Abstract 951: LY500307 as a novel therapeutic agent for treatment of glioblastoma

Abstract

Abstract Glioblastoma (GBM) is the most common type of primary brain tumor with poor prognosis. A gender bias exists in the development of GBM with incidence of developing GBM is greater in males compared to females. Epidemiological studies and several lines of evidence suggest tumor suppressive role of female sexual hormone estrogen on brain tumors. However, estrogen as potential therapy for GBM has limited therapeutic application due to safety concerns including breast cancer, uterine cancer, heart disease, and feminization in men. Therefore alternative agents that mimic estrogen effects will have potent utility in treating GBM. Estrogen effects are mediated though its cognate receptors ERα and ERβ and ERβ functions as a tissue-specific tumor suppressor. Recent studies identified a synthetic LY500307 as a selective ERβ agonist (developed by Eli Lilly and Company) with an excellent preclinical profile and is currently in clinical trials for treating Schizophrenia. We recently showed that ERβ is the major ER subtype expressed in GBM. The objective of this study is to determine the therapeutic effects of novel ERβ agonist LY500307 using both in vitro and orthotopic preclinical models and to determine its mechanism(s) of action. In this study, we have tested the therapeutic efficacy of LY500307 using several established as well as patient derived GBM cells. Treatment of LY500307 significantly reduced the proliferation of GBM cells with no activity on normal astrocytes suggesting its tumor specific effects. Overexpression of ERβ reduced proliferation of GBM cells and knockdown of ERβ compromised the treatment effect of LY500307 further suggesting the specificity. RNA sequencing analysis of LY500307 treated and untreated GBM cells revealed several novel pathways related to apoptosis, cell cycle, stem cells and differentiation that were significantly modulated by LY500307. Mechanistic studies revealed that LY500307 mediated apoptosis of GBM involve genes activated by both ERβ- classical as well as AP1 mediated non-classical pathways and also involve p38MAPK and JNK pathways. Since Glioma Stem Cells (GSCs) are implicated in tumor initiation, invasion and therapy resistance of GBM, we also tested the effect of LY500307 on GSCs. LY500307 treatment significantly inhibited the proliferation, neurosphere formation and self-renewal of GSCs and also resulted in the loss of stemness of GSCs and induction of differentiation and apoptosis. Further, LY500307 treatment significantly reduced the tumor growth in in vivo orthotopic GBM models and promoted apoptosis of tumors. Together, our results demonstrate that LY500307 as a potential therapeutic agent for treatment of GBM. Since LY500307 has good blood-brain barrier permeability and less neuronal toxicity, it can be readily transferred to clinical use with current radiation and chemotherapies, thereby providing an additional tool for enhancing survival in GBM patients. Citation Format: Gangadhara R. Sareddy, Aleksandra Gruslova, David A. Cavazos, Rajeshwar R. Tekmal, Andrew J. Brenner, Ratna K. Vadlamudi. LY500307 as a novel therapeutic agent for treatment of glioblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 951. doi:10.1158/1538-7445.AM2015-951