High-Fat Diet May Enhance Cancer Patients’ Response to Treatments

Division of Cancer Treatment and Diagnosis

The goal of cancer treatments such as chemotherapy and radiation is to kill cancer cells while minimizing damage to healthy cells and tissues. A growing number of researchers are studying cancer cell metabolism – that is, the chemical processes in the cell that convert or use energy – as an avenue to developing new cancer treatments. They hope to selectively kill cancer cells by taking advantage of fundamental metabolic differences between cancer cells and normal cells.

With support from NCI*, Douglas Spitz, Ph.D., professor and director of the Free Radical and Radiation Biology Program at the Holden Comprehensive Cancer Center at the University of Iowa, along with his colleagues Daniel Berg, M.D. and John Buatti, M.D., hope to use a special diet to exploit metabolic differences between cancer cells and normal cells to enhance cancer patients’ responses to combined chemotherapy and radiation therapy (chemo-radio-therapy).

“Radiation is believed to kill cancer cells by causing the formation of free radicals in tumor tissue, inducing a condition known as oxidative stress that can be enhanced by chemotherapy to achieve better treatment responses,” Dr. Spitz noted. Oxidative stress occurs when the balance between cellular anti-oxidants and pro-oxidants – free radicals and reactive oxygen species – shifts to favor the accumulation of pro-oxidants, he explained. If left unchecked, these highly reactive pro-oxidants can damage DNA, proteins, and other biological molecules in the cell and may cause cell death.

“Tumor cells appear to have disruptions in mitochondrial oxidative metabolism that lead them to produce more superoxide and other reactive oxygen species, compared with normal cells,” Dr. Spitz explained. “Oxidative metabolism is a chemical process that occurs in the mitochondria of cells in which oxygen consumption is used to make energy from food sources. Altered oxidative metabolism in cancer cell mitochondria is thought to result in chronic oxidative stress in cancer cells, relative to normal cells.”

Ketogenic diets, which are high in fat and low in protein and carbohydrates, deprive cells of glucose and force them to rely more heavily on mitochondrial oxidative metabolism, Dr. Spitz said, adding that healthy cells don’t appear to have the defects in mitochondrial metabolic pathways that are present in tumor cells.

Dr. Spitz is pursuing the idea that “we should be able to induce oxidative stress selectively in cancer cells by feeding patients a ketogenic diet that forces the use of mitochondrial metabolic pathways leading to the production of superoxide.” The augmented level of oxidative stress in cancer cells would in turn be expected to selectively sensitize cancer cells to conventional cancer therapies that kill cells via oxidative stress in an additive fashion, he said.

To test the feasibility of this approach, Dr. Spitz and his colleagues conducted preliminary studies in mouse models of human pancreatic cancer, lung cancer, and head and neck cancer. These mice were implanted with human cancer cells and treated with standard chemo-radio-therapy combinations used clinically with and without feeding a ketogenic diet.

“We’ve been able to show that if you feed tumor-bearing mice a ketogenic diet, you can inhibit tumor growth and delay the progression of disease in animals that have been treated with radiation and chemotherapy,” Dr. Spitz reported. The researchers also saw an increase in chemical markers of oxidative stress in blood samples and tumor samples from animals that were fed the ketogenic diet during therapy.

“We think there might be a causal relationship between the oxidative stress and the enhanced chemo-radio-therapy responses of tumors in animals fed ketogenic diets, but we’re still doing experiments to try to prove if that is true,” Dr. Spitz added.

Meanwhile, in collaboration with his physician colleagues, Dr. Spitz has launched an early-phase clinical trial (phase I) in which six patients with advanced, inoperable pancreatic cancer and six patients with inoperable non-small cell lung cancer (NSCLC) will be put on a ketogenic diet for six weeks. The trial will test whether patients can safely tolerate the high-fat diet while being treated with standard chemo-radio-therapy protocols, he said. The researchers will also test blood samples from the patients for markers of oxidative stress and ketosis – a state of elevated levels of ketone bodies in the body, which would be caused from eating a ketogenic diet.

“Ketogenic diets have been used safely for more than 20 years for treating epilepsy and we’re only asking people to eat it for six weeks,” Dr. Spitz said. If this preliminary clinical trial shows that the ketogenic diet is safe for cancer patients, Dr. Spitz and his colleagues plan to conduct a clinical trial in a larger number of patients with pancreatic cancer and NSCLC. The goal of that trial will be to find out whether a ketogenic diet can enhance the effectiveness of standard chemo-radio-therapy in humans.

Dr. Dan Xi, the program director at OCCAM responsible for overseeing this grant, commented that “using the ketogenic diet as adjuvant approach with standard therapies in humans is very innovative. This multiple PI grant is led by a strong team with proper expertise in both basic and clinical sciences, and addresses a research area of special interest for our office and the Division of Cancer Treatment and Diagnosis, i.e., complementary approaches that augment the therapeutic index of conventional cancer therapies.”