Prostate cancer and the androgen receptor: Strategies for the development of novel therapeutics

The early demonstrations that prostate cancer was hormone-sensitive initiated a therapeutic strategy of hormone ablation that is still in use today. Although chemical or surgical castration reduces androgen stimulation of the androgen receptor (AR) and produces tumor regression, little survival benefit is achieved. Patients with metastatic cancer eventually relapse as their tumors progress to hormone independence. The AR is a member of the steroid receptor family; however, it manifests many unique features including: N-terminal, C-terminal interactions and antiparallel dimerization, unique N-terminal domains for co-factor recruitment, AR-specific co-activators and upstream promoter/enhancer response elements that amplify AR-mediated responses. The AR is regulated by phosphorylation and cross-talk with several signaling pathways, including MAP kinases, PKA and PKC. Non-genomic effects of AR to regulate transcription factors elk-1 and -2 have also been demonstrated. These unique features suggest mechanisms by which novel therapeutics might target and influence AR-mediated actions. Progress in this direction has been realized with the recent synthesis of non-steroidal androgen agonists that may have tissue-selective effects.