Roles for the backdoor pathway of androgen metabolism in prostate cancer response to castration and drug treatment

Abstract

Almost all men who present with advanced prostate cancer (CaP) and many men who fail potentially curative therapy are treated with androgen deprivation therapy (ADT). ADT is not curative and CaP recurs as the lethal phenotype. The goal of this review is to describe the evolution of adrenal androgen blockade, how new androgen measurement methods have furthered understanding of androgen metabolism, and how further understanding of the backdoor pathway of androgen metabolism may lead to interventions that extend survival even more.

Keywords: "Backdoor" Pathway; Adrenal androgens; CYP17A1.; Dihydrotestosterone; Prostate cancer.

Figure 1

Four androgen metabolism pathways to DHT synthesis. Pathway 1 is the 5α-reduction of T to DHT (dashed lines). Pathway 2 uses adrenal androgens, DHEA or ASD, to synthesize T or 5α-dione that are converted to DHT (faint gray long dashes). Pathway 3 is the cholesterol pathway (small gray dashes). Pathway 4 is the backdoor pathway of DHT synthesis using androstanediol instead of T to generate DHT (outlined in bold). Abiraterone inhibits 17α-hydroxylase and 17,20-lyase of CYP17A1 (relevant to Pathways 2 and 4) whereas TAK-700 or TOK-001 inhibit only 17,20-lyase (relevant to Pathway 2).