DIPG-13. TARGETING HYPOXIA AND MITOCHONDRIA WITH REPURPOSED METABOLIC DRUGS AS AN APPROACH TO RADIOSENSITIZATION FOR DIFFUSE INTRINSIC PONTINE GLIOMAS (DIPG)

DIPG is the leading cause of brain tumor-related death in children. Currently, radiation is the only treatment that offers transient benefit. Compared to normal brain tissue, DIPGs are hypoperfused with tumors being exposed to hypoxia, a potent barrier to effective radiotherapy. Biguanides are hypoglycemic agents that can reduce the oxygen consumption rate (OCR) in mitochondria, thereby reducing hypoxia. Our previous study has shown that metformin significantly improves the radiosensitivity of DIPG and extends survival in a patient-derived xenograft (PDX) model. In the present study, phenformin, a second biguanide derivative, demonstrated even greater anti-DIPG activity and radiosensitising effect in vitro. As a single agent, phenformin dose-dependently inhibited OCR and increased extracellular acidification rate (ECAR). Low-dose phenformin reduced mitoATP/glycoATP ratio, whereas high doses significantly suppressed net ATP production. To attenuate the phenformin-induced ECAR, phenformin was combined with dichloroacetate (DCA), a clinically relevant pyruvate dehydrogenase kinase inhibitor that can suppress the elevated glycolytic rate of cancers. This combination significantly blocked the phenformin-induced ECAR and killed DIPG cells synergistically by inducing apoptosis, DNA damage and metabolic catastrophe. Moreover, protein expression of HIF-1α and c-Myc, two master regulators that collaboratively enhance the metabolic capacity of tumor cells through increased glycolysis thereby contributing to radioresistance, were also suppressed by phenformin-DCA treatment in vitro. This combination therapy upregulated genes inhibiting cell proliferation while downregulating genes for DNA repair. The triple combination of phenformin, DCA and irradiation demonstrated the most potent efficacy in vitro and is currently being tested in our PDX cohort in vivo.