The efficacy of an unrestricted cycling ketogenic diet in preclinical models of IDH wild-type and IDH 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) or, less commonly, IDH2 (together called “IDHmut”). These mutations alter cellular biochemistry, and IDHmut gliomas are generally less aggressive than IDH wild-type (IDHwt) 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 IDHmut 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 IDHwt versus IDHmut gliomas. In vitro, simulating KD by treatment with the ketone body β-hydroxybutyrate had no effect on the proliferation of patient-derived IDHwt or IDHmut 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 IDHwt or IDHmut 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 IDHmut or IDHwt glioma. These data suggest that neither IDHwt nor IDHmut gliomas are particularly responsive to an unrestricted, cycling form of KD.

Anti-tumor effects of ketogenic diets and their synergism with other treatments in mice: Bayesian evidence synthesis of 1755 individual mouse survival data

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The Effect of Ketogenic Metabolic Therapy on Recurrent High-Grade Gliomas: Case Series

“…Several clinically relevant molecular markers that assist in diagnosis and prognosis have recently been identified for high-grade gliomas. Knowing the current changes in the classification of high-grade gliomas, it is important to note that all those observed impacts were positive, regardless of the IDH mutation [30,31]. However, it is still unclear whether the MGMT status could have an impact on the results obtained with the use of KMT.…”

Ketogenic Diet in the Treatment of Gliomas and Glioblastomas

“…In recent years, the mutation of isocitrate dehydrogenase, an enzyme that is part of the Krebs cycle and frequently mutated in gliomas, has been studied in particular. From the studies, there seems to be no difference in the use of KD on wild-type and IDH mutated IDH gliomas [68].…”