DIPG-02. A NOVEL STRATEGY TO RADIOSENSITISE DIFFUSE MIDLINE GLIOMAS VIA DUAL-TARGETING OF GLUCOSE METABOLISM

Abstract Diffuse Midline Gliomas (DMG) is the leading cause of brain tumor-related death in children. Currently, radiation is the only treatment that offers transient benefit but almost all DMG relapse due to radioresistance. Compared to normal brain tissue, DMG are hypo-perfused with tumor cells being exposed to hypoxia, a low oxygen microenvironment serves as a potent barrier to effective radiotherapy. Biguanides are hypoglycemic agents that can reduce the oxygen consumption rate (OCR) in mitochondria, thereby sparing more oxygen and alleviating hypoxia. Our previous study has shown that metformin significantly improves the radiosensitivity of DMG and extends survival in a patient-derived xenograft (PDX) model. In comparison with metformin, phenformin demonstrated greater efficacies in anti-proliferation, OCR and hypoxia inhibition, and radiosensitization in a panel of DMG cultures. These effects were possibly induced by phenformin through inhibition of mitochondrial complex I in DMG cells. The anti-tumor effect of phenformin was further enhanced by combining a second drug dichloroacetate that simultaneously attenuated phenformin-induced acidification. Specifically, the combination treatment induced higher levels of reactive oxygen species and DNA damage, which subsequently resulted in a much stronger effect in cell-cycle and proliferation arrest, apoptosis, and hypoxia inhibition. Metabolically, the co-treatment simultaneously targeted multiple pathways, which significantly reduced ATP production and further triggered metabolic catastrophe. RNA sequencing demonstrated significant alterations induced by the combination in cell-cycle, DNA repair, unfolded protein response and alternative energetic pathways. Furthermore, the combination treatment significantly improved the radiosensitivity of DMG cells, evidenced by higher levels of DNA damage, apoptosis, and clonogenic inhibition. Our preliminary in vivo data demonstrated a possible reduction in tumor burden following 4 weeks of combination treatment, with no elevation of serum L-lactate level in phenformin-treated groups. This therapeutic efficacy is currently being validated in multiple orthotopic DMG models with optimized treatment schedules.