Intermittent Fasting and Carbohydrate Restriction in Cancer Management

Colin E. Champ, M.D.Assistant Professor and PhysicianDepartment of Radiation OncologyUniversity of Pittsburgh Medical Center

Cavemandoctor.com

Disclosure

• Conflicts of interest: None

Overview

• History of dietary manipulation in prevention and cancer care

• Hypothesis and methods of action

• Current methods of dietary intervention during treatment

• Methods of implementation

• Future directions

Cancer• In this room:• Women: 1 in 8 will be diagnosed with breast cancer• Men: 1 in 6 with prostate cancer

• Intense metabolic & cellular dysfunction• Diet/Lifestyle• Environment• Genetics

• *Some increase due to diagnostic measures

Introduction - History

Tannenbaum, A. Effects of Varying Caloric Intake Upon Tumor Incidence and Tumor Growth.

Annals NY Acad Sci.

Conclusions thus far…• All studies:• 1. Placed mice on restricted diet (CR or

carbohydrates)• 2. Applied a cancerous toxin/insult • 3. Observed:

• Decrease in tumor formation/slowed tumor growth

• Cancer not eliminated!

• Can we harness the effects of nutrient restriction to aid in the treatment of cancer?

Saleh A, et al. Caloric restriction augments radiation efficacy in breast cancer. Cell Cycle 2013

Is it Calorie Restriction?

If I were a mouse…

200 lbs. 40 lbs.

Champ CE, Baserga R, et al. Nutrient Deprivation and Radiation Therapy – When Less is More. The

Oncologist, 1:2012

How does it work? - Autophagy

Conclusions thus far…• CR augments RT efficacy:• 1. Decreased IGF pathway • 2. Increases AMPK pathway• 3. Decreases mTOR pathway

• Intermittent fasting = less weight loss• Calories restricted = primarily carbohydrates

Insulin

Can CR alone decrease the insulin pathway?

Fontana L, Long-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3 concentration in humans. Aging Cell. 2008

IGF and CR

Halberg, N et al. Effect of intermittent fasting and refeeding on insulin action in healthy men. J Applied Phys 2005.

Intermittent Fasting

Ancel Keys Starvation Study

• 1570 calories/day• “The major food items served were whole wheat bread, potatoes,

cereals, and considerable amounts of turnips and cabbage.”

Hite A H et al. Nutr Clin Pract 2011;26:300-308

Glucose/Insulin Pathway

Fasting/Carbohydrate restriction better downregulate the insulin pathway…but what about the AMPK pathway?

Amp Kinase

Action Effect

Increases glucose uptake Pulls glucose from circulation

Increases glycolysis Glycogen and glucose burned

Inhibit gluconeogenesis Decreases available glucose

Increases fatty acid oxidation

Inhibits fatty acid/cholesterol synthesis

Increases mitochondrial biogenesis More mitochondria available

Increases insulin sensitivity Per above

Downregulates mTOR Per above

Draznin, B., et al., Effect of Dietary Macronutrient Composition on AMPK and SIRT1 Expression and Activity in Human Skeletal Muscle.

Horm Metab Res, 2012. 44(09): p. 650-655.

Draznin, B., et al., Effect of Dietary Macronutrient Composition on AMPK and SIRT1 Expression and Activity in Human Skeletal Muscle.

Horm Metab Res, 2012. 44(09): p. 650-655.

Draznin, B., et al., Effect of Dietary Macronutrient Composition on AMPK and SIRT1 Expression and Activity in Human Skeletal Muscle.

Horm Metab Res, 2012. 44(09): p. 650-655.

Draznin, B., et al., Effect of Dietary Macronutrient Composition on AMPK and SIRT1 Expression and Activity in Human Skeletal Muscle.

Horm Metab Res, 2012. 44(09): p. 650-655.

Draznin, B., et al., Effect of Dietary Macronutrient Composition on AMPK and SIRT1 Expression and Activity in Human Skeletal Muscle.

Horm Metab Res, 2012. 44(09): p. 650-655.

Draznin, B., et al., Effect of Dietary Macronutrient Composition on AMPK and SIRT1 Expression and Activity in Human Skeletal Muscle.

Horm Metab Res, 2012. 44(09): p. 650-655.

Crossed-over

Conclusions thus far…• Carbohydrate restriction/Intermittent fasting:• 1. Decreases IGF pathway • 2. Increases AMPK pathway• 3. Makes RT work more effectively

• Intermittent fasting may provide similar benefits vs. CR• With less potentially detrimental weight loss• Increased downregulation of IGF

Does carbohydrate restriction simply reduce available glucose for cancer cells?

Kubicek G, Champ C, FDG-PET staging and importance of lymph node SUV in head and neck cancer. Head and Neck Onc. 2010

Simone BA, Champ CE, Selectively starving cancer cells through dietary manipulation: Methods and clinical implications. Future Oncology, 2013.

Metabolic Flexibility

Ketogenic Diet• Ultimate lowering of blood glucose• Less than 20-50 g carbs/day & 70-80% fat• Aggressively lowers IGF and upregulates AMPK

Fine E et. al. Targeting insulin inhibition as a metabolic therapy in advanced cancer: a pilot safety and feasibility dietary trial in 10 patients. Nutrition 2012.

⬆ Ketones = Insulin⬇

Blood Glucose Values KD Pts.

Another Benefit…

Illustrates the power of the mind and human spirit

• Our patients must be involved in their care• Control & Autonomy

• Diet and an ancestral lifestyle empowers patients to take control of their health

• The days of medicine = sit back while we irradiate you and inject you with chemo must end!

• In many cancers, cure is possible but futile without lifestyle changes • Future cancers/metabolic disorders will lead to significant

morbidity and mortality

Killing Weeds

The Ancestral Solution

In Conclusion & Going Further• Intermittent fasting/Ketogenic Diet• Potentially reduces risk of cancer in preclinical data• Aids current treatments like chemotherapy and radiotherapy

• Does it work with all cancer types• ?

• Does it replace current therapy• NO!!! – Available data points to synergy• Maybe (hopefully) one day

Acknowledgements• Eugene M. Fine, M.D.• Albert Einstein College of Medicine

• Jeff S. Volek, Ph.D., R.D. • University of Connecticut

• Nicole L. Simone, M.D.• Kimmel Cancer Center of Thomas Jefferson University

• Rainer Klement, Ph.D.• University of Würzburg

• My amazing patients