Abstract 638: Mechanistic studies of the ketogenic diet as an adjuvant therapy for malignant gliomas

The ketogenic diet (KD) is a high-fat, low carbohydrate diet which leads to high rates of fatty acid oxidation and an increase in the production of acetyl-CoA. When the level of acetyl-CoA exceeds the capacity of the tricarboxylic acid cycle there is an increase in the production of the ketone bodies β-hydroxybutyrate (BHB) and acetoacetate (ACA) which are then used as an energy source in the brain. The utility of the KD for the treatment of epilepsy has been known for many years; however, its potential for use in other disease states is just beginning to be recognized. We and others have demonstrated that when used alone, the KD can prolong survival in intracranial mouse models of malignant glioma. We have also shown that there is a statistically significant increase in the survival of animals fed KD and treated with radiation or temozolomide versus those receiving the same treatment but maintained on a standard diet (SD). The addition of the gene encoding luciferase to our mouse glioma cells allowed us to follow tumor growth using non-invasive in vivo imaging. We showed that tumors grow slower in mice fed KD versus SD. Additional in vivo analyses of tumors and surrounding brain using dihydroethidium demonstrated the presence of increased reactive oxygen species (ROS) in mice maintained on SD, and an overall reduction in ROS in the tumors from animals fed KD. Despite this, the KD potentiates the anti-tumor activity of radiation. Whether the KD actually blocks the increase in ROS that occurs immediately following radiation treatment is under investigation. To further identify mechanisms that contribute to the enhanced survival seen in tumor bearing animals fed KD, total RNA was isolated from tumors and contralateral normal brain of animals fed either ketogenic or standard diets and gene expression profiling analysis using the Affymetrix GeneChip® Mouse Genome 430 2.0 array was done. Despite reports suggesting that tumor inhibition was due to nutrient deprivation in the tumor, genes involved in autophagy were not uniformly up regulated in the tumor versus the normal brain of animals fed a KD. A 2-way ANOVA for interaction showed that the KD drives overall gene expression back toward non-tumor SD conditions, and further analyses suggest this may be due, in part, to genes involved in oncogenic signaling pathways. An analysis of tumor tissue from animals fed a KD versus those fed SD showed the down regulation of genes involved in the insulin-like growth factor 1 (IGF-1), platelet-derived growth factor (PDGF) and epidermal growth factor receptor (EGFR) signaling pathways. Furthermore, many of the genes involved in glycolysis are up regulated in tumors from animals fed KD versus those fed SD. These data suggest that when used alone, the KD may inhibit tumor growth by down-regulating growth factor pathways. Gene expression profiling analyses of tissue from animals treated with the KD in addition to radiation and temozolomide are underway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 638.