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

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 st...

Full description

Bibliographic Details
Main Authors:	Li, Zhenfei, Alyamani, Mohammad, Li, Jianneng, Rogacki, Kevin, Abazeed, Mohamed, Upadhyay, Sunil K., Balk, Steven P., Taplin, Mary-Ellen, Auchus, Richard J., Sharifi, Nima
Format:	Online
Language:	English
Published:	2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5111629/

id	pubmed-5111629
recordtype	oai_dc
spelling	pubmed-51116292016-11-25 Redirecting abiraterone metabolism to fine tune prostate cancer anti-androgen therapy Li, Zhenfei Alyamani, Mohammad Li, Jianneng Rogacki, Kevin Abazeed, Mohamed Upadhyay, Sunil K. Balk, Steven P. Taplin, Mary-Ellen Auchus, Richard J. Sharifi, Nima Article 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. 2016-05-25 /pmc/articles/PMC5111629/ /pubmed/27225130 http://dx.doi.org/10.1038/nature17954 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
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
spellingShingle	Li, Zhenfei Alyamani, Mohammad Li, Jianneng Rogacki, Kevin Abazeed, Mohamed Upadhyay, Sunil K. Balk, Steven P. Taplin, Mary-Ellen Auchus, Richard J. Sharifi, Nima Redirecting abiraterone metabolism to fine tune prostate cancer anti-androgen therapy
author_facet	Li, Zhenfei Alyamani, Mohammad Li, Jianneng Rogacki, Kevin Abazeed, Mohamed Upadhyay, Sunil K. Balk, Steven P. Taplin, Mary-Ellen Auchus, Richard J. Sharifi, Nima
author_sort	Li, Zhenfei
title	Redirecting abiraterone metabolism to fine tune prostate cancer anti-androgen therapy
title_short	Redirecting abiraterone metabolism to fine tune prostate cancer anti-androgen therapy
title_full	Redirecting abiraterone metabolism to fine tune prostate cancer anti-androgen therapy
title_fullStr	Redirecting abiraterone metabolism to fine tune prostate cancer anti-androgen therapy
title_full_unstemmed	Redirecting abiraterone metabolism to fine tune prostate cancer anti-androgen therapy
title_sort	redirecting abiraterone metabolism to fine tune prostate cancer anti-androgen therapy
description	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.
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5111629/
_version_	1613729305232146432

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

Similar Items