Abstract 1053: Redirecting abiraterone metabolism to biochemically fine tune prostate cancer therapy

Abstract

Abstract Prostate cancer is the most diagnosed cancer in men and Abiraterone is used for castration resistant prostate cancer therapy by suppressing androgen production. In patients, abiraterone is converted to D4A, a novel metabolite with more potent anti-tumor activity and structural similarities to endogenous steroidal 5α-reductase substrates, such as testosterone. Here, we show that D4A is further metabolized by the related steroidogenic enzymes to at least 3 5α-reduced and 3 5β-reduced metabolites. The initial 5α-reduced metabolite, 3-keto-5α-abi, is more abundant than D4A in patients taking abiraterone, and is an androgen receptor (AR) agonist, which promotes prostate cancer progression. In a clinical trial with patients taking abiraterone alone, followed by abiraterone plus dutasteride (a 5α-reductase inhibitor), 3-keto-5α-abi and downstream metabolites are depleted by dutasteride, while D4A concentrations rise, effectively blocking production of a tumor promoting metabolite and permitting D4A accumulation. Our findings suggest a previously unappreciated and biochemically specific method of clinically fine tuning abiraterone metabolism to optimize therapy. Citation Format: zhenfei li, Mohammad Alyamani, Nima Sharifi. Redirecting abiraterone metabolism to biochemically fine tune prostate cancer therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1053.