Molecular Biology of Novel Targets Identified Through Study of Castration-Recurrent Prostate Cancer



Prostate cancer that recurs in men after complete androgen deprivation therapy remains today a lethal disease. Reactivation of androgen receptor (AR) signaling in the setting of castrate levels of androgen is widely accepted to be the dominant factor leading to prostate cancer progression. The mechanisms driving AR activation in clinical castration-recurrent prostate cancer (CRPC) are poorly understood. A number of hypotheses have been put forth to explain castrate-activated AR based on examination of patient material and the use of prostate cancer model systems. AR ligand binding domain mutations that confer gain-of-function properties through expanded use of alternative steroid ligands and overexpression of the non-mutated AR, with or without concurring genomic amplification, are two of the most widely cited hypotheses. Recently, much attention has been paid to the hypothesis that CRPC acquires the capacity to synthesize testosterone directly. Perturbation of AR signaling remains the main therapeutic objective. New drugs currently in clinical trials may offer some improved management of CRPC through antagonism of AR activity or blockage of extratesticular androgen production. Ultimately, the identification of drugs that promote selective AR degradation may have the greatest impact against the continued action of AR in CRPC.


Androgen Receptor Androgen Deprivation Therapy Androgen Receptor Gene Abiraterone Acetate Human Prostate Cancer Cell Line 
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© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Memorial Sloan-Kettering Cancer CenterNew York, NY, USA

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