Development and Potential Clinical Uses of Human Prolactin Receptor Antagonists

Abstract

There is a large body of literature showing that prolactin (PRL) exerts growth-promoting activities in breast cancer, and possibly in prostate cancer and prostate hyperplasia. In addition, increasing evidence argues for the involvement of locally produced (autocrine) PRL, perhaps even more than pituitary-secreted (endocrine) PRL, in tumor growth. Because dopamine analogs are unable to inhibit PRL production in extrapituitary sites, alternative strategies need investigation. To that end, several PRL receptor antagonists have been developed by introducing various mutations into its natural ligands. For all but one of these analogs, the mechanism of action involves a competition with endogenous PRL for receptor binding. Such compounds are thus candidates to counteract the undesired actions of PRL, not only in tumors, but also in dopamine-resistant prolactinomas. In this review, we describe the different versions of antagonists that have been developed, with emphasis on the controversies regarding their characterization, and the limits for their potential development as a drug. The most recently developed antagonist, Delta1-9-G129R-hPRL, is the only one that is totally devoid of residual agonistic activity, meaning it acts as pure antagonist. We discuss to what extent this new molecule could be considered as a lead compound for inhibiting the actions of human PRL in the above-mentioned diseases. We also speculate on the multiple questions that could be addressed with respect to the therapeutic use of PRL receptor antagonists in patients.

Crystal Structure of an Affinity-matured Prolactin Complexed to Its Dimerized Receptor Reveals the Topology of Hormone Binding Site 2

“…However, despite obvious similarities, GH⅐GHR and PRL⅐PRLR also appeared to have their own distinctive features. For example, the G129R-hPRL antagonist was shown to exhibit significant residual agonistic properties in various PRLR-mediated bioassays (3), whereas, to the best of our knowledge, there are no similar observations for G120R-hGH in GH-responsive bioassays. In addition, although mutation of Gly 120 in GHR antagonists does not affect binding affinity for GHR at the cell surface, every mutation of Gly 129 tested so far in hPRL was shown to decrease 10-fold their affinity for cell-expressed PRLR, which is clearly detrimental to the efficacy of these antagonists (2,20).…”

“…Competitive prolactin (PRL) 5 receptor antagonists have recently emerged as a new class of molecules with high therapeutic potential for treating unresolved PRL-sensitive pathologies (1)(2)(3). The main indications include hyperprolactinemia resulting from dopamine-resistant prolactinomas and tumors affecting peripheral PRL-target tissues such as the prostate and the breast.…”

Clinicopathological significance of prolactin receptor expression in colorectal carcinoma and corresponding metastases

“…20,25 As pointed out above, prolactin and its receptor are promising anti-cancer targets, wherein prolactin receptor antagonism appears to be the most promising interventional approach. [15][16][17]33 First, results showing a beneficial effect of prolactin/prolactin receptor-targeted therapy in breast cancer have been reported from both in vitro and in vivo models using either pure prolactin receptor antagonists, such as D1-9-G129R-hPRL or D1-14-G129R-hPRL, or fusion peptides between a prolactin receptor antagonist and potential anti-tumor peptides, such as G129R-hPRL-IL2, G129R-hPRL-endostatin, or G129R-hPRL-PE40-KDEL. 12,[34][35][36] However, these drugs are in early stages of development and application, and difficulties regarding stability and binding affinity of prolactin receptor antagonist must be overcome before entering the clinic.…”

“…[12][13][14] Thus, prolactin and its receptor are promising therapeutic targets, wherein prolactin receptor antagonism appears to be the most promising interventional approach. [15][16][17] The significance of prolactin and its receptor in colorectal cancer, however, is largely unknown. The expression of prolactin receptor in primary colorectal cancer has so far been analyzed by three studies, reporting significant higher level of prolactin receptor protein and mRNA expression in cancer tissue as compared with normal colorectal tissue.…”

Prolactin modulates phosphorylation, signaling and trafficking of epidermal growth factor receptor in human T47D breast cancer cells

“…Thus, our data also suggest the novel hypothesis that effects of PRL (and possibly other ERK-activating cytokines) on breast cancer cells could in part be related to modulation of EGF signaling by alteration of EGFR trafficking. As both PRL and EGF are potentially manipulatable targets in breast cancer (Nicholson et al, 2001;Chen et al, 2002;Clevenger et al, 2003;Lichtner, 2003;Harari, 2004;Laskin and Sandler, 2004;Goffin et al, 2005), this hypothesis is worthy of further testing in both cellular reconstitution systems and in vivo models.…”