Androgen metabolism in prostate cancer: from molecular mechanisms to clinical consequences

Despite our most vigorous efforts, prostate cancer remains the second leading cause of cancer death in men. Understanding the intricacies of androgen metabolism is vital to finding therapeutic targets, particularly with progression of advanced prostate cancer after initial hormone therapy, where adrenal precursors are involved. Such is the case with castration-resistant prostate cancer, where adrenal androgens, for example, dehydroepiandrosterone, are a source for intratumoural synthesis of dihydrotestosterone. As prostate cancer progresses, androgen metabolism changes due to altered expression of steroidogenic enzymes and mutations in the components of the steroidogenic machinery. These alterations sustain disease and allow progression; mechanistically, they may also enable development of hormone therapy resistance. With the development of the newer agents, abiraterone acetate and enzalutamide, efforts have been made to better define the basis for response and resistance. This work can be carried out in cell lines, animal models, as well as with ex vivo analysis of tissues obtained from patients. Efforts to further elucidate the finer details of the steroidogenic pathway are necessary to move toward a curative paradigm for patients with localised disease at high risk for recurrence.