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

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

Multistage Cancer ProgressionInitiation

EnvironmentalGenetic

NormalGrowth

Preneoplasm

PromotionEnvironmental

Genetic

NeoplasmBenign

Or Malignant

Identify and/orPrevent Exposures

Very Early DetectionIdentify Genetic Risks

Cancer Prevention/Chemoprevention

Risk/Benefit

Normal Initiation Promotion Progression Metastases

Multi-stage Carcinogenesis

Cancer Prevention/Chemoprevention

Epidemiology

Biomarkers/ImagingEarly Detection

MolecularMechanisms

Clinical Trials Policy

BehavioralModeling

HealthcareSystems/Communication

Modifiable/Environment

BehaviorModificationMethodology

Animal Models

ChemopreventiveCompounds

Genetics

Cells

Nutrition

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

Oncological Sciences CenterResearch Areas

• Cancer Prevention and Control

• Cancer Nanotechnology

• Cancer Biomarkers

• Novel Engineered Diagnostic and Therapeutic Devices

• Cancer Care Engineering

A Systems Approach to the Prevention & Treatment of Cancer

Cancer Care Engineering

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

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

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

CCE ModelBedside to Bench and Back

1. Sample Acquisition/ManagementCommunity-based oncology clinics

Undiagnosed populations

2. Data AcquisitionOMICS, Prevention Data

Indiana University School of MedicineRegenstrief InstitutePurdue University

3. Data Storage/Query CenterPurdue University

4. Predictive Statistical ModelingPurdue University

5. Real-time Visualization of DataPurdue University

6. Immediate Clinical Analysis & Clinical FeedbackIndiana University Cancer Center

7. Discovery Research Driven by Model Predictions

Purdue UniversityIndiana University Cancer Center

New Directed SamplingIterative Models Refined

Predictive Outcomes Analyzed

CCE Leadership TeamPurdue 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 Centere-Enterprise Center Regenstrief Center for Healthcare EngineeringPurdue Cancer Center

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

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 ParametersVitamin D StatusDietary Intake

Environment

Bioinformatics

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 EngineeringPrevention and Control

Situation Room

1. Input Patient “omics” Data Input Healthy Control “omics” Data

Biomarker Identification & Validation

Early Detection and Risk Assessment

www3.cancer.gov/atlasplus/

High Epithelial Cell Cancer Rates are Associated with Low UV Exposure

- 28 oN

- 35 oN

- 42 oN

500*

450

400

350

300

* Mean daily solar radiation in g-cal/cm2

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 CenterLisa Kamendulis IU Cancer Center

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

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.

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 ParametersVitamin D StatusDietary Intake

Environment

Bioinformatics

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!!!!

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

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