ATPS-76ESTROGEN RECEPTOR β AGONISTS: NOVEL THERAPEUTIC AGENTS FOR GLIOBLASTOMA

Abstract

Glioblastoma (GBM) are the most common primary brain tumors with poor prognosis. A gender bias exists in the development of GBM with greater incidence of GBM in males compared to females, suggesting the tumor suppressive role of estrogen. However, estrogen as potential therapy for GBM is limited due to safety concerns. Therefore, alternative agents that mimic estrogen effects are needed. Estrogen effects are mediated though Estrogen Receptor α (ERα) and Estrogen Receptor β (ERβ). ERβ functions as a tissue-specific tumor suppressor. Our studies demonstrated that GBM uniquely express ERβ but not ERα. Recent studies identified Liquiritigenin and LY500307 as selective ERβ agonists that are currently in clinical trials for treating hot flashes and Schizophrenia. The objective of this study is to determine the therapeutic effects of novel ERβ agonists and to determine their mechanism(s) of action. Treatment with ERβ agonists significantly reduced the proliferation of GBM cells with no activity on normal astrocytes. Overexpression of ERβ reduced proliferation of GBM cells and knockdown of ERβ compromised the effect of ERβ agonists. ERβ agonists mediated apoptosis of GBM involve genes activated by both ERβ- classical as well as non-classical pathways and also involve p38MAPK and JNK pathways. Since Glioma Stem Cells (GSCs) are implicated in tumor initiation, invasion and therapy resistance, we also tested the effect of ERβ agonists on GSCs. ERβ agonists significantly inhibited the neurosphere formation and self-renewal of GSCs and also reduced the stemness and induced differentiation and apoptosis. RNA sequencing analysis revealed several novel pathways related to apoptosis, cell cycle, stem cells and differentiation were significantly modulated by ERβ agonists. Further, Liquiritigenin and LY500307 treatment significantly reduced the in vivo tumor growth and promoted apoptosis of tumors. Together, our results demonstrate that ERβ agonists as a potential therapeutic agents for treatment of GBM.