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

• Autores: Zhenfei Li, Mohammad Alyamani, Jianneng Li, Kevin Rogacki, Mohamed Abazeed, Sunil K. Upadhyay, Steven P. Balk
• Localización: Nature: International weekly journal of science, ISSN 0028-0836, Vol. 533, Nº 7604, 2016, págs. 547-551
• Idioma: inglés
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• Resumen

  • Abiraterone blocks androgen synthesis and prolongs survival in patients with castration-resistant prostate cancer, which is otherwise driven by intratumoral androgen synthesis 1,2. Abiraterone is metabolized in patients to [DELTA]4-abiraterone (D4A), which has even greater anti-tumour activity and is structurally similar to endogenous steroidal 5[alpha]-reductase substrates, such as testosterone 3. Here, we show that D4A is converted to at least three 5[alpha]-reduced and three 5[beta]-reduced metabolites in human serum. The initial 5[alpha]-reduced metabolite, 3-keto-5[alpha]-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 5[alpha]-reductase inhibitor), 3-keto-5[alpha]-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 5[beta]-reduced metabolites, which were also clinically detectable, demonstrating the specific biochemical effects of pharmacological 5[alpha]-reductase inhibition on abiraterone metabolism. Our findings suggest a previously unappreciated and biochemically specific method of clinically fine-tuning abiraterone metabolism to optimize therapy