Conversion of abiraterone to D4A drives anti-tumour activity in prostate cancer
Prostate cancer is driven by androgens, particularly 5alpha-dihydrotestosterone (5alpha-DHT). Therapeutic options include systemic androgen deprivation therapy to limit 5alpha-DHT availability. However, many prostate tumours develop resistance to this line of therapy as they can synthesis their own androgens to maintain growth. Abiraterone (Abi) inhibits 17beta-hydroxylase/17,20-lyase (CYP17A1), a key enzyme in androgen synthesis, and has shown significant clinical promise.
Research published in Nature demonstrates the more active D4A, a metabolite of Abi, also inhibits CYP17A1 along with two additional enzymes, 3beta-hydroxysteroid dehydrogenase (3betaHSD) and 5alpha-reductase (SRD5A), responsible for androgen synthesis. Furthermore, D4A also blocks the androgen receptor thus rendering existing androgens inactive. Twelve patients on active abiraterone therapy had detectable serum levels of D4A. D4A levels varied among patients, however, suggesting that individuals may differ in their metabolism of Abi to D4A. These findings suggest that the clinical success of Abi might be explained by its metabolism to D4A in patients. Thus, use of D4A as a direct treatment may provide greater benefit to prostate cancer patients compared to Abi alone.
Nature. 2015 Jul 16;523(7560):347-51.
Li Z, Bishop AC, Alyamani M, Garcia JA, Dreicer R, Bunch D, Liu J, Upadhyay SK, Auchus RJ, Sharifi N
A version of this article will be appearing in the August (20150 edition of the Endocrinologist, the quarterly magazine from the Society for Endocrinology.