Prostate cancer is
androgen-dependent in its early stages and
androgen deprivation
therapy represents the most effective first-line therapeutic approach. However, after an initial remission,
prostate cancer progresses towards the
castration resistant
prostate cancer (CRPC) stage, with increased
malignancy and resistance to conventional
chemotherapy. Pituitary
gonadotropin-releasing hormone receptors (
GnRH-Rs) represent the most effective molecular target for the treatment of
steroid-dependent
prostate cancer.
GnRH agonists (through
GnRH-Rs desensitization) suppress the pituitary-testicular axis and, therefore, represent the treatment of choice for
prostate cancer patients.
GnRH-Rs are also expressed in
prostate cancer, even when the
tumor has reached the CRPC stage, and are endowed with antitumor activity, supporting the notion that they might represent a molecular target for
GnRH analog-based therapeutic strategies. In addition to
GnRH agonists and antagonists,
GnRH-based bioconjugates (cytotoxic
GnRH bioconjugates,
GnRH-conjugated lytic
peptides and
GnRH-toxin bioconjugates) have been developed and are now undergoing intensive investigations; some of them (i.e., AN-152, Dox-[d-Lys(6)]-
GnRH) have entered clinical trials. The advantage of these treatments is the specific delivery of
cytotoxic agents to
cancer cells. Interestingly, other
isoforms of the
peptide have been identified. One of them is
GnRH-III, which was isolated from sea lamprey.
GnRH-III specifically binds to
GnRH-Rs in
cancer cells and exerts antiproliferative effects; on the other hand, its endocrine effects at pituitary level are insignificant, supporting its selective antitumor activity. Based on these observations, different cytotoxic
GnRH-III bioconjugates have recently been synthesized; preliminary in vitro studies suggest that these compounds might represent a new promising treatment strategy for
prostate cancer.