Targeting the Warburg effect for cancer treatment: Ketogenic diets for management of glioma

Abstract

Gliomas are a highly heterogeneous tumor, refractory to treatment and the most frequently diagnosed primary brain tumor. Although the current WHO grading system (2016) demonstrates promise towards identifying novel treatment modalities and better prediction of prognosis over time, to date, existing targeted and mono therapy approaches have failed to elicit a robust impact on disease progression and patient survival. It is possible that tumor heterogeneity as well as specifically targeted agents fail because redundant molecular pathways in the tumor make it refractory to such approaches. Additionally, the underlying metabolic pathology, which is significantly altered during neoplastic transformation and tumor progression, is unaccounted for. With several molecular and metabolic pathways implicated in the carcinogenesis of CNS tumors, including glioma, we postulate that a systemic, broad spectrum approach to produce robust targeting of relevant and multiple molecular and metabolic regulation of growth and survival pathways, critical to the modulation of hallmarks of carcinogenesis, without clinically limiting toxicity, may provide a more sustained impact on clinical outcomes compared to the modalities of treatment evaluated to date. The objective of this review is to examine the emerging hallmark of reprogramming energy metabolism of the tumor cells and the tumor microenvironment during carcinogenesis, and to provide a rationale for exploiting this hallmark and its biological capabilities as a target for secondary chemoprevention and treatment of glioma. This review will primarily focus on interventions to induce ketosis to target the glycolytic phenotype of many cancers, with specific application to secondary chemoprevention of low grade glioma- to halt the progression of lower grade tumors to more aggressive subtypes, as evidenced by reduction in validated intermediate endpoints of disease progression including clinical symptoms.

Ketogenic Diets for Adult Neurological Disorders

“…In rodent glioma models, KDs decrease serum glucose, serum insulin-like growth factor and tumor weight when administered as a stand-alone therapy. When administered in combination with glycolytic inhibitor 2-deoxy-D-glucose (2-DG), radiation therapy, or temozolomide, the diet also reduced peritumoral edema and tumor microvasculature and increased median survival time [37][38][39][40][41][42]. Thus, KDs favor a metabolic shift in malignant cells towards an anti-angiogenic, anti-invasive, pro-apoptotic, and antiinflammatory state that contributes to suppressed tumor growth in vivo [43].…”

“…Potential mechanisms include enhanced cytotoxic T cell anti-tumor immunity [44], attenuated insulinactivated Akt/mTOR and Ras/MAPK signaling pathways [45,46], and reduced inflammation as previously described. Other proposed mechanisms include the induction of genes involved in oxidative stress protection, angiogenesis, and vascular remodeling [29,39,42].…”

Association Between Pretreatment Serum Apolipoprotein A1 and Prognosis of Solid Tumors in Chinese Population: A Systematic Review and Meta-Analysis

“…A shift towards aerobic glycolysis with high glucose uptake even under sufficient oxygen is one of the most prominent characteristic of metabolic alterations in cancer. This phenomenon is called the “Warburg effect” [3]. Glucose was once considered as the major fuel, if not the only factor, that support tumor growth [4].…”

The Expanding Role of Ketogenic Diets in Adult Neurological Disorders

“…In the GL-261 malignant glioma model, KD fed mice had reduced peritumoral edema and tumor microvasculature, 20–30% increased median survival time and achieved complete and long-term remission when used concomitantly with radiation therapy [81,82,83]. A similar synergistic effect was observed between KD and temozolomide in the GL-261 model [84]. Comparable effects of KDs on tumor growth and survival time have also been shown in glioma derived mouse models of metastatic cancer and in patient-derived GBM subcutaneous and orthotopic implantation models [85,86].…”