for Metastatic Castration-Resistant Prostate Cancer Patients. Cancer J 22:315-320|
|Braun, Katharina; Sjoberg, Daniel D; Vickers, Andrew J et al. (2016) A Four-kallikrein Panel Predicts High-grade Cancer on Biopsy: Independent Validation in a Community Cohort. Eur Urol 69:505-11|
|Preston, Mark A; Batista, Julie L; Wilson, Kathryn M et al. (2016) Baseline Prostate-Specific Antigen Levels in Midlife Predict Lethal Prostate Cancer. J Clin Oncol 34:2705-11|
Showing the most recent 10 out of 424 publications