Development of Pure Prolactin Receptor Antagonists

Abstract

Prolactin (PRL) promotes tumor growth in various experimental models and leads to prostate hyperplasia and mammary neoplasia in PRL transgenic mice. Increasing experimental evidence argues for the involvement of autocrine PRL in this process. PRL receptor antagonists have been developed to counteract these undesired proliferative actions of PRL. However, all forms of PRL receptor antagonists obtained to date exhibit partial agonism, preventing their therapeutic use as full antagonists. In the present study, we describe the development of new human PRL antagonists devoid of agonistic properties and therefore able to act as pure antagonists. This was demonstrated using several in vitro bioassays, including highly sensitive assays able to detect extremely low levels of receptor activation. These new compounds also act as pure antagonists in vivo, as assessed by analyzing their ability to competitively inhibit PRL-triggered signaling cascades in various target tissues (liver, mammary gland, and prostate). Finally, by using transgenic mice expressing PRL specifically in the prostate, which exhibit constitutively activated signaling cascades paralleling hyperplasia, we show that these new PRL analogs are able to completely revert PRL-activated events. These second generation human PRL antagonists are good candidates to be used as inhibitors of growth-promoting actions of PRL.

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

“…[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. 33 Nevertheless, a single clinical therapy trial using the anti-prolactinemic drug cabergoline combined with docetaxel in woman with metastatic breast cancer and concomitant hyperprolactinemia showed that tumor regression rate was significantly higher in patients treated with cabergoline than in those who received docetaxel alone.…”

JAK-STAT pathway in carcinogenesis: Is it relevant to cholangiocarcinoma progression?

“…Taking together these observations we can suggest that local manipulation of JAK-STAT activation can be a very perspective therapeutic approach for managing of cholangiocarcinoma at different stages of its progression. Recent advances in development of hormonal and cytokine antagonists (recombinant proteins for Prl and GH and peptide for IL-6 [145][146][147] ) give us an efficient tool for this treatment. Since synthetic specific inhibitors of JAK and other tyrosine kinases are intensively developed, we could suggest their efficient application for managing of cholangiocarinoma in addition to antagonists.…”

Identification of a gain-of-function mutation of the prolactin receptor in women with benign breast tumors

“…Tyrphostin B42 (AG490) is a pharmacological inhibitor of JAK2 activity and Del1-9-G129R-hPrl is a specific, competitive PrlR antagonist (18). Both inhibited constitutive phosphorylation of PrlR I146L stably expressed in HEK cells (Fig.…”