Putting the brakes on continued androgen receptor signaling in castration-resistant prostate cancer

Abstract

Patients with advanced prostate cancer initially respond very well to medical or surgical castration. Despite a good initial response, the disease progresses to a castration-resistant state. Castration-resistant prostate cancer (CRPC) remains addicted to androgen receptor signaling. The addition of conventional anti-androgen agents, such as bicalutamide, only provides a transient benefit. This has led to a search for further drug targets. Cytochrome P450 17 (CYP17) is an enzyme that is vital for the adrenal biosynthesis of androgens. The CYP17 inhibitor abiraterone acetate has a proven benefit in a phase III randomized trial and other CYP17 inhibitors are currently being evaluated. The novel antiandrogen MDV3100 is a small molecule androgen receptor antagonist with promising activity. Heat shock proteins (HSPs) bind to the androgen receptor and modify its activity. Several HSP inhibitors are under evaluation in clinical trials. This review explores the role of CYP17 inhibitors, MDV3100, and HSP inhibitors.