Abstract 1177: Ketogenic diet sensitizes FaDu human head and neck cancer xenografts to cisplatin as well as ionizing radiation combined with cetuximab

Purpose: Ketogenic diets (KDs) used in the treatment of epilepsy are high fat, low carbohydrate diets that force cells to utilize fatty acid oxidation for mitochondrial energy metabolism. KDs have been suggested to sensitize tumors to standard radio-chemotherapy because cancer cells, relative to normal cells, produce more reactive oxygen species from mitochondrial metabolism and increased cancer cell glucose metabolism is thought to provide reducing equivalents to compensate for the metabolic production of hydroperoxides (PMID: 23743570). The current study was designed to determine if the improved KetoCal® formula that includes more polyunsaturated fatty acids was efficacious in sensitizing human head and neck cancer xenografts to standard radio-chemotherapies. Experimental Design: Mice bearing FaDu human head and neck cancer xenografts were assigned to either standard mouse chow or new KetoCal® KD and treated with cetuximab (6 mg/kg i.p. 2 times per week for 2 weeks), cisplatin (2 mg/kg 2 i.p. times per week for 2 weeks), and/or IR (6 Gy x 2 dose followed by 1.8 Gy x 2 doses). In similar experiments mice were fed either standard chow or the new KetoCal® formula and treated with IR (6 Gy 2 times a week for 2 weeks, and then 1.8 Gy 3 times a week indefinitely) and cetuximab (6 mg/kg cetuximab 2 times a week indefinitely). In parallel, tumors were harvested from treated animals and blood samples were collected from head and neck cancer patients treated with standard of care radio-chemotherapy and the new KetoCal® KD. Blood samples were used to confirm ketosis as well as using tumors and blood to measure markers of redox homeostasis (protein carbonyls, GSH/GSSG, and 4HNE-modified proteins). Results: Mice tolerated all treatments as indicated by no change in general health status as assessed by body condition scoring. Mice treated with new KetoCal® + cisplatin demonstrated increased survival relative to cisplatin alone. Furthermore, mice treated with new KetoCal® + IR + cetuximab showed a significant decrease in tumor growth rate and survival, relative to any other group. Western blot analysis of tumor homogenates demonstrated increased phosphorylated epidermal growth factor in mice fed a KD which was suppressed with the addition of cetuximab as well as increased 4HNE modified proteins. Preliminary results from human studies indicated ketosis was achieved without serious adverse event. Furthermore, patients on KD demonstrate an increase in carbonyl content and a decrease in both GSH and GSSG. Conclusions: KD remains an attractive adjunct therapy for cancer patients, especially for head and neck cancer patients due to their feeding status. The mice xenograft studies support the hypothesis that the new KetoCal® diet combined with standard of care treatments for head and neck cancer has the potential to improve clinical outcomes. Note: This abstract was not presented at the meeting. Citation Format: Daniel C. Ma, Samuel N. Rodman, John M. Buatti, Carryn Anderson, Bryan G. Allen, Douglas R. Spitz, Melissa A. Fath. Ketogenic diet sensitizes FaDu human head and neck cancer xenografts to cisplatin as well as ionizing radiation combined with cetuximab. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1177. doi:10.1158/1538-7445.AM2015-1177