Targeting CYP17: established and novel approaches in prostate cancer.
There is a growing body of evidence that although medical or surgical castration blocks the generation of gonadal testosterone in prostate cancer, androgens originating from other sources may continue to drive androgen receptor (AR) signaling. Recent studies have demonstrated high intratumoral levels of androgens and continued AR signaling in castration-resistant prostate cancer (CRPC), suggesting that androgens may also be synthesized de novo. Inhibiting the systemic biosynthesis of androgens in CRPC by targeting CYP17 may thus represent a rational therapeutic approach since this enzyme catalyses two key steroid reactions involving 17alpha-hydroxylase and C(17,20)-lyase in the androgen biosynthesis pathway. This review will discuss the rationale for and implications of targeting CYP17 in CRPC and focus on established and novel CYP17 inhibitors, including ketoconazole, abiraterone acetate, and VN/124-1, which are agents currently at different stages of development.
Yap
Timothy A
TA
The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey, UK.
Carden
Craig P
CP
Attard
Gerhardt
G
de Bono
Johann S
JS
D059002:Androgen Receptor Antagonists; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000187:drug effects; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000187:drug effects
D059002:Androgen Receptor Antagonists; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011944:Receptors, Androgen; D013254:Steroid 17-alpha-Hydroxylase