The efficacy of an unrestricted cycling ketogenic diet in preclinical models of IDH wild-type and IDH mutant glioma

Infiltrative gliomas are the most common neoplasms arising in the brain, and remain largely incurable despite decades of research. A subset of these gliomas contains mutations in isocitrate dehydrogenase 1 (IDH1(mut)) or, less commonly, IDH2 (together called “IDH(mut)”). These mutations alter cellular biochemistry, and IDH(mut) gliomas are generally less aggressive than IDH wild-type (IDH(wt)) gliomas. Some preclinical studies and clinical trials have suggested that various forms of a ketogenic diet (KD), characterized by low-carbohydrate and high-fat content, may be beneficial in slowing glioma progression. However, adherence to a strict KD is difficult, and not all studies have shown promising results. Furthermore, no study has yet addressed whether IDH(mut) gliomas might be more sensitive to KD. The aim of the current study was to compare the effects of a unrestricted, cycling KD (weekly alternating between KD and standard diet) in preclinical models of IDH(wt) versus IDH(mut) gliomas. In vitro, simulating KD by treatment with the ketone body β-hydroxybutyrate had no effect on the proliferation of patient-derived IDH(wt) or IDH(mut) glioma cells, either in low or normal glucose conditions. Likewise, an unrestricted, cycling KD had no effect on the in vivo growth of patient-derived IDH(wt) or IDH(mut) gliomas, even though the cycling KD did result in persistently elevated circulating ketones. Furthermore, this KD conferred no survival benefit in mice engrafted with Sleeping-Beauty transposase-engineered IDH(mut) or IDH(wt) glioma. These data suggest that neither IDH(wt) nor IDH(mut) gliomas are particularly responsive to an unrestricted, cycling form of KD.