Abstract 3217: Mechanistic analysis of the ketogenic diet versus KetoCal® as adjuvant treatments for malignant glioma

Abstract

Abstract Patients with malignant brain tumors have a median survival of approximately one year following diagnosis, regardless of currently available treatments which include surgery followed by radiation and chemotherapy. Improvement in the survival of brain cancer patients requires the design of new therapeutic modalities that take advantage of common phenotypes. One such phenotype is the metabolic dysregulation that is a hallmark of cancer cells. It has therefore been postulated that one approach to treating brain tumors may be by 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. There are varying formulations of the diet that alter the ratio of fats to carbohydrates & protein, and it is not clear whether any one is more effective than another. Bio-Serv F3666 (Frenchtown, NJ) is a rodent KD with a 6:1 ratio of fat:carbohydrate & protein. We have previously shown that ad libitum feeding of this diet significantly increased survival in albino C57BL/6 mice (NCI, Frederick, MD) stereotactically implanted with GL261-luc2 cells, a syngeneic bioluminescent mouse model of malignant glioma. Radiation in combination with KD was synergistic, and survival was significantly increased over either treatment alone. Ad libitum feeding of KetoCal® (KC; Nutricia North America, Gaithersburg, MD); a nutritionally complete, commercially available 4:1 (fat: carbohydrate & protein) ketogenic formula used for the treatment of pediatric epilepsy, also resulted in a significant increase in survival. However, the combination of radiation with KetoCal® caused the tumors to completely regress in 9 of 11 mice, and the tumors did not recur when these animals were switched back to standard rodent chow. The mechanism(s) by which the KD and KC exert their anti-tumor effects are not completely understood. We have begun to compare these 2 formulations to identify their anti-tumor effects. Animals on KC showed a more pronounced drop in blood glucose than those maintained on KD. Blood levels of α-hydroxybutyrate were significantly higher in animals fed KC than those in animals fed KD. Total AKT was reduced in tumor tissue from animals fed KC, but not in animals fed KD; however, phospho-AKT(Thr308) was reduced in tumor and non-tumor tissue from animals maintained on KD, but not those maintained on KC. Furthermore, tumor tissue from animals fed KD had a more pronounced decrease in insulin growth factor-1 than did tumor tissue from animals fed KC. These data suggest that the mechanisms leading to increased survival may be different in animals fed KC versus those fed KD. A greater understanding of the effects of different ketogenic formulations will allow for a more rational approach to its clinical use. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3217. doi:1538-7445.AM2012-3217