HG-04: DICHLOROACETATE AND METFORMIN COMBINE TO MODULATE GLUCOSE METABOLISM AND POTENTLY SENSITISE DIPG CELLS TO RADIATION THERAPY

Diffuse intrinsic pontine glioma (DIPG) is the leading cause of brain tumor-related death in children and radiotherapy (RT) is the only form of treatment that offers a transient benefit. It is well established that derangements in glucose metabolism of cancer cells can lead to radio-resistance. Dichloroacetate (DCA), currently being used to treat lactic acidosis, can modify tumor metabolism by forcing glycolytic tumor cells into oxidative phosphorylation. DCA alone demonstrated profound anti-proliferative effects in a panel of DIPG cells but had little effect on non-cancerous cells. Additionally, DCA-treated DIPG cells were more sensitive to irradiation with synergistic inhibition of clonogenicity induced by DCA / RT combination compared to RT alone. Subsequent cell-cycle analysis demonstrated that DCA sensitised DIPG cells by inducing cell-cycle arrest at G2/M phase, the most radiosensitive cell-cycle phase. Strikingly, the anti-tumor effect of DCA was significantly enhanced by the addition of metformin, a widely used anti-diabetic agent with anti-cancer activity. Specifically, the combination of DCA and metformin synergistically elevated oxidative stress in DIPG cells, which in turn induced proliferation arrest, mitochondrial depolarisation and apoptosis. Importantly, the radiosensitising effect of DCA was further enhanced when metformin was combined, with the triple combination leading to increased clonogenic inhibition. Taken together, this study provides the proof of concept that DCA can effectively sensitise DIPG cells to RT and this radiosensitising effect was further enhanced by combination with metformin. These findings are currently being evaluated with testing of the combination of DCA, metformin and RT in vivo using a DIPG orthotopic model.