Ketogenic Diet As a Metabolic Vehicle for Enhancing the Therapeutic Efficacy of Mebendazole and Devimistat in Preclinical Pediatric Glioma

Invasion of high-grade glioma (HGG) cells through the brain and spinal cord is a leading cause of cancer death in children. Despite advances in treatment, survivors often suffer from life-long adverse effects of the toxic therapies. This study investigated the influence of nutritional ketosis on the therapeutic action of mebendazole (MBZ) and devimistat (CPI-613) against the highly invasive VM-M3 glioblastoma cells in juvenile syngeneic p20-p25 mice; a preclinical model of pediatric HGG. Cerebral implantation of the VM-M3 glioblastoma cells invaded throughout the brain and the spinal column similar to that seen commonly in children with malignant glioma. The maximum therapeutic benefit of MBZ and CPI-613 on tumour invasion and mouse survival occurred only when the drugs were administered together with a ketogenic diet (KD). MBZ reduced VM-M3 tumour cell growth and invasion when evaluated under in-vitro and in-vivo conditions through inhibition of both the glutaminolysis and the glycolysis pathways.Moreover, administration of the drugs with the KD allowed a low dosing for the juvenile mice, which minimized toxicity while improving overall survival. This preclinical study in juvenile mice highlights the potential importance of a diet/drug therapeutic strategy for managing childhood brain cancer.### Competing Interest StatementThe authors have declared no competing interest.* DMSO : - dimethyl sulfoxide; PBS : – phosphate bufferered saline; PDH : – pyruvate dehydrogenase; α-KGDH : – α - ketoglutarate dehydrogenase; OxPhos : – oxidative phosphorylation; Na2EDTA : - Disodium ethylenediaminetetraacetate dihydrate; Na3PO4 : – trisodium phosphate; FBS : – fetal bovine serum.