Malignant
brain tumors are a significant health problem in children and adults and are largely unmanageable. As a metabolic disorder involving the dysregulation of glycolysis and respiration (the Warburg effect), malignant
brain cancer can be managed through changes in metabolic environment. In contrast to malignant
brain tumors that are mostly dependent on glycolysis for energy, normal neurons and glia readily transition to
ketone bodies (
beta-hydroxybutyrate) for energy in vivo when
glucose levels are reduced. The transition from
glucose to
ketone bodies as a major energy source is an evolutionary conserved adaptation to food deprivation that permits the survival of normal cells during extreme shifts in nutritional environment. Only those cells with a flexible genome, honed through millions of years of environmental forcing and variability selection, can transition from one energy state to another. We propose a different approach to
brain cancer management that exploits the metabolic flexibility of normal cells at the expense of the genetically defective and less metabolically flexible
tumor cells. This approach to
brain cancer management is supported from recent studies in orthotopic mouse
brain tumor models and in human pediatric
astrocytoma treated with calorie restriction and the
ketogenic diet. Issues of implementation and use protocols are discussed.