The ketogenic diet as an adjuvant therapy for brain tumors and other cancers

Abstract

Altered metabolism was first identified in cancer cells by Otto Warburg, who identified a higher reliance on anaerobic glycolysis rather than cellular respiration even in the presence of sufficient oxygen levels, a phenomenon called the Warburg Effect. Deregulated metabolism is now considered a driving hallmark of cancer and an attractive therapeutic target. While a great deal of work is being done to find genetic therapeutic targets that can be used for personalized medicine, current targeted approaches are typically ineffective because tumors are heterogeneous and contain multiple genetic subpopulations. This often precludes a particular targeted molecule from being found on all cells. In contrast to many genetic alterations, dysregulation of metabolism resulting in the need for high amounts of glucose is found in virtually all cancer cells. Targeting metabolism by reducing blood glucose may be a way to inhibit tumor growth since this, to a large extent, should circumvent the inherent problems associated with tumor heterogeneity. Methods that also provide an energy source for normal tissues such as ketones should reduce side effects associated with an overall reduction in blood glucose. The high-fat, low carbohydrate, and protein ketogenic diet (KD) results in reduced blood glucose and increased blood ketones, as does caloric restriction and fasting. In preclinical mouse models of malignant brain tumors, animals fed a KD had increased survival, particularly when used in combination with radiation or chemotherapy. Metabolic modulation through the use of a KD, caloric restriction, or fasting has been found to change the expression of a number of genes and pathways thought to inhibit tumor growth. Metabolic therapy has also recently been explored in other cancer types. In this chapter, we will examine the mechanisms underlying the KD which suggests its potential as an adjuvant therapy for cancer treatment.