1. Cancer Care Engineering: The Cancer Prevention Perspective Dorothy Teegarden, Ph.D. Oncological Sciences Center Lead, Cancer Prevention and Control Program Department of Foods and Nutrition

2. Cancer Prevention Impact Diet – 30% of cancer deaths are related to diet (Doll, 1981). Tobacco use – 30% or 170,000 cancer deaths in the United States in 2006 (ACS, 2006). Other modifiable factors – Environmental exposures – Obesity – Lack of physical activity. Could achieve by 2015 (IoM, 2004): – 19% decline in new cancer cases – 29% decline in the rate of cancer deaths

3. Multistage Cancer Progression Initiation Environmental Genetic Normal Growth Preneoplasm Promotion Environmental Genetic Neoplasm Benign Or Malignant Identify and/or Prevent Exposures Very Early Detection Identify Genetic Risks

4. Cancer Prevention/Chemoprevention Risk/Benefit NormalInitiationPromotionProgressionMetastases Multi-stage Carcinogenesis

5. Cancer Prevention/Chemoprevention Epidemiology Biomarkers/Imaging Early Detection Molecular Mechanisms Clinical Trials Policy Behavioral Modeling Healthcare Systems/Communication Modifiable/Environment Behavior Modification Methodology Animal Models Chemopreventive Compounds Genetics Cells Nutrition

6. Cancer Research in Indiana Purdue University NCI Cancer Center Oncological Sciences Center Indiana University NCI Cancer Center IU School of Medicine Hoosier Oncology Group Family Practice Network

7. Oncological Sciences Center Research Areas Cancer Prevention and Control Cancer Nanotechnology Cancer Biomarkers Novel Engineered Diagnostic and Therapeutic Devices Cancer Care Engineering

8. A Systems Approach to the Prevention & Treatment of Cancer Cancer Care Engineering

9. Cancer Care Engineering Goals We want to know who will develop specific cancers (environment/gene interactions) and what strategies will prevent the development of that cancer. Cancer Prevention and Chemoprevention

10. Cancer Prevention & Chemoprevention Cancer Prevention by Dietary Agents – Nutrient and botanical Chemoprevention Very early detection – Biomarkers and imaging Identification of risk factors Behavioral modification/Public Policy approaches to reduce risk – Smoking cessation – Reducing incidence of obesity Application of knowledge in healthcare settings

11. Treat Cancer and Cancer Prevention as a System Interdisciplinary Team Approach Enabling Systems Infrastructure Data Integration Patient Data, Literature Data, HSR Data Rapid Communication Efficient clinical validation Hypothesis generation Community-based Approach

12. CCE Model Bedside to Bench and Back 1. Sample Acquisition/Management Community-based oncology clinics Undiagnosed populations 2. Data Acquisition OMICS, Prevention Data Indiana University School of Medicine Regenstrief Institute Purdue University 3. Data Storage/Query Center Purdue University 4. Predictive Statistical Modeling Purdue University 5. Real-time Visualization of Data Purdue University 6. Immediate Clinical Analysis & Clinical Feedback Indiana University Cancer Center 7. Discovery Research Driven by Model Predictions Purdue University Indiana University Cancer Center New Directed Sampling Iterative Models Refined Predictive Outcomes Analyzed

13. CCE Leadership Team Purdue University Don Bergstrom, PhD Richard Borch, MD, PhD Marietta Harrison, PhD Julie Nagel, PhD Joseph Pekny, PhD Dorothy Teegarden, PhD IU Cancer Center Mark Kelley, PhD James Klaunig, PhD Pat Loehrer, MD Chris Sweeney, MBBS Stephen Williams, MD Oncological Sciences Center e-Enterprise Center Regenstrief Center for Healthcare Engineering Purdue Cancer Center

14. Immediate Communication A System Wide Awareness Instantaneous Picture of Indiana Cancer Care System Multidisciplinary Staffing Community Oncologist Accessibility Dissemination of New Data Patterns Allow Data Driven Resource Allocation

