Androgen Receptor Action in Castration Resistant Prostate Cancer

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This is a revised competitive renewal application for our P01 entitled “Androgen Receptor Action In Castration Resistant Prostate Cancer”. The past several years have seen a paradigm shift in prostate cancer (PCa) therapy, as it is now clear that the androgen receptor (AR) remains active and is a therapeutic target in PCa that relapses after surgical or medical castration (castration-resistant prostate cancer, CRPC). Previous basic, translational and clinical research conducted by investigators in this P01 proposal made major contributions to this paradigm shift by elucidating fundamental mechanisms of AR action and mechanisms of castration- resistance in patients. The CYP17A1 inhibitor abiraterone, and the AR antagonist enzalutamide, are now standard second line hormonal therapies for men who relapse after castration. Unfortunately, most men who respond to these therapies will relapse within 1-2 years. Significantly, while a subset of abiraterone or enzalutamide-resistant PCa may become AR independent, recent results from investigators in this P01 and others indicate that most continue to express high levels of AR that appears to be transcriptionally active. Therefore, a major hypothesis in this proposal is that AR activity still persists and is contributing to tumor growth in abiraterone and enzalutamide-resistant PCa. Moreover, we hypothesize that adaptations made by PCa cells in response to AR targeted therapies create vulnerabilities that can be exploited therapeutically. Hence, overall program goals are to elucidate clinically relevant mechanisms that contribute to CRPC and abiraterone/enzalutamide-resistance, to identify therapeutic approaches that can overcome these resistance mechanisms and/or exploit new vulnerabilities, and to assess these therapeutic approaches in preclinical models that can form foundations for clinical trials. The Projects are as follows: 1) Determining and Exploiting Mechanisms of AR-Mediated Suppression of Cell, 2) Mechanisms Driving AR Full Length and Splice Variant Activities and Antagonist Resistance, 3) Protein Kinases Influencing Androgen Receptor in Castrate Resistant Prostate Cancer, 4) Identification of Essential Genes Underlying AR Activity in Antagonist-Resistant CRPC.