M011L-deficient oncolytic myxoma virus to induce apoptosis in brain tumor initiating cells and to enhance survival in a novel immunocompetent mouse model of glioblastoma.

Abstract

e13521Background: Myxoma virus (MYXV) is a promising oncolytic agent, highly effective against immortalized glioma cells but less effective against brain tumor initiating cells (BTICs), which are believed to mediate glioma development/recurrence. MYXV encodes various proteins to attenuate host cell apoptosis, including an anti-apoptotic Bcl-2 homologue known as M011L. Such proteins may limit the ability of MYXV to kill BTICs, which have heightened resistance to apoptosis. We hypothesized that infecting BTICs with an M011L-deficient MYXV construct would overcome BTIC resistance to MYXV. Methods: We used patient-derived BTICs to evaluate the efficacy of M011L knock-out virus (vMyx-M011L-KO) versus wild type MYXV (vMyx-WT) and characterized the mechanism of virally-induced cell death in vitro. To extend our findingsin a novel immunocompetent animal model, we derived, cultured, and characterized a C57Bl/6J murine BTIC (mBTIC0309) from a spontaneous murine glioma and evaluated vMyx-M011L-KO efficacy with and w...