Abstract 1701: Estrogen receptor beta agonists as anti-tumor and immune-modulatory agents in malignant glioma

Abstract

Abstract High grade, or malignant gliomas are Grade III and IV primary brain tumors that are among the most treatment-resistant human cancers. They have the worst prognosis of any central nervous system malignancy with a median survival of only 14 months and a 5-year survival rate of less than 5%. The standard-of-care (SOC) for high-grade glioma has remained unchanged for over a decade and more than half of newly diagnosed patients do not see any therapeutic benefit with existing regimens. Targeted immunotherapies have not improved the prognosis for glioma patients due to tumor-mediated mechanisms of immune evasion and suppression. Estrogen, or 17β- estradiol (E2), is a sex steroid hormone that inhibits development of gliomas in animal models and mediates its effects via Estrogen Receptor alpha (ERα), beta (ERβ), and the G-protein Coupled Estrogen Receptor (GPER). Early studies indicated that exogenous administration of estrogen mediates protection against glioma development in animal models, but estrogen therapy has adverse side effects due to non-specific targeting of Estrogen Receptors (ER) (α and β). In contrast to ERα, ERβ is a tumor-suppressor in gliomas, with lower expression correlating to increased tumor aggressiveness and worse prognosis. Thus, we have developed a novel, potent, and selective ERβ agonist, ent-28, and our data demonstrate its anti-glioma functions in patient cell lines in vitro, patient-derived xenografts, and orthotopic syngeneic models in vivo. While the more selective ERβ agonists have 200 to 1000-fold selectivity for ERβ, ent-28 has a 9000-fold beta-selectivity. Thus, the specificity of ent-28 for ERβ over ERα will allow us to minimize side-effects of non-selective ER-targeted therapy and maximize therapeutic benefit. ERβ agonists also have anti-inflammatory effects through inhibiting NF-κB activity and decreasing subsequent inflammatory cytokine secretion. Our preliminary gene set analyses indicate that immune signaling pathways are highly enriched in ent-28-treated patient cells compared to vehicle control, suggesting that ent-28 has immune-modulatory effects. To further elucidate the extrinsic effects of ERβ agonism on the tumor microenvironment (TME), we have assessed infiltration of immune subsets between ent-28 and vehicle-treated syngeneic tumor-bearing mice using immunohistochemistry (IHC). Here, we have demonstrated that ERβ agonists have anti-tumor activity in animal models of glioma and modulate the brain TME. Lack of immune infiltration and suppression within the glioma TME are a major barrier to immunotherapy responsiveness; thus, ERβ-mediated immune modulation may sensitize patients to immune-based therapies. Citation Format: Jordan Fredriksen Isaacs, Divya Ravi, Carmen L. del Genio, Zachary A. Shalit, Glenn C. Micalizio, Arti B. Gaur. Estrogen receptor beta agonists as anti-tumor and immune-modulatory agents in malignant glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1701.