Redirecting abiraterone metabolism to fine tune prostate cancer anti-androgen therapy

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Redirecting abiraterone metabolism to fine tune prostate cancer anti-androgen therapy

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Title: Redirecting abiraterone metabolism to fine tune prostate cancer anti-androgen therapy
Author: Li, Zhenfei; Alyamani, Mohammad; Li, Jianneng; Rogacki, Kevin; Abazeed, Mohamed; Upadhyay, Sunil K.; Balk, Steven P.; Taplin, Mary-Ellen; Auchus, Richard J.; Sharifi, Nima

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Citation: 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.
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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.
Published Version: doi:10.1038/nature17954
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5111629/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:29626087
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