Molecular pathways: Inhibiting steroid biosynthesis in prostate cancer

Abstract

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.

©2013 AACR.

Figures

Figure. Androgen biosynthesis pathways

The basic pathways are demarcated with respect to CYP17A1 and SRD5A activities. The 17-deoxy, 21-carbon steroids upstream of CYP17A1 are shown at left in green box, including 11-deoxycorticosterone (DOC). The 17-hydroxy, 21-carbon steroids are in center in peach box, and 19-carbon steroids are at right in blue box, generated via 17-hydroxylase and 17,20-lyase reactions of CYP17A1, respectively. The 5-reduced steroids are highlighted with darker background at lower right. Reversible interconversions catalyzed by HSDs are shown with double arrows at terminal steps. CYP17A1, cytochrome P450c17; 3β-HSD, 3-beta-hydroxysteroid dehydrogenase/isomerase; 11 α -HSD, 11-beta-hydroxysteroid dehydrogenase; 17β-HSD, 17-beta-hydroxysteroid dehydrogenase; 3α-HSD, 3-alpha-hydroxysteroid dehydrogenase; SRD5A, steroid 5α reductase; DHEA, Dehydroepiandrosterone; DHEA-S, Dehydroepiandrosterone sulfate; STS, steroid sulfatase; SULT2A1, sulfotransferase 2A1