Abstract 1867: Preclinical characterization of OSU- ERb-12, a novel ERβ agonist in Glioblastoma
Authors: Sharma Pratibha , Ghose Jayeeta , Coss Christopher , Bennett Chad , Raval Raju R. , Puduvalli Vinay 
Published: June 2022

Background: Glioblastoma (GBM) is the most aggressive primary brain tumor, representing approximately 15% of all primary CNS malignancies. Historically, the occurrence of GBM is higher in male than in female of reproductive age. Usage of exogenous hormones are known to reduce the risk of glioma development and estrogen improves survival in a glioblastoma animal models, suggesting a potential protective role in GBM. Estrogen receptor β (ERβ) may play a role as a tumor suppressor in GBM, and interestingly its expression decreases in higher-grade tumor samples with loss of differentiation. Therefore, a selective ERβ agonist could be a potential therapy against GBM. OSU-ERb-12 is brain penetrant, orally bioavailable ERβ agonist and demonstrates selectivity of ERβ: ERα = 46:1. In this work, we have tested the efficacy of this drug in vitro against glioma cells and in an orthotopic, syngeneic, immune-intact GBM mouse model.

Materials & Methods: We tested the efficacy of OSU-ERb-12, a novel selective ERβ agonist against commercial glioma cell lines and patient derived glioma stem like cells, cell proliferation rate via cell titer Glo assay. To evaluate the cell death Annexin-PI assay was performed using flow cytometry. We also tested impact of this drug on cell cycle distribution using flow cytometry-based assay. For in vivo studies, C57BL/6 mice were intracranially implanted with the murine glioma cell line GL261-Luc2 and treated with 30 mg/kg and 100 mg/kg of OSU-ERb-12. Tumor growth was evaluated post implantation using bioluminescent IVIS imaging and animal survival (Kaplan-Meier) was recorded.

Results: Treatment with OSU-ERb-12 significantly reduced the cell proliferation rate of commercial cells and patient derived glioma stem cells from various molecular classifications with IC50= 5 µM, 72h. Cells treated with OSU-ERb-12 showed a time and dose dependent enhancement in programmed cell death. Activation of ERβ did not lead to any significant change in cell cycle pattern. Although treatment with 30 mg/kg OSU-ERb-12 did not show any change in survival (median survival 28 days) of tumor bearing mice, a significantly improved median survival was observed for mice dosed at 100 mg/kg (median survival 45 days) in comparison to vehicle (median survival 28 days).

Conclusions: Our study demonstrates an important role of ERβ for glioma cell survival as observed by the potent biological effects of OSU-ERb-12 against glioma cell lines and immune intact murine glioma model that supports the potential for targeting the ERβ as a novel therapeutic strategy for treatment of GBM.

Citation Format: Pratibha Sharma, Jayeeta Ghose, Christopher Coss, Chad Bennett, Raju R. Raval, Vinay Puduvalli. Preclinical characterization of OSU- ERb-12, a novel ERβ agonist in Glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1867.