Compensatory steroidogenesis mechanisms in castration-resistant prostate cancer

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DESCRIPTION (provided by applicant: Prostate cancer is the most common non-skin malignancy and second leading cause of cancer death for men in the United States and is therefore a major public health problem. Localized disease is highly treatable; metastatic prostate cancer, however, remains incurable. Androgen deprivation therapy (ADT) by means of medical or surgical castration is the upfront standard treatment for advanced prostate cancer. Although initially effective, tumors become resistant to ADT, a disease state termed castration-resistant prostate cancer (CRPC). It has become clear that CRPC is driven in large part by the intratumoral synthesis of dihydrotestosterone (DHT), which permits a reengagement of the androgen receptor (AR). The dependence of CRPC on DHT is evidenced in part by the clinical efficacy of the androgen synthesis inhibitor, abiraterone. However, the metabolic mechanisms that induce DHT synthesis have not been elucidated. We have recently identified the first gain-of-function mutation in a steroidogenic enzyme that is responsible for increasing DHT synthesis and the development of CRPC. This mutation in 3�ydroxysteroid dehydrogenase-1 (3�D1) blocks ubiquitination, increasing steady-state enzyme levels and hastens metabolic flux from precursor steroids in what is otherwise the rate-limiting step for DHT synthesis. However, the mutation is present in a minority of CRPC tumors from patients; consequently, other changes that promote 3�D enzymatic activity, DHT synthesis, and permit the development of CRPC in the absence of mutant 3�D1 must be elucidated. Our overarching hypothesis is that alternative mechanisms block wild-type 3�D1 ubiquitination, stabilize protein levels and compensate for the absence of mutant 3�D1, not only in CRPC models but also clinical tumors. Our current proposal will identify compensatory mechanisms of steroidogenesis that occur in the absence of mutant 3�D1. In Aim 1, we will identify whether expression of the ubiquitin E3-ligase, AMFR, is suppressed when wild-type 3�D1 is present. Furthermore, we will determine how AMFR regulates DHT synthesis, the androgen response and development of CRPC. In Aim 2, we will define the clinical relevance of AMFR dysregulation in tumors from patients with CRPC, as well as matched clinical tumors that are abiraterone-na�ve and abiraterone-resistant. Together, these studies will identify and clinically validate compensatory mechanisms of steroidogenesis that circumvent the mutation in 3�D1. It is anticipated that this work will lead to the identification of biomarkers of treatment response and identify new treatment modalities for CRPC and thus will have a broad and potentially rapid clinical impact.