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

Zhenfei Li, Mohammad Alyamani, Jianneng Li, Kevin Rogacki, Mohamed Abazeed, Sunil K. Upadhyay, Steven P. Balk, Mary Ellen Taplin, Richard J. Auchus, Nima Sharifi

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Abiraterone blocks androgen synthesis and prolongs survival in patients with castration-resistant prostate cancer, which is otherwise driven by intratumoral androgen synthesis. Abiraterone is metabolized in patients to Δ4-abiraterone (D4A), which has even greater anti-tumour activity and is structurally similar to endogenous steroidal 5α-reductase substrates, such as testosterone. Here, we show that D4A is converted to at least three 5α-reduced and three 5β-reduced metabolites in human serum. The initial 5α-reduced metabolite, 3-keto-5α-abiraterone, is present at higher concentrations than D4A in patients with prostate cancer taking abiraterone, and is an androgen receptor 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-abiraterone and downstream metabolites were depleted by the addition of dutasteride, while D4A concentrations rose, showing that dutasteride effectively blocks production of a tumour-promoting metabolite and permits D4A accumulation. Furthermore, dutasteride did not deplete the three 5β-reduced metabolites, which were also clinically detectable, demonstrating the specific biochemical effects of pharmacological 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.

Original languageEnglish (US)
Pages (from-to)547-551
Number of pages5
JournalNature
Volume533
Issue number7604
DOIs
StatePublished - May 25 2016

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Androgens
Prostatic Neoplasms
Therapeutics
Oxidoreductases
abiraterone
Castration
Testosterone
Neoplasms
Clinical Trials
Pharmacology
Survival
Dutasteride
Serum

ASJC Scopus subject areas

  • General
  • Medicine(all)

Cite this

Li, Z., Alyamani, M., Li, J., Rogacki, K., Abazeed, M., Upadhyay, S. K., ... Sharifi, N. (2016). Redirecting abiraterone metabolism to fine-tune prostate cancer anti-androgen therapy. Nature, 533(7604), 547-551. https://doi.org/10.1038/nature17954

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.

In: Nature, Vol. 533, No. 7604, 25.05.2016, p. 547-551.

Research output: Contribution to journalArticle

Li, Z, Alyamani, M, Li, J, Rogacki, K, Abazeed, M, Upadhyay, SK, Balk, SP, Taplin, ME, Auchus, RJ & Sharifi, N 2016, 'Redirecting abiraterone metabolism to fine-tune prostate cancer anti-androgen therapy', Nature, vol. 533, no. 7604, pp. 547-551. https://doi.org/10.1038/nature17954
Li Z, Alyamani M, Li J, Rogacki K, Abazeed M, Upadhyay SK et al. Redirecting abiraterone metabolism to fine-tune prostate cancer anti-androgen therapy. Nature. 2016 May 25;533(7604):547-551. https://doi.org/10.1038/nature17954
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. In: Nature. 2016 ; Vol. 533, No. 7604. pp. 547-551.
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