Castration Resistant Prostate Cancer: From Emerging Molecular Pathways to Targeted Therapeutic Approaches
Patrizia Limonta, Roberta M. Moretti, Monica Marzagalli and Marina Montagnani Marelli
Affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Sezione di Biomedicina ed Endocrinologia, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy.
Keywords: Abiraterone, androgen receptor, apoptosis, cabazitaxel, castration resistant prostate cancer, cell-based immunotherapy,
chemotherapy, clusterin, custirsen, cytotoxic GnRH bioconjugates, cytotoxic GnRH-III bioconjugates, docetaxel, enzalutamide,
GnRH agonists, GnRH antagonists, sipuleucel-T, targeted therapy, cell survival pathways, GnRH receptors.
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.
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