Barbara A. Gower, PhD UAB Department of Nutrition Sciences “You can’t run from a bad diet*.” A dietary approach to prevention and treatment of cancer Barbara A. Gower, PhD UAB Department of Nutrition Sciences *http://fanaticcook.com/2014/05/08/study-inactivity-does-not-lead-to-fatness-its-the-other-way-around/

Obesity and Cancer “Obesity is a major under-recognized contributor to the nation’s cancer toll and is quickly overtaking tobacco as the leading preventable cause of cancer.” “As many as 84,000 cancer diagnoses each year are attributed to obesity, and overweight and obesity are implicated in 15% to 20% of total cancer-related mortality.” J. Clin. Oncol. 32:3568, 2014. American Society of Clinical Oncology Position Statement

Why is obesity associated with cancer? High blood insulin, High blood sugar, inflammation Genes Diet Obesity Diabetes CVD PCOS AD Cancer Obesity is a MARKER for a metabolic environment that predisposes to chronic diseases including cancer

Insulin (not obesity!) predicts breast cancer Sub-cohort (n=2830) of WHI with fasting sera 497 incident cases of breast cancer over ~8 yr follow-up Cancer Research 2014 75:270

Insulin is commonly elevated in obesity; only insulin predicts BC * ** Adjusted for age, ethnicity, age at menarche and menopause, parity, 1st degree relative, education, alcohol, physical activity, site, arm, study, assignment.

Insulin and cancer “Mitogenic”: causes cancer cells to divide Promotes glucose (blood sugar) uptake Cancer cells burn sugar as a fuel Damaged “engines” (mitochondri)a “Warburg effect” (aerobic glycolysis) ↑oxidative stress/inflammation/mutations Prevents burning fat as a fuel Normal products of fat burning inhibit cancer cell metabolism

Insulin is secreted in response to carbohydrate foods: sugar, starch, grain

Diet quality affects blood sugar and insulin High glycemic load (standard) vs. Low glycemic load (reduced carbohydrate) diet Chandler-Laney and Gower 2014 Appetite, 80:236-41

Carbohydrate quality associated with breast density 5-yr longitudinal study; n=1668 Tested hypothesis that total carbohydrate (CHO), starches, sugars, or Glycemic Index, Glycemic load would increase risk for high mammographic breast density Breast density is a risk factor for cancer Masala G et al. 2013 PLoS1 8:e70943

>Glycemic load = denser breast Dietary Glycemic Load >GL, total CHO, and simple sugar intake = >breast density

Our Model Genetic Oxidative Changes Stress CH3 Insulin Glucose “Engines” of the cells; Burn fuel, produce energy (ATP) Insulin Glucose Mitochondria Genetic Changes Oxidative Stress Gene expression ↑Fermentation genes ↑Oncogenes Myc TOR NFKB CHOP Ras ↓DNA repair genes Mutations CH3 Genomic instability

Summary: Obesity-cancer connection Obesity is a “marker” for high blood sugar and high insulin Cancer cells need sugar and insulin Reducing sugar and insulin may reduce cancer risk Reducing sugar and insulin could be used to treat cancer

Treatment of cancer with a carbohydrate restricted diet 10 cancer patients Different types of cancer (lung, ovarian, etc.) 9/10 with progressive disease 28-d diet intervention (26-28 d) “Ketogenic” diet PET scan for glucose uptake Serum insulin and ketones Fine et al 2012 Nutrition 28:1028-1035

What is a ketogenic diet? Carbohydrate <5% total energy Healthy cells burn mainly fat Fat burning by the liver produces ketones Ketones are used as a fuel for the brain Ketones inhibit cancer cell metabolism X

Higher ketone production = stable disease and partial remission

Current (ongoing) cancer project UAB CCC support Recurrent ovarian cancer 12 weeks of ketogenic diet (KD) Outcomes related to cancer, metabolic health, quality of life

UAB Ketogenic diet prescription Transition to fat oxidation and ketone production <20 g/d CHO 2 cup/day salad greens 1 cup/day non-starchy vegetables <100 g/d protein (poultry, fish, red meat, pork, eggs) Unlimited fat Olive oil, coconut oil, coconut milk, butter, meat fat Limited fat Cheese (4 oz/d) Olives (6/d); ½ avocado Mayonnaise and cream (2 Tb/d) This diet will “starve” cancer cells

Sample menu Calories Fat (g) Carbohydrates (g) Protein (g) Breakfast Coffee 2 0.1 0.2 Cream 117 10.3 3.9 2.7 Three eggs 262 20.3 1.3 18.7 Bacon 54 4.2 3.7 Broccoli, cooked 16 0.8 2.1 0.7 Lunch Greek salad 212 14.6 6.7 14 Olive oil 239 27 Dinner Coconut oil 234 27.2 Kale, cooked 138 8.4 14.7 4.9 Salmon, cooked 118 19.9 Snack Macadamia nuts 406 43.1 7.3 4.4 Total 1,799 159.6 36.2 69.3

Preliminary data 9 patients enrolled 1 completed Patient 1: 22 lb weight loss Decrease in CA-125: 380-135 (-245 units/mL) Smaller tumor 20x17mm to 7x5 mm (one-tenth) Decrease in total cholesterol (-30 mg/dL) Elected to stay on the diet

Upcoming cancer project Funded by the AICR Recurrent ovarian or endometrial cancer 60 patients (30 KD + 30 AICR diet) 12 weeks of diet therapy Outcomes:

Body composition by DXA GE-Lunar Prodigy

Body composition by impedance analysis

Blood work Markers of inflammation Blood sugar (glucose) Insulin IGF-1 Cholesterol and triglycerides

Quality of Life Questionnaires: Hunger and satiety Fatigue and perceived energy Depression

Cancer outcomes Tumor size by CT scan Blood cancer markers RECIST criteria Blood cancer markers CA-125 marker

More information Treatment Ketogenic diet 2-bromo-pyruvate (blocks glucose metabolism) Hyperbaric oxygen

3-bromo-pyruvate to treat cancer Hexokinase 2 (glucose→ G6P) inhibitor The pivotal player in the Warburg effect Complete eradication (19 mice); normal life span 1 case report No toxicity