Abstract
e13022 Background: ONC201 is a novel small molecule that inactivates MEK and Akt to induce Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL) tumor suppressor expression in a Foxo3a-dependent manner and is able to cross the blood-brain barrier. Previous studies have verified preclinical cytotoxic activity in numerous cancer models including glioma. We sought to determine activity of ONC201 against patient-derived glioma tumor initiating cell (TIC) models in vitro and in orthotopic xenograft. Methods: We tested 5 TIC lines derived using the neurosphere system from untreated (MGG4, MGG8, MGG18) and recurrent (MGG67R and MGG152) glioblastomas. Several lines are known to have variable sensitivity to secreted TRAIL, including one (MGG4) that was reported to be resistant to secreted TRAIL-mediated cell death. We performed cell viability assays using ONC201 and IC50 values were calculated. SCID mouse brains were stereotactically implanted with TICs and mice were treated with ONC201 by oral gavage fo...
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