Significance of the Prolactin Receptor in Glioblastoma

Compounds blocking the prolactin receptor (PRLR) have not yet reached the clinic. There are however several observations supporting a future use of PRLRA for tumor treatments. In particular, this could be the case for treatment of glioblastoma (GBM). We have previously developed a recombinant protein that blocks the PRLR and our goal is to link this protein with established drugs used for GBM treatment. The idea is to use receptor internalization to enrich a drug of interest in the target cells in addition to provide a growth inhibitory effect of the antagonist alone. TSC proteins suppress the mTOR pathway and the discovery that certain tumors have lost TSC functionality immediately suggested how to treat the over-activity of mTOR in some cancers. Rapamycin is a clinical drug blocking mTOR and it has been used for many years as an immune suppressant. The use of Rapamycin in cancer treatment, although it does not provide a cure, serves to slow down tumor progression. A further problem with Rapamycin is related to the immunosuppressing activity of this drug. We found an interesting connection between the PRL system and some forms of tumors. In essence, we observed that PRLR levels commonly is increase in different type of tumors including GBM. This provides a rationale to use PRLRA for two reasons (1) to reduce PRL induced growth by blocking the PRLR, JAK-STAT/AKT-PI3 pathways and (2) to use the PRLR to deliver Rapamycin preferentially to GBM cells.

Compounds blocking the prolactin receptor (PRLR) have not yet reached the clinic. There are however several observations supporting a future use of PRLRA for tumor treatments. In particular, this could be the case for treatment of glioblastoma (GBM). We have previously developed a recombinant protein that blocks the PRLR and our goal is to link this protein with established drugs used for GBM treatment. The idea is to use receptor internalization to enrich a drug of interest in the target cells in addition to provide a growth inhibitory effect of the antagonist alone. TSC proteins suppress the mTOR pathway and the discovery that certain tumors have lost TSC functionality immediately suggested how to treat the over-activity of mTOR in some cancers. Rapamycin is a clinical drug blocking mTOR and it has been used for many years as an immune suppressant. The use of Rapamycin in cancer treatment, although it does not provide a cure, serves to slow down tumor progression. A further problem with Rapamycin is related to the immunosuppressing activity of this drug. We found an interesting connection between the PRL system and some forms of tumors. In essence, we observed that PRLR levels commonly is increase in different type of tumors including GBM. This provides a rationale to use PRLRA for two reasons (1) to reduce PRL induced growth by blocking the PRLR, JAK-STAT/AKT-PI3 pathways and (2) to use the PRLR to deliver Rapamycin preferentially to GBM cells.

Prolactin role in cancer There are many different causes of cancer including infection, chemical exposure, genetic mutations and local cytokine production. The hallmarks of cancer are self-sufficiency growth signals, unlimited proliferation, permanent angiogenesis, and failure of apoptotic mechanisms and insensitivity to anti-growth signals.Many human cancers develop as a result of exposure to viral infection. The most common one is Human Papillomavirus (HPV) infection specifically HPV-16 and -18, contributing to a high risk of cervical cancer. In this context a clinical screening programs for cervix cancer in some countries, i.e. test for HPV, has been introduced. A new line of research in the last years suggest that human cytomegalovirus (CMV) infection also can contribute to several human malignancies including: breast, colon, and prostate cancer, rhabdomyosarcoma, hepatocellular cancer, salivary gland tumors, neuroblastoma, and brain tumors (15).Since hormones regulate cell growth and differentiation they also have a role in cancer development. In fact many tumors respond therapeutically to agents interfering with hormone actions. The influence of PRL on different forms of cancers in humans has been widely discussed and the realizations that PRL also have paracrine/autocrine actions is much relevant in this context. Overproduction of PRL has been reported to increase the aggressively of colorectal cancer in human(158), and to contribute in the pathogenesis and progression of human breast cancer [16]. Animal data suggest that PRL increases the rate of tumor cells growth and metastases [17]. Contradictory findings suggest that PRL have a favorable role in breast cancer prognosis [18]. Local production of PRL in myometrium smooth muscle tumors (uterine leiomyomas) indicate that mitogenic PRL actions participate in the progression of such tumors [19]. It has been suggested that PRL might be involved in the progression of LAM (see below) since females are only affected and that the disease is aggravated during pregnancy ? a condition associated with elevation of lactogenic hormones [20]. In human ovarian cancer cells, studies also showed that lower levels of tumoral PRL/PRLR in clinical samples were associated with longer patient survival suggestive of an important role for PRLR in the pathogenesis of such tumour. Glioblastoma multiforme (GBM) GBM is the most common and most aggressive primary brain tumor in humans, accounting for approximately 12-15% of all intracranial tumors, with a median survival of 15 months despite advanced cytotoxic therapy including surgical intervention [22]. Angiogenesis, the process of forming new vessels, is essential for tumor growth and metastasis. One main feature characterizing GBM is neovascularization, i.e. an imbalance between pro-, and anti- angiogenic factors [22,23]. A number of different alterations of cell signaling molecules have been found to promote angiogenesis in GBM exemplified by increased signaling from: VEGF receptors (VEGFR), epidermal growth factor receptor (EGFR) [24], platelet?derived growth factor. On a genetic level, primary GBM are characterized by deletion or mutation of tumor suppressors INK4a, P53 and phosphatase and tensin homologue deleted on chromosome 10 (PTEN). As previously mentioned, both SOCS2 and TSC2 are intracellular proteins that regulate the JAK-STAT and the mTOR pathways respectively. Previous experimental and clinical studies have reported an increased STAT and mTOR activity in GBM. Studies on SOCS/TSC expression in brain tumors have shown that SOCS1 and SOCS3 are apparently expressed in GBM and play a significant role in the tumor pathogenesis. Of note, loss of TSC1 accelerates malignant glioma genesis when it is combined with oncogenic signals. Patients with tuberous sclerosis have a bi-allelic loss of TSC1/TSC2 and a few clinical cases have been reported on the occurrence of glioblastoma in such patients [24]. The limited success of using EGFR inhibitors to treat recurrent glioblastoma open up gates for other new treatment such as combination therapy that also inhibit the mTOR pathway through PI3K. With regard to PRL, it has been suggested that, in the mouse placenta, initiation and cessation of vascularization correlates with the sequential expression of proliferin and proliferin-related peptide [25,26]. These non-classical members of the PRL/GH family have been shown to act in autocrine/paracrine fashion to either stimulate or inhibit various stages of angiogenesis. It is however interesting to note that anti-angiogenic factors induce local production of PRL, as a pro-survival response. A recent study showed a combined application of the angiogenic inhibitors, i.e. endostatin and tumastatin, up-regulate the PRLR in GBM in vivo and that the activation of PRLR signaling stimulates proliferation of tumor cells [27]. All these suggest an important rule of PRL and its receptor in the pathogenesis of GBM and targeting such receptor (our study aim) offer a new therapeutic line in the field of GBM brain tumor.