Androgen Receptor Action in Castration Resistant Prostate Cancer

Beth Israel Deaconess Medical Center, Boston MA

Investigators

Linked publications, trials & patents

Abstract

Project Summary A central hypothesis that drove the studies proposed in the currently funded P01 was that androgen receptor (AR) remained an important driver in prostate cancer (PC) that becomes resistant to AR targeted therapies, and that adaptations made by tumor cells as they progress create new dependencies and subsequent vulnerabilities that can be exploited therapeutically. Hence, our overall goals were to elucidate clinically relevant mechanisms and subsequent vulnerabilities that contribute to resistance to AR targeted therapy, and to identify therapeutic approaches that exploit these resistance mechanisms. Work from us and others has supported the continued central role for AR, and provide the rationale for the continued focus on AR in the studies proposed in this renewal. Project 1 (Peter Nelson, PI) Identifying and Targeting Specific Determinants of the AR Cistrome that Drive Prostate Cancer Cell Survival and Proliferation, focuses on identification of the critical functions regulated by AR. It will test the hypotheses that AR directly transcriptionally regulates a signaling program that promotes cell survival (anti-apoptosis) and cell division/proliferation, and that PCs resisting potent AR repression may ‘bypass’ a requirement for AR signaling through genomic or epigenomic events that serve to maintain the key survival/growth pathways normally regulated through AR activity. Project 2 (Steven Balk, PI) Identify Mechanisms Driving Resistance to AR Antagonists in CRPC, remains focused on basic mechanisms of AR transcriptional activity and mechanisms of resistance to AR antagonists such as enzalutamide (ENZ). The project will tets the hypothesis that ENZ-resistant tumors are drive by ARv7, and that ARv7 activity is dependent on increased chromatin accessibility mediated by FOXA1 and NFI proteins. Project 3 (Myles Brown, PI) Functional Interplay Between PARP, AR and DNA Damage, builds upon efforts in the Brown lab to identify critical modulators of AR activity in CRPC that may be therapeutic targets. PARP1 and PARP2 have been implicated in various aspects of AR regulated gene expression, but the impact of PARP inhibition on the AR cistrome and AR regulated gene expression has not been fully elucidated. Whether DNA damage resulting from the loss of BRCA1 or BRCA2 alters AR function or whether BRCA1 or BRCA2 play direct roles in AR function also remain to be defined. This provides the rationale for the proposed studies to obtain a detailed understanding of the functional interplay between AR, PARP, BRCA1 and 2, and DNA damage. Core B (Biospecimen Core, led by Eva Corey) will provide the Projects with access to a unique collection of well-characterized CRPC PDX models, and more recently cell lines, as well as clinical samples and pathology expertise. Core C (Functional Epigenetics Core, led by Henry Long) will provide each Project with expertise and resources for a variety of genomic studies and associated computational support. Administrative Core (Core A, led by Steven Balk), will provide administrative and biostatistical support.