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

  • Nature. 2016 May 26;533(7604):547-51. doi: 10.1038/nature17954.
Zhenfei Li  1 ,  Mohammad Alyamani  1 ,  Jianneng Li  1 ,  Kevin Rogacki  2 ,  Mohamed Abazeed  2 ,  Sunil K Upadhyay  3 ,  Steven P Balk  4 ,  Mary-Ellen Taplin  5 ,  Richard J Auchus  3 ,  Nima Sharifi  1  6  7
Affiliations
  • 1. Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
  • 2. Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
  • 3. Departments of Pharmacology and Internal Medicine, Division of Endocrinology and Metabolism, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
  • 4. Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
  • 5. Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
  • 6. Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
  • 7. Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
PMID: 27225130 DOI: 10.1038/nature17954
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 Δ(4)-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.

Products