Ketogenic diet as a metabolic vehicle for enhancing the therapeutic efficacy of mebendazole and devimistat in preclinical high-grade gliomas grown in juvenile mice

Abstract

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 lifelong adverse effects of the current toxic therapies used for management. 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 and non-invasive CT-2A glioblastoma cells grown orthotopically in juvenile syngeneic mice. Additionally, both drugs were tested in the human pediatric GBM cell line SF-188. DON (6-Diazo-5-oxo-L-norleucine) was used as a positive drug control for glutamine targeting. Cerebral implantation of the VM-M3 cells, which are mesenchymal origin, invaded throughout the brain and the spinal column similar to that seen in children with HGG. Neither the CT-2A nor the VM-NM1 glioblastoma stem cell tumors showed distal invasion in syngeneic juvenile mouse brains. The maximum therapeutic benefit of MBZ and CPI-613 on tumor invasion, growth, and mouse survival occurred only when the drugs were administered together with a ketogenic diet (KD). MBZ treatment inhibited both the glutaminolysis and the glycolysis pathways in VM-M3 cells grown either in vivo or in vitro. Both MBZ and CPI-613 significantly reduced the in vitro growth and viability of the SF-188 cells. Moreover, drug administration together with the KD allowed for lower dosing thus minimizing toxicity while improving overall survival of the mice. This preclinical study in two different HGGs, grown in syngeneic juvenile mice, highlights the potential importance of diet/drug therapeutic strategies for managing childhood brain cancer.