Steven K. Clinton, MD, PhD

AICR / WCRF Annual Research Conference – Washington DC

November 8, 2013

Diet, Nutrition, and Cancer

Mechanisms

The Role of Clinical Trials

2

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

AICR’s 2013 Annual Research Conference on

Food, Nutrition, Physical Activity and Cancer

November 7-8, 2913

Hyatt Regency Bethesda

Name of Speaker: Steven K. Clinton, MD, PhD

3

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

What is a clinical trial?

“a prospective study involving human subjects designed to answer specific questions about the effects or impact of particular biomedical or behavioral interventions; these may include drugs, treatments, devices, or behavioral or nutritional strategies”

- NIH / NCI Definition

4

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

Fragment of

Daniel’s Protocol

Biblical Description of a Clinical Trial

Daniel 1:12-16

5

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

The “First” Clinical Trial in Nutrition

“Please test your servants for ten days:

Give us nothing but vegetables to eat and water to drink. Then compare our appearance with that of the young men who eat the royal food, and treat your servants in accordance with what you see.

So he consented them and tested them for ten days. At the end of the ten days they looked

healthier and better nourished than any of the young men who ate the royal food.

So the guard took away their choice food and the wine they were to drink and gave them

vegetables instead.” Daniel 1:12-16

6

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

A definitive trial….

The Selenium and Vitamin E Cancer Prevention Trial (SELECT), a Phase III, randomized, double blind, 2x2 factorial, placebo-controlled trial to prevent prostate cancer.

200 μg/day from L-selenomethionine and/or vitamin E at 400 IU/day of all rac α-tocopheryl acetate

32,400 healthy men, 2001-2004

After 7 years (5.5 on agents), there were 17 percent more cases of prostate cancer in men taking only vitamin E than in men taking only placebos.

Quote: “the study failed”

7

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

The Monday morning quarterback….

…did not consider preclinical studies.

…preclinical studies did not exist.

…the epidemiology was weak.

…the wrong form of selenium or vitamin E.

…the wrong dose.

…etc.

We do not learn from experience, we learn from reflecting upon experience. John Dewey?

8

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

A,B,C and Ds of a Diet/Nutrition Clinical Trial on Mechanisms

Agents

Biomarkers

Cohort

Dollars

9

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

Agent Considerations

Pure Chemical / Pharmacologic model.

Nutrient or non-nutrient dietary compound

Form, safety, dose response, placebo possible.

Food / Functional Foods

Variation due to source, cultivar, season, growing conditions, soil, processing, cooking, stability over time.

Placebo and double blinding may be problematic

Dietary Patterns

Heterogeneity among participants, compliance

Control group is problematic.

10

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

Biomarkers

Exposure

Validated analytic technology.

Dose response (linear, nonlinear)

Bio accessibility.

Pharmacokinetic / pharmacodynamic modeling.

Context (meal and composition).

Efficacy

Surrogate endpoints (polyps, intraepithelial neoplasia)

Mechanisms

-omics, (miRNA, mRNA, proteins, epigenetics, genomics, metbolomics)

Targeted approach.

“Hallmarks of Cancer”

11

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

Cohorts

Broad and “generalizable” / public health model

Focused and “personalized” / medical model

Host

Genetics

Carcinogen exposure (tobacco)

Premalignancy (dysplasia, CIS, polyps)

Nutritional criteria (deficiency)

Infection (HepB, HPV)

Immune suppressed (post-organ transplant)

Cancer (recurrence of primary)

Genomic signature

Histopathology subtype

12

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

Dollars

Budgets begin in US Congress.

Clinical research is expensive.

Arbitrary cuts compromise studies

Statistical power

Dose response

Reduction of outcomes measured.

Disproportionate funding for therapy of advanced Ca.

Privatization of cancer research.

Human Cancer Genome Atlas, etc.

Molecular targeting is the current “theme”.

Complexity is enormous, evolution of resistance common.

High cost to develop drugs for smaller populations.

My conclusion: prevention is the goal!

Thank You