Reducing Insulin, Growth Hormones, and Tumors

The objective of this project is to compare the effect of two widely implemented cancer diets, differing drastically in macronutrient content, on biomarkers of inflammation, compared to a control diet. Diet A will be a low-carbohydrate, high-fat ketogenic-type diet with an emphasis on whole foods. By limiting carbohydrate, the diet will have an extremely low glycemic load, thereby minimizing diurnal glucose and insulin excursions. Diet B will be a low-fat, high-carbohydrate whole foods plant-based diet. It will include only fiber-rich, low-glycemic index sources of carbohydrates and largely eliminate animal protein, which will minimize rapid spikes in blood glucose and insulin and the production of IGF-1. This diet is also hypothesized to improve glucose tolerance and insulin sensitivity, which should further help minimize diurnal glycemic and insulinemic excursions. Both diets will be compared to a control diet based on the 2015 USDA Dietary Guidelines for Americans (Diet C) in patients suffering from advanced lung cancer as they are completing medical therapy. The overarching hypothesis motivating this work is that a nutrient dense diet that minimizes known factors involved in tumor growth and progression may improve the effectiveness of therapy. Our specific hypothesis is that participants following either of the experimental diets, A or B, will experience a reduction in biomarkers of insulin resistance and chronic inflammation, both of which are known risk factors for progression in lung cancer, and a greater median time to progression compared to those on the control diet (Diet C).

Little is known about the role of diet in the treatment of lung and other cancers, yet physicians are constantly confronted with the question 'what should I eat' by their patients. Very few randomized controlled dietary interventions have been carried out in this population, hence physicians and dietitians must use their best professional judgement to provide nutrition advice to their patients. Because most believe that nutrition is an important part of the treatment process, patients are eager to implement dietary recommendations and take control of this portion of their medical care. As such, upwards of 64% of patients use the internet to access health information related to cancer treatment with nutrition websites being among the most popular sites visited. However, the dietary advice on the internet aimed at cancer patients is highly discrepant, and even so among cancer treatment centers and research institutions. Within the National Comprehensive Cancer Network (NCCN), of which Fred Hutchinson is a member, only 43% (9 of 21 centers) either provide nutritional information on their website or linked to outside websites. Of those, roughly half recommended a low-fat diet during cancer treatment and the other half recommended a calorie-dense eating plan with the inclusion of high-fat foods. Clearly, this presents a potential pitfall for patients as they, without guidance from their physician or dietitian, may follow dietary advice that is misleading or potentially harmful. While there is a need for further studies to elucidate the role diet plays during the treatment of cancers in general, lung cancer in particular is understudied in comparison to other types of cancers, and presents a unique opportunity to study the impact of diet during treatment. Primarily, lung cancer patients do not typically suffer from constraints to eating that affect colorectal, esophageal, or head/throat/neck cancer sufferers. Therefore, diet interventions using whole-foods may be fairly well tolerated in this population. A review of nutrition interventions in lung cancer patients carried out through October 2012 indicated that only three controlled studies in 149 patients had been completed, all of which used nutritional supplement products to prevent unintentional weight loss. The authors concluded that nutrition interventions in this population are safe and that more research is needed to determine optimal nutrition recommendations for advanced, inoperable lung cancers . Through the manipulation of diet, it is possible to selectively target key pathways involved in cancer growth and proliferation. For instance, it is known that cancer cells generate energy through the process of anaerobic glycolysis (the Warburg Effect) which relies primarily on glucose as a fuel source. Evidence from in vitro studies of non-small cell lung cancer (NSCLC) suggests that reducing the glucose availability from the diet might be particularly effective in the treatment of squamous cell carcinomas because the glucose transporter (GLUT-1) expression is markedly elevated in these cancer cells and is associated with enhanced uptake of, and dependence upon, glucose. Case-control studies show that dietary glycemic index is strongly associated with squamous cell carcinoma among NSCLC patients, suggesting that dietary strategies that limit carbohydrate may be effective in 'starving' these predominately glycolytic cells. A diet pattern in which overall energy is not limited, but sources of glucose are selectively reduced, is one mechanism by which cancer progression might be abated. Such low-carbohydrate or - in their most extreme form - ketogenic diets, which provide energy primarily from fat and protein while minimizing carbohydrates, are increasingly shown to be therapeutic for the treatment of glioblastoma and other cancers, as well as neurological diseases, including epilepsy, and cardiovascular disease risk factors. It is also known that activation of the IGF pathway is critical for tumor cell proliferation, invasiveness, and survival in NSCLC and downregulation of this pathway through dietary manipulation might also be an effective means to suppress cancer growth. The insulin-like growth factor-1 receptor (IGF-1R) is abundantly present on surfaces of tumor cells, and high circulating levels of IGF-1, the ligand for the IGF-1R, are a risk factor for future lung malignancy. As individuals who consume diets high in protein from animal sources have greater levels of circulating IGF-1 compared to those consuming a vegetarian/vegan diet, limiting the intake of animal products may be an intriguing dietary strategy that might influence cancer progression. In our lab, we have shown that insulin sensitivity and glucose tolerance improved after subjects adhered to a diet rich in whole grains, legumes, fruits, and vegetables, that excluded refined sources of energy (added sugar, refined grains, added fats and oils) (Kratz et al. unpublished data). This suggests that such a diet would also reduce the diurnal exposure of tumor cells to both glucose and insulin, which would decrease the availability of fuel and growth hormones for cancer cells. Taken together, both low-carbohydrate/ketogenic diets and low-fat, whole foods plant-based diets could plausibly affect pathways involved in cancer growth or progression by minimizing diurnal exposure to glucose, insulin, and IGF-1.