Molecular pathways: Inhibiting steroid biosynthesis in prostate cancer

A significant proportion of castration-resistant prostate cancers (CRPC) remains driven by ligand activation of the androgen receptor. Although the testes are the primary source of testosterone, testosterone can also be produced from peripheral conversion of adrenal sex hormone precursors DHEA and androstenedione in the prostate and other tissues. CYP17A1 catalyzes two essential reactions in the production of DHEA and androstenedione: the hydroxylation (hydroxylase activity) and the subsequent cleavage of the C17-20 side chain (lyase activity). Potent and selective inhibition of CYP17A1 by abiraterone depletes residual nongonadal androgens and is an effective treatment for CRPC. Elucidation of the mechanisms that underlie resistance to abiraterone will inform the development of novel therapeutic strategies post-abiraterone. Preclinical evidence that androgen biosynthesis in prostate cancer cells does not necessarily follow a single dominant pathway, and residual androgens or alternative ligands (including administered glucocorticoids) can reactivate androgen receptor signaling, supports cotargeting of more than one enzyme involved in steroidogenesis and combining a CYP17A1 inhibitor with an antiandrogen. Furthermore, given the drawbacks of 17α-hydroxylase inhibition, there is considerable interest in developing new CYP17A1 inhibitors that more specifically inhibit lyase activity and are therefore less likely to require glucocorticoid coadministration.