Elucidating a novel molecular biomarker for castration-resistant prostate cancer

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DESCRIPTION (provided by applicant): Prostate cancer is the most common cause of cancer and second leading cause of cancer death for men in the United States. Localized disease is potentially curable with radiation or surgery; however, advanced disease remains incurable. Androgen deprivation therapy by depletion of gonadal testosterone is the upfront standard therapy for advanced disease. Metastatic disease almost invariably recurs as castration-resistant prostate cancer (CRPC), which is the lethal form of this disease. It is now clear that CRPC remains driven by the intratumoral synthesis of androgens, despite the depletion of serum testosterone. The survival benefit conferred by abiraterone acetate, which blocks CYP17A1 and was approved by the United States Food and Drug Administration in April 2011 for the treatment of CRPC, is the best evidence for the necessity of androgen synthesis in the progression of CRPC. Although the majority of patients with CRPC respond to abiraterone acetate, a subset do not have any initial response and nearly all responding tumors will eventually acquire resistance. A recent discovery that has been clinically validated has demonstrated that conversion from adrenal precursor steroids to dihydrotestosterone (DHT), the most potent androgen that drives CRPC progression, unexpectedly bypasses testosterone. This finding alters the current working model and suggests that 3¿-hydroxysteroid dehydrogenase/isomerase (3¿HSD) is a critical point of regulation in the synthesis of DHT and development of CRPC. The overarching hypothesis of this proposal is that a somatic gain-of-function mutation occurs in 3¿HSD1 in the development of a subset of CRPC cases, increases mutant enzyme stability, augments DHT synthesis and confers resistance to abiraterone acetate. In Aim 1, a pilot clinical study will be undertaken to determine how CRPC tumors harboring wild-type and mutant 3¿HSD1 regulate flux to DHT and respond to abiraterone acetate. In Aim 2, the validity of mutant 3¿HSD1 as a potential pharmacologic target will be assessed. In Aim 3, the consequences of wild-type and mutant 3¿HSD1 interaction will be assessed. The ultimate anticipated benefit of this proposal is the identification of a first-in-clas gain-of-function mutation in a steroidogenic enzyme in CRPC that may serve as a biomarker of response or resistance to hormonal therapies, including abiraterone acetate. Furthermore, it is anticipated that similar to EGFR and BRAF mutations in lung cancer and melanoma, respectively, this work will validate mutant 3¿HSD1 as a pharmacologic target for therapy in CRPC.