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Biology of Progressive, Castration-Resistant Prostate Cancer: Directed Therapies Targeting the Androgen-Receptor Signaling Axis

Howard I. Scher, Charles L. Sawyers

From the Genitourinary Oncology Service, Department of Medicine, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center; Joan and Sanford E. Weill College of Medicine of Cornell University, New York, NY; Howard Hughes Medical Institute, University of California, Los Angeles/Hematology-Oncology, Los Angeles, CA

Address reprint requests to Howard I. Scher, MD, Genitourinary Oncology Service, Department of Medicine, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center1275 York Ave, New York, NY 10021; e-mail: Scherh{at}mskcc.org.

Prostate cancers that are progressing on medical and surgical therapies designed to ablate the action of androgens continue to express androgen receptor (AR) and to depend on signaling through the receptor for growth. A more clinically relevant classification of castration-resistant disease focuses on the mechanisms of receptor activation, which include (1) changes in the level of ligand(s) in tumor tissue; (2) increased levels of the protein due to gene amplification or altered mRNA expression; (3) activating mutations in the receptor that affect structure and function; (4) changes in coregulatory molecules including coactivators and corepressors; and (5) factors that lead to activation of the receptor independent of the level of ligand or receptor allowing kinase cross talk. From an AR perspective, the term "hormone refractory" is inappropriate. On the basis of this schema, we discuss strategies that are focused on the AR either directly or indirectly, as single agents or in combination, that are in clinical development.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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