Canonical and Noncanonical Androgen Metabolism and Activity

Abstract

Androgens are critical drivers of prostate cancer. In this chapter we first discuss the canonical pathways of androgen metabolism and their alterations in prostate cancer progression, including the classical, backdoor and 5α-dione pathways, the role of pre-receptor DHT metabolism, and recent findings on oncogenic splicing of steroidogenic enzymes. Next, we discuss the activity and metabolism of non-canonical 11-oxygenated androgens that can activate wild-type AR and are less susceptible to glucuronidation and inactivation than the canonical androgens, thereby serving as an under-recognized reservoir of active ligands. We then discuss an emerging literature on the potential non-canonical role of androgen metabolizing enzymes in driving prostate cancer. We conclude by discussing the potential implications of these findings for prostate cancer progression, particularly in context of new agents such as abiraterone and enzalutamide, which target the AR-axis for prostate cancer therapy, including mechanisms of response and resistance and implications of these findings for future therapy.

Keywords: 11-ketodihydrotestosterone; 11-ketotestosterone; 11β-hydroxyandrostenedione; Abiraterone; Adrenal androgen; Androgen receptor; CYP17A1; Castration resistant prostate cancer; Deoxycorticosterone; Enzalutamide; Intracrine; Primary prostate cancer; Splice variant; Steroidogenesis.