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Genitourinary Oncology Service, Division of Solid Tumor Oncology, Memorial Sloan-Kettering Cancer Center, Department of Medicine, Joan and Sanford I Weill College of Medicine, New York, New York 10021, USA
1 Dame Roma Mitchell Cancer Research Laboratories, Department of Medicine, University of Adelaide & Hanson Institute, Adelaide SA 5000, Australia
2 Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA
(Requests for offprints should be addressed to Howard I Scher, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA; Email: scherh{at}mskcc.org or Wayne Tilley, The Hanson Institute, PO Box 14 Rundle Mall, Adelaide SA 5000, Australia; Email: wayne.tilley{at}adelaide.edu.au)
The categorization of prostate cancers that are progressing after castration as ‘hormone-refractory’ evolved from the clinical observation that surgical or medical castration (i.e. androgen ablation therapy; AAT) is not curative and, despite an initial response, virtually all tumors eventually regrow. Successful AAT is contingent on the dependence of prostate cancer cells for androgen signaling through an intracellular mediator, the androgen receptor (AR) for survival. Current preclinical and clinical data imply that the AR is expressed and continues to mediate androgen signaling after failure of AAT. As AAT does not completely eliminate circulating androgens, sufficient concentrations of dihydrotestosterone may accumulate in tumor cells to maintain AR signaling, especially in the context of upregulated receptor levels or increased sensitivity of the AR for activation. In addition, ligands of non-testicular origin or ligand-independent activation can contribute to continued AR signaling. In many cases, therefore, from the perspective of the AR, a ‘hormone-refractory’ classification after failure of AAT is inappropriate. Classifying prostate tumors that progress after AAT as ‘castration-resistant’ may be more relevant. Clinical responses to second- and third-line hormonal therapies suggest that the mechanisms of AR activation are in part a function of previously administered AAT. Accordingly, the increasing trend to utilize AAT earlier in the course of the clinical disease may have a greater influence on the genotype and phenotype of the resistant tumor. In this article, we detail strategies to inhibit the growth of prostate cancer cells that specifically target the AR in addition to those practiced traditionally that indirectly target the receptor by reducing the amount of circulating ligand. We propose that treatment regimes combining AAT with direct AR targeting strategies may provide a more complete blockade of androgen signaling, thereby preventing or significantly delaying the emergence of treatment-resistant disease.
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