15. Study Design Genetic Variants (SNPs) Oxidative Stress (enzymatic production and removal) Epigenetic Methylation Vitamin D Metabolism Colon Cancer Development and Progression Colon Cancer Susceptibility: Role of Oxidative Stress (and Vitamin D) Oxidative Stress Parameters Vitamin D Status Dietary Intake Environment Bioinformatics

17. System Analysis Model 3. Input Clinical Data (Disease Development in Healthy Controls, biomarkers) 4. Model Identifies Necessary New Data 5. Input Necessary New Data 2. Predict Subject Response to Intervention 6. Predict Development of Disease in Healthy Individuals and Effectiveness of Nutritional Interventions Cancer Care Engineering Prevention and Control Situation Room 1. Input Patient “omics” Data Input Healthy Control “omics” Data Biomarker Identification & Validation Early Detection and Risk Assessment

18. www3.cancer.gov/atlasplus/ High Epithelial Cell Cancer Rates are Associated with Low UV Exposure - 28 o N - 35 o N - 42 o N 500* 450 400 350 300 * Mean daily solar radiation in g-cal/cm 2

19. Colon Cancer Susceptibility: Role of Oxidative Stress (and Vitamin D) James Klaunig Center for the Environment; IU Cancer Center Dorothy Teegarden Purdue University Cancer Center, Oncological Sciences Center Mark Kelley IU Cancer Center Lisa Kamendulis IU Cancer Center

20. Oxidative Stress, Vitamin D and Colon Cancer Oxidative stress – Balance oxidant>antioxidants – Damage (proteins, lipid and nucleic acids) – Cancer Factors that Impact Oxidative Stress – Overproduction of reactive oxygen species – Faulty or inadequate enzymatic antioxidant defenses – Inadequate intake of antioxidants – Faulty or inadequate DNA repair – Association with genetic variants Vitamin D Status – Colon cancer prevention – Inhibits proliferation, induces differentiation, stimulates apoptosis – Genetic variants associated with colon cancer progression – Promote enhanced oxidative defenses

21. Colon Cancer Susceptibility: Role of Oxidative Stress (and Vitamin D) Chemoprevention strategies involving both antioxidant and vitamin D supplementation may be useful for preventing colon carcinogenesis. Hypothesis The formation and progression of preneoplastic colon lesions (or a subset thereof) is dependent on the induction of oxidative stress and damage that is due in part, to genetic susceptibility factors and/or dietary and lifestyle factors that influence oxidative stress status.

22. Study Design Genetic Variants (SNPs) Oxidative Stress (enzymatic production and removal) Epigenetic Methylation Vitamin D Metabolism Colon Cancer Development and Progression Colon Cancer Susceptibility: Role of Oxidative Stress (and Vitamin D) Oxidative Stress Parameters Vitamin D Status Dietary Intake Environment Bioinformatics

23. Factors Influencing Serum 25OH D Levels White vs African American = +12.8 nmol/L South vs North = +6.4 nmol/L Low vs High BMI = +8.6 nmol/L Active vs Inactive = +13.5 nmol/L High vs Low Diet vitamin D = +10.4 nmol/L Autumn vs Winter = +13.5 nmol/L Giovannucci et al. J Natl Cancer Inst 2006;98:451 Active, skinny, white Southerner = +41.3 nmol/L!!!!

24. Systems Infrastructure Sample Acquisition OMIC Analyses Iterative Predictive Modeling Instant Feedback to Clinics Clinical Data Driving Basic Research BEDSIDE LABORATORY Enabling Individualized Treatment & Prevention Plans

25. Project Long Term Goals Establish Cancer Care System Infrastructure Provide Instantaneous Communication Vehicle Stratify Patients Prevention Strategies Response to Therapy Clinical Trials ID and Validate Clinically Relevant Biomarkers ID Therapeutic Targets ID Barriers to Effective Healthcare Delivery