Abstract 4441: The ketogenic diet potentiates radiation therapy in a mouse model of glioma: effects on inflammatory pathways and reactive oxygen species.

Patients with malignant brain tumors have a median survival of approximately one year following diagnosis, regardless of currently available treatments which include surgery, radiation and chemotherapy. Although there have been advances in the development of novel treatments, targeted therapies face the challenge of overcoming phenotypic variability resulting from tumor heterogeneity. One phenotypic trait shared by virtually all cancer cells is dysregulation of metabolism. It has therefore been postulated that one approach to treating brain tumors may be through metabolic alteration such as that which occurs through the use of the ketogenic diet (KD). The KD is high-fat, low-carbohydrate diet that has been utilized for the non-pharmacologic treatment of refractory epilepsy. We and others have shown that this diet enhances survival in mouse models of malignant gliomas. Further, radiation in combination with KD was synergistic, and survival was significantly increased over radiation treatment alone. To gain an understanding of the mechanism(s) by which the KD exerts anti-tumor effects and enhances the efficacy of radiation therapy we performed gene expression profiling analyses on tumor tissue and non-tumor containing brain using the Affymetrix GeneChip® Mouse Genome 430 2.0 array. To identify changes in gene expression representing chronic effects of KD and radiation plus KD we harvested tissue when the animals became symptomatic. We previously reported that tissue from animals maintained on the KD in the absence of radiation treatment showed a reduction in reactive oxygen species (ROS) and cyclooxygenase-2 (COX-2) expression compared to those maintained on a standard diet (Stafford et al, Nutr and Metab (7):74, 2010). We now report that peritumoral edema is significantly reduced early in tumor progression in animals fed the KD when compared to those fed a standard rodent diet. Furthermore, gene expression profiling of animals treated with radiation and KD demonstrated alterations in the chronic expression of crucial genes involved in radiation-induced inflammation including COX-2 and the nuclear transcription factor NF-кB, both of which are implicated in radioresistance. We are repeating these studies using tissues harvested shortly after radiation therapy to identify genes acutely affected by radiation therapy in animals fed a KD. Taken together, our data to date suggests that the KD may be interfering with the radiation-induced inflammatory signaling network implicated in tumor progression. A greater understanding of the effects of the ketogenic diet as an adjuvant therapy will allow for a more rational approach to its clinical use. Citation Format: Eric C. Woolf, Phillip Stafford, Mohammed G. Abdelwahab, Kathryn Fenton, Mark C. Preul, Adrienne C. Scheck. The ketogenic diet potentiates radiation therapy in a mouse model of glioma: effects on inflammatory pathways and reactive oxygen species. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4441. doi:10.1158/1538-7445.AM2013-4441