Establishing Genetic and Molecular Markers of Sensitivity to a Novel and Potent Tetracyclic Terpenoid Therapy Against High-Grade Gliomas

INTRODUCTION: High-grade gliomas have the worst prognosis of all intracranial tumors, and therapeutic options are very limited. We have previously described a novel, highly selective and potent agonist of ERβ called ent-28 that inhibits the proliferation of patient-derived glioma cells in vitro. In addition, ent-28 significantly decreases the sizes of orthotopically implanted high-grade glioma patient-derived xenografts and induces apoptosis of tumor-derived cells with varying sensitivity. METHODS: ent-28 induced cell death of patient-derived tumor adherent- and stem-cells was analyzed in combination with the histopathologic, molecular, and genetic characteristics of each primary resected tumor for respective cell lines. GI50 values and apoptotic death induced by ent-28 were compared to IDH1 and ATRX mutational status as well as MGMT methylation. RESULTS: Compared to both untreated and control groups, ent-28-treated tumor-derived MGMT unmethylated cells demonstrated sensitivity. Additionally, tumor adherent cells underwent apoptosis at a higher rate compared to tumor stem cells. CONCLUSIONS: We have completed pre-clinical testing, safety, pharmacokinetics, metabolic stability, in vivo efficacy, and species rationalization for developing a novel compound, ent-28, as an anti-glioma therapy. To further enhance the efficacy of ent-28 against high-grade gliomas, we have used histopathologic characteristics of resected primary tumors to identify specific molecular and genetic markers that correlate to drug-sensitivity. Our findings suggest that specific molecular markers of sensitivity to ent-28 can be used to stratify response in patient derived cells, target tumor stem cells specifically, and further support the development of a potent therapy against high-grade gliomas.