Targeting hormonal signaling pathways in castration resistant prostate cancer

It is now well established that hormonal pathways are involved in the development of prostate cancer towards the castration resistant (CRPC) stage and can be effective molecular targets for novel treatment strategies. Most CRPC are sensitive to androgens and this can be due to the intratumoral production of androgens, androgen receptor (AR) amplification/ mutations and epigenetic modifications of AR expression/signaling. Based on these observations, potent agents targeting the AR axis were developed: 1) inhibitors of CYP17 (a key enzyme in the production of androgens), such as abiraterone and orteronel; 2) AR antagonists that bind to AR and impair AR activation, such as enzalutamide and ARN-509. Moreover, gonadotropin-releasing hormone receptors (GnRH-R), associated with a strong antitumor activity, are expressed in CRPC cells, indicating that they might represent an important target for GnRH analog-based therapeutic strategies. In addition to GnRH agonists and antagonists (i.e., degarelix), cytotoxic GnRH-based bioconjugates, delivering chemotherapeutic drugs to cancer cells expressing the GnRH-R, were developed and reported to exert antitumor effects on CRPC cells; some of them (i.e., AN-152) have already entered clinical trials. This review discusses the most relevant patents and recent observations on the anti-cancer efficacy of novel drugs targeting the AR and the GnRH-R pathways in CRPC.