Redirecting abiraterone metabolism to fine tune prostate cancer anti-androgen therapy
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Li, Zhenfei
Alyamani, Mohammad
Li, Jianneng
Rogacki, Kevin
Abazeed, Mohamed
Upadhyay, Sunil K.
Auchus, Richard J.
Sharifi, Nima
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https://doi.org/10.1038/nature17954Metadata
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Li, Zhenfei, Mohammad Alyamani, Jianneng Li, Kevin Rogacki, Mohamed Abazeed, Sunil K. Upadhyay, Steven P. Balk, Mary-Ellen Taplin, Richard J. Auchus, and Nima Sharifi. 2016. “Redirecting abiraterone metabolism to fine tune prostate cancer anti-androgen therapy.” Nature 533 (7604): 547-551. doi:10.1038/nature17954. http://dx.doi.org/10.1038/nature17954.Abstract
Abiraterone blocks androgen synthesis and prolongs survival in castration-resistant prostate cancer, which is otherwise driven by intratumoral androgen synthesis1,2. Abiraterone is metabolized in patients to D4A, which has even greater anti-tumor activity and structural similarities to endogenous steroidal 5α-reductase substrates, such as testosterone3. Here, we show that D4A is converted 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 with prostate cancer taking abiraterone, and is an androgen receptor (AR) agonist, which promotes prostate cancer progression. In a clinical trial of abiraterone alone, followed by abiraterone plus dutasteride (a 5α-reductase inhibitor), 3-keto-5α-abi and downstream metabolites are depleted, while D4A concentrations rise, effectively blocking production of a tumor-promoting metabolite and permitting D4A accumulation. Furthermore, dutasteride does not deplete three 5β-reduced metabolites, which were also clinically detectable, demonstrating the specific biochemical effects of pharmacologic 5α-reductase inhibition on abiraterone metabolism. Our findings suggest a previously unappreciated and biochemically specific method of clinically fine-tuning abiraterone metabolism to optimize therapy.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5111629/pdf/Terms of Use
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