Gonadotropin-Releasing Hormone (GnRH) Receptors in Tumors: a New Rationale for the Therapeutical Application of GnRH Analogs in Cancer Patients?

Abstract

Gonadotropin-Releasing Hormone (GnRH) is the hypothalamic decapeptide which plays a key role in the control of reproductive functions. By binding to specific receptors present on the pituitary gonadotropes, GnRH regulates gonadotropin release and, consequently, steroid hormone secretion from the gonads. When given continuously and at high doses, GnRH agonists suppress the pituitary gonadal axis through the down-regulation and desensitization of its own receptors. Based on this rationale, pituitary GnRH receptors represent the target for the successful utilization of GnRH agonists (that are more stable than the native peptide) for the treatment of hormone-dependent tumors (e.g., prostate, breast, endometrial, ovarian cancers). The observation that GnRH receptors are expressed in steroid-dependent tumors, and that their activation reduces cell proliferation and metastatic behavior of cancer cell lines, both in vitro and in vivo (when inoculated into nude mice), indicates a possible additional and more direct antitumor activity for these compounds. Interestingly, GnRH receptors have been shown to be expressed also in androgen-independent prostate carcinoma, as well as in tumors that are not classically considered hormone-related (e.g., melanoma), suggesting a clinical utility of the administration of GnRH analogs also in these tumors. More recently, GnRH agonists have been proposed as useful carriers to target cytotoxic drugs or toxins to cancer cells displaying the specific GnRH receptors. A second form of GnRH (designated GnRH-II) has been discovered in most vertebrates, including humans. GnRH-II has been suggested to act through a 'putative' cognate type II GnRH receptor, which is distributed in different tissues, both normal and tumoral. In humans, a full-length functional type II GnRH receptor has not been found. Therefore, its functions as well as its possible utility as a molecular target for a GnRH-II based therapy in oncology still has to be clarified. This review will focus on the role of GnRH receptors in the control of tumor growth, progression and dissemination. It will also be discussed whether the presence of these receptors might represent an additional rationale for the clinical utility of GnRH analogs as anticancer drugs.

Evaluation of a Stable Gonadotropin-Releasing Hormone Analog in Mice for the Treatment of Endocrine Disorders and Prostate Cancer

“…Proliferation studies based on a hormone-dependent prostate cancer cell line (LNCaP cells) indicated that analog 1 was as potent as the superagonist leuprolide in terms of inhibiting cell proliferation. It is possible that analog 1 can play a significant role for the treatment of hormone-dependent cancers, by acting not only at the pituitary level (thus suppressing the pituitary-testicular axis) but also by exerting antitumor activity directly on cancer cells, as has been previously shown for other GnRH agonists Montagnani Marelli et al, 2006). On the basis of the binding affinities of both analogs (leuprolide or analog 1), perhaps antiproliferative effects should have been expected at nanomolar concentrations.…”

“…A significant proportion of patients develop locally advanced or metastatic disease not amenable to surgery or radiotherapy (Labrie et al, 2005). Recent advances suggest that GnRH analogs not only inhibit testicular androgen secretion via the pituitarygonadal axis but are also capable of direct inhibition of tumor growth, exerting specific (receptor-mediated) antiproliferative, antimitogenic, and antimetastatic activities on cancer cells (Montagnani Marelli et al, 2006. Because several types of cancer cells overexpress the GnRH receptor, novel structures based on GnRH analogs that act as carriers to cancer cells, coupled with cytotoxic molecules (e.g., doxorubicin), have been prepared and evaluated in preclinical cancer models with promising results (Mezo and Manea, 2010).…”

Diversity of actions of GnRHs mediated by ligand-induced selective signaling

“…The presence of GnRH receptors in breast cancer tissue [31] and the demonstration of antiproliferative actions of GnRH analogs in breast cancer cell lines [32,47,96] supported this interpretation. Antiproliferative effects of GnRH analogs and the expression of GnRH receptors have now been demonstrated in a number of cell lines of reproductive tract tumors, including prostate, uterine and ovarian cancers, and also in nonreproductive tract tumors [21,43,47,70,73,79]. In contrast to GnRH actions at the gonadotrope, which are mediated through the G αq protein, these antiproliferative and apoptotic effects on tumor cells are thought to be mediated via the G αi protein [42,54,81], focal adhesion complexes involving c-Src, and the JNK and P38 stress-activated kinases [42,54,70,73,81].…”

Anti-GnRH Receptor Monoclonal Antibodies, First-In-Class GnRH Analog

“…Therefore, preclinical and clinical studies with humanized Mab may be the final proof to demonstrate the efficacy of hGHR106 in anti-cancer therapy, despite the fact that the slow-release long-acting GnRH peptide analogs or small organic molecules are also currently available for clinical studies [4,5,8,10,11,22,34,38,39].…”