Ketogenic diet as a metabolic vehicle enhancing the therapeutic efficacy of mebendazole and devimistat in juvenile syngeneic high-grade glioma.

Invasive pediatric high-grade gliomas (HGGs) are associated with poor clinical outcomes, and current therapies often cause significant long-term toxicities. This study investigates the influence of nutritional ketosis on the therapeutic efficacy of mebendazole (MBZ) and devimistat (CPI-613) in invasive VM-M3 and non-invasive CT-2A glioblastoma models in juvenile syngeneic mice. Both drugs were also evaluated in the human pediatric glioma cell line SF-188. Mesenchymal-origin VM-M3 tumors exhibited extensive invasion throughout the brain and spinal cord, whereas neural stem cell-derived CT-2A and VM-NM1 tumors did not show distal spread. The greatest reductions in tumor invasion and progression, together with prolonged survival, occurred when drug treatment was combined with a ketogenic diet (KD). MBZ inhibited glycolysis and glutaminolysis in VM-M3 cells and reduced proliferation and viability of SF-188 cells. KD-enabled combination therapy allowed lower drug dosing, reduced toxicity, and improved survival, supporting further investigation of metabolically informed diet-drug strategies for pediatric gliomas.