MON-LB054 Activity of Prolactin Receptor Antagonist-Rapamycin Conjugate in Glioblastoma Multiform

Background: Glioblastoma multiform (GBM) is the most common and aggressive primary brain tumor in humans, accounting for approximately 12-15% of all intracranial tumors, with a median survival of 15 months. Although GBM is not considered a hormone sensitive cancer but recent studies showed significant increased levels of prolactin receptors (PRLR) in response to combined application of angiogenic inhibitors on GBM in vivo. Tuberous Sclerosis complex (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. Patients with TSC have bi-allelic loss of TSC1/TSC2, and a few clinical cases have been reported the occurrence of GBM in such patients and experimental studies reported increased STAT and mTOR activity in GBM. Hypothesis: Compounds blocking the PRLR have not yet reached the clinic and rapamycin is a clinical drug blocking mTOR, which serves to slow down tumor progression. All these provide a rationale to use PRLRA for two reasons (1) to reduce growth by blocking the PRLR JAK-STAT/AKT-PI3 pathways and (2) to use the PRLR to deliver rapamycin preferentially to GBM cells. Methodology: GBM cell line (U251-MG) obtained from ATCC, then we quantified levels of both PRL and PRLR in these cells. We used PRL induced STAT5 and SK6 phosphorylation as a standard read-out for PRL effects. Using this system, we tested how rapamycin interfere with PRL signals and we determined to what extent the PRLR antagonist facilitates action of rapamycin. Results: we found that PRLR are significantly expressed in U251-MG cells. PRLR antagonist block STAT5 phosphorylation and facilitate rapamycin effect on U251-MG cells by reduce S6k phosphorylation on dose dependent manner. Conclusion developing PRLR antagonist -rapamycin conjugate might open new line of GBM treatment by using the PRLR as delivering system for rapamycin. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.