Targeting the androgen receptor in hormone-refractory prostate cancer--new concepts.

The androgen receptor (AR) plays a key regulatory role in hormone-naive, as well as in advanced, therapy-resistant prostate cancer. Therefore, the development of novel treatment strategies using new means for targeting AR function in prostate tumors aims at providing better options for control of progression and progressive disease. This review summarizes recent attempts in this field with a critical view on their clinical usefulness. In addition to classic endocrine therapy by surgical and/or chemical castration, there are concepts to inhibit the AR directly through anti-androgens, selective AR modulators, naturally occurring AR inhibitors, neutralizing antibodies and dominant-negative peptides. A unique possibility to prevent AR expression at the transcriptional level represents the use of antisense technology. The advantage of this method is that AR expression, and thus any aberrant route of its activation is prevented. Furthermore, there are several approaches by which AR signaling is inactivated indirectly. Degradation of heat-shock proteins, which direct appropriate AR protein folding, or modulation of various growth factor signaling cascades, which are thought to contribute to AR activation in the androgen-deprived patient, have been investigated.