Targeting the androgen receptor pathway in prostate cancer

• Published in: Current opinion in pharmacology 2008-08, Vol.8 (4), p.440-448
• Main Authors: Chen, Yu, Sawyers, Charles L, Scher, Howard I
• Format: Article
• Language: English
• Subjects: Androgen Antagonists - pharmacology; Androgen Antagonists - therapeutic use; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Histone Deacetylase Inhibitors; HSP90 Heat-Shock Proteins - antagonists & inhibitors; Humans; Internal Medicine; Male; Medical Education; Orchiectomy; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - pathology; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Receptors, Androgen - drug effects; Signal Transduction - drug effects
• ISSN: 1471-4892; 1471-4973
• DOI: 10.1016/j.coph.2008.07.005

When prostate cancers progress following androgen depletion therapy, there are currently few treatment options with only one, docetaxel, that has been shown to prolong life. Recent work has shown that castration-resistant prostate cancers (CRPCs) continue to depend on androgen receptor (AR) signaling which is reactivated despite low serum androgen levels. Currently available AR-targeted therapy, including GnRH agonists and antiandrogens, cannot completely shut down AR signaling. Several mechanisms that enhance AR signaling in an androgen-depleted environment have been elucidated. These include AR mutations that allow activation by low androgen levels or by other endogenous steroids, AR overexpression, increased local intracrine synthesis of androgens, and upregulation of tyrosine kinase pathways. This has led to the development of a number of novel agents targeting the AR signaling pathway, including more effective antiandrogens, inhibitors of CYP17, an enzyme required for androgen synthesis, inhibitors of 5α-reductase, inhibitors of HSP90 which protects AR from degradation, inhibitors of histone deacetylases which is required for optimal AR-mediated transcription, as well as inhibitors of tyrosine kinase inhibitors. Many of these strategies are currently being tested in clinical trials in CRPC.