Castration Resistant Prostate Cancer : from Emerging Molecular Pathways to Targeted Therapeutic Approaches

Abstract: Prostate cancer is the most commonly diagnosed nonskin cancer and the second leading cause of cancer-related deaths among men in Western Countries. Most prostate cancers are dependent on androgens for growth and progression in the early stages. In the case of locally advanced or metastatic prostate cancers the most effective treatment is represented by androgen ablation therapy, aimed at blocking androgen secretion/activity, such as the so called chemical castration. This can be achieved either by GnRH agonist monotherapy or by a GnRH agonist in combination with a pure antiandrogen. Unfortunately, despite an excellent initial response, relapse occurs in approximately 2-3 years with the appearance of castration resistant prostate cancer (CRPC). Until recently, the only therapy shown to be life prolonging was limited to the microtubule-stabilizing agent docetaxel. Thus, efforts have been made in order to elucidate the molecular mechanisms underlying CRPC development with the aim to identify novel molecular targets for effective therapeutic approaches. These mechanisms include: reactivation of the androgen receptor axis (receptor amplification, mutations, transactivation); tubulin stabilization and mitotic arrest; development of immunologic tolerance together with the failure of the body's immune system to elicit antitumor effects; cell survival signaling pathways (clusterin); gonadotropin-releasing hormone (GnRH) receptors. In this review, we'll focus on the currently available agents targeting these molecular pathways: abiraterone, enzalutamide (MDV3100), cabazitaxel, sipuleucel-T, custirsen, GnRH analogs and cytotoxic GnRH bioconjugates. Some of these agents have already received U.S. Food and Drug Administration approval, some are at present under intensive investigation in preclinical and clinical studies.