New Approaches Targeting Androgen Receptor Signal Pathways for Treatment of Castration-Resistant Prostate Cancer

Even orchiectomy/androgen depletion was proposed for treating prostate cancer in the middle of the last century (Attar et al., 2009a; Ross et al., 2008; Vis & Schroder, 2009), androgen deprivation remains to be the mainstay for advanced prostate cancer treatment. However, androgen depletion is usually effective for a limited duration (i.e., a median time of 2-3 years) and majority of the treated prostate cancer patients will develop unresponsiveness to the initial androgen depletion treatment and then evolves to regain the ability to grow despite low levels of androgens in the circulation (Chen et al., 2008; Mostaghel et al., 2009). These so called “castration-resistant prostate cancer (CRPC)” is almost incurable and becomes insignificantly responsive or resistant to most of anti-cancer, cytotoxic drugs except docetaxel and cabazitaxel that seem to show modest but significant improvement of patient survival time (de Bono et al., 2010; Petrylak et al., 2004; Vaishampayan et al., 2009). Evidence strongly suggests that the nuclear androgen receptor (AR) still plays an important role in CRPC and may be, in part, attributed to the resistance to cytotoxic anti-cancer drugs. Intriguingly, these CRPC patients may still respond to second line of AR–related treatment. Thus, it has been urgent to develop novel and more effective AR-related treatments for CRPC. Acquired resistance has been the main limitation of efficacy of cytotoxic drug chemotherapy and hormonal therapy for CRPC. Recently, new molecules or agents aiming at local angiogenesis, immunotherapy, apoptosis, chaperone proteins, the insulin-like growth factor (IGF) pathway, mammalian target of rapamycin (mTOR), RANK ligand, endothelin receptors, and the Src family kinases in CRPC have been developed for treating CRPC, some of which have been either approved by US Food and Drug Administration (FDA) or entering into different phases of clinical trial (Aggarwal & Ryan, 2011; Leo et al., 2011; Macfarlane & Chi, 2010; Seruga et al., 2011). This chapter will only focus on AR related targeting approaches for CRPC treatments.