The efficacy of a 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 ) 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 a ketogenic diet (KD), characterized by low-carbohydrate and high-fat content, may be beneficial in slowing glioma progression. However, not all studies have shown promising results, and to date, no study has addressed whether IDH mut gliomas might be more sensitive to KD. The aim of the current study was to compare the effects of KD 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. Likewise, a cycling KD, wherein mice alternated between KD and a standard diet (SD), 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, KD conferred no survival benefit in mice engrafted with Sleeping-Beauty transposase-engineered IDH mut glioma. These data suggest that neither IDH wt nor IDH mut gliomas are particularly responsive to KD.