The Prostate 71:550 ^557 (2011) Androgen Hypersensitivity in Prostate Cancer: Molecular Perspectives on Androgen Deprivation Therapy Strategies Ruth Foley, 1 Laure Marignol, 1 John P. Keane, 1,2 Thomas H. Lynch, 1,2 and Donal Hollywood 1 * 1 Prostate Molecular Oncology Group, Academic Unit of Clinical and Molecular Oncology,Trinity College, Dublin, Ireland 2 Department of Urology, St. James’ Hospital, Dublin, Ireland Androgen deprivation therapy is initially successful in treating advanced prostate cancer. However, after a period of time tumors inevitably recur. Improved understanding of the various biochemical causes of resistance to hormonal therapy is of crucial importance for developing more effective therapeutic strategies in this cohort of patients. This review discusses the preclinical evidence for androgen hypersensitivity (AH), as a mechanism by which tumors become hormone-refractory (HR). We propose that the growth of some such tumors may be not only stimulated by, but also dependent on low hormone levels, and furthermore, that normal hormone concentrations can have an inhibitory effect on growth. The incidence and importance of AH merits further investigation both in preclinical studies and during clinical trials of intermittent androgen withdrawal or testosterone replacement. We suggest that a subset of HR prostate cancer patients who have androgen-hypersensitive tumors could be particularly amenable to these treatments. Finally, potential approaches for developing biomarkers to identify such patients are explored. Prostate 71: 550 – 557, 2011. # 2010 Wiley-Liss, Inc. KEY WORDS: intermittent androgen withdrawal; testosterone replacement; prolifer- ation; biomarkers INTRODUCTION Androgen deprivation therapy (ADT) is increas- ingly becoming a central component in the manage- ment of prostate cancer. Advanced prostate cancer patients are routinely treated with luteinizing hor- mone-releasing hormone analogs (LHRHa) such as goserelin acetate [1]. However, although initially effective, patients acquire resistance and their tumors inevitably recur after a period of time. At this stage, the only therapeutic option which offers a survival benefit is docetaxel [2], which is associated with significant risks of adverse events. Patients with disease progres- sion on LHRHa therapy may be treated with continued LHRHa and a non-steroidal anti-androgen such as bicalutamide, as combined androgen blockade (CAB) [3]. Intermittent androgen withdrawal (IAW) is under active investigation but evidence is not yet strong enough for incorporation into routine therapy [4,5]. Other hormonal therapy regimens including testosterone replacement have also been investigated in clinical trials [6,7]. The molecular factors behind the hormone- refractory (HR) phenotype are varied. The androgen Abbreviations: AD, androgen-dependent; ADT, androgen depriva- tion therapy; AH, androgen hypersensitivity; AR, androgen recep- tor; CAB, combined androgen blockade; CTC, circulating tumor cells; CMV, cytomegalovirus; DHT, dihydrotestosterone; HIF, hypoxia-inducible factor; HR, hormone-refractory; HRPC, hor- mone-refractory prostate cancer; IAW, intermittent androgen with- drawal; LHRHa, luteinizing hormone-releasing hormone analogs; PET, positron emission tomography; PSA, prostate-specific antigen; VEGF, vascular endothelial growth factor. Grant sponsor: Irish Cancer Society. *Correspondence to: Donal Hollywood, Academic Unit of Clinical and Molecular Oncology, Trinity Centre for Health Sciences, St. James’s Hospital, Dublin 8, Ireland. E-mail: dhlywood@tcd.ie Received 18 March 2010; Accepted 9 August 2010 DOI 10.1002/pros.21266 Published online 14 October 2010 in Wiley Online Library (wileyonlinelibrary.com). ß 2010 Wiley-Liss, Inc.