The ketogenic diet is not effective in preclinical models of IDH1 wild-type and IDH1 mutant glioma

Abstract

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 (IDH1mut). This mutation disrupts cellular biochemistry, and IDH1mut gliomas are generally less aggressive than IDH1 wild-type (IDH1wt) 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 IDH1mut gliomas might be more sensitive to KD. The aim of the current study was to compare the effects of KD in preclinical models of IDH1wt versus IDH1mut gliomas. In vitro, simulating KD by treatment with the ketone body {beta}-hydroxybutyrate had no effect on the proliferation of patient-derived IDH1wt or IDH1mut glioma cells. Likewise, KD had no effect on the in vivo growth of these patient-derived gliomas. Furthermore, mice engrafted with Sleeping-Beauty transposase-engineered IDH1wt and IDH1mut glioma showed no difference in survival while on KD. These data suggest that IDH1mut gliomas are not more responsive to KD, and that clinical trials further exploring KD in this subset of glioma patients may not be warranted.