Hormone treatment for prostate cancer: current issues and future directions

Most prostate cancers are androgen-dependent and essentially respond to androgen ablation therapy. However, these tumors eventually become androgen-independent and progress despite androgen ablation. Since the androgen receptor (AR) sequence was determined, numerous studies have shown that AR plays a critical role in the development of androgen-refractory prostate cancer. Amplification of AR, mutations of AR, and deregulation of growth factors, cytokines and AR co-activators, which could be classified as AR-dependent pathways, are frequently observed in this condition. There are other pathways, AR-independent pathways that bypass AR, which involve neuroendocrine differentiation of prostate cancer cells, deregulation of apoptotic genes and unknown mechanisms related to down-regulation of AR. Androgen-refractory prostate cancers with the AR-dependent pathway could be treated by suppressing AR activity, whereas AR-independent tumors would require alternative management strategies. When more cell survival pathways are defined, improvement of patients' survival could be achieved by developing specific gene-targeting therapies that interfere with those pathways.