Glycemic modulation in neuro-oncology: experience and future directions using a modified Atkins diet for high-grade brain tumors

Abstract

Dietary glycemic modulation through high-fat, low-carbohydrate diets, which induce a state of systemic ketosis and alter systemic metabolic signaling, have been incorporated into the clinical management of patients with neurological disease for more than a century. Mounting preclinical evidence supports the antitumor, proapoptotic, and antiangiogenic effects of disrupting glycolytic metabolism through dietary intervention. In recent years, interest in incorporating such novel therapeutic strategies in neuro-oncology has increased. To date, 3 published studies incorporating novel dietary therapies in oncology have been reported, including one phase I study in neuro-oncology, and have set the stage for further study in this field. In this article, we review the biochemical pathways, preclinical data, and early clinical translation of dietary interventions that modulate systemic glycolytic metabolism in the management of primary malignant brain tumors. We introduce the modified Atkins diet (MAD), a novel dietary alternative to the classic ketogenic diet, and discuss the critical issues facing future study.

Keywords: cancer metabolism; glioma; ketogenic diet; modified Atkins diet; seizure.

Figures

Fig. 1.

Molecular mechanisms underlying the oncogenic metabolic phenotype. Oncogenic pathway alterations driving the Warburg effect involve (i) activation of the PI3 K/Akt/mTOR pathway driving a glycolytic state (light green arrows); (ii) pyruvate kinase induced negative regulation of glycolysis, which provides glycolytic intermediates necessary to facilitate macromolecular biosynthesis (orange arrows); and (iii) shunting of glucose through the pentose phosphate pathway to build redox potential (dark green arrows). In the first of these major metabolic alterations (light green arrows), PI3 K activates Akt, which stimulates aerobic glycolysis and enhances transcription factor expression including hypoxia-inducible factor 1 (HIF1) through the action of the mammalian target of rapamycin (mTOR). Expression of transcription factors including HIF1 and Oct 1 further drives a proglycolytic state by enhancing the activity of mitochondrial pyruvate dehydrogenase kinases, which shunt pyruvate back towards glycolysis and away from mitochondrial oxidative phosphorylation. In the second of these major metabolic alterations (orange arrows), C-myc-induced expression of cytosolic dimeric pyruvate kinase M2 functionally negatively regulates glycolysis, shunting free carbons back toward macromolecular biosynthesis, which supports cell proliferation. In the third major metabolic alteration, PKM2-mediated regulation of glycolysis also shunts glycolytic intermediates toward alternative carbon-consuming pathways (dark green arrows) including the pentose phosphate and hexosamine pathways, which generate reducing power in the form of NADPH. C–myc-driven conversion of glutamate to glutathione (GSH) and isocitrate dehydrogenase (IDH) mediated conversion of isocitrate to alpha-ketoglutarate (dark green arrows) also resulting in additional reducing power in the form of NADPH and GSH necessary to scavenge excess reactive oxygen species generation. Abbreviations: αKG, alpha-ketoglutarate; 2-HG, 2-hydroxyglutarate; AMPK, AMP-activated protein kinase; CHO, carbohydrate; EGFR, epidermal growth factor receptor; G6P, glucose-6-phosphate; GLUT, glucose transporter; GSH, glutathione; HIF, hypoxia-inducible factor; IDH, isocitrate dehydrogenase; IDH-mu, IDH-mutant; IGF-R1, insulin-like growth factor-1 receptor; MCT, monocarboxylic acid transporter; mTOR, mammalian target of rapamycin; NADPH, nicotinamide adenine dinucleotide phosphate; Oct 1, Octamer transcription factor 1; PI3 K, phosphoinositide 3-kinase; P53, tumor protein 53; PDGFR, platelet-derived growth factor receptor; PDH, pyruvate dehydrogenase; PDK, pyruvate dehydrogenase kinase; PEP, phosphoenolpyruvic acid; PKB, protein kinase B, also known as Akt; PKM2, pyruvate kinase-M2 isoenzyme; PPP, pentose phosphate pathway; PTEN, phosphatase and tensin homolog; RTK, receptor tyrosine kinase; TCA, tricarboxylic acid.