Mechanistic insights from animal/in vitro studies
Opportunities and Challenges
Looking back-moving ahead
Henry J. Thompson
Cancer Prevention Laboratory
Colorado State University, Fort Collins, CO.
([email protected])
AICR’s 2013 Annual Research Conference on
Food, Nutrition, Physical Activity and Cancer
November 7-8, 2913
Hyatt Regency Bethesda
Name of Speaker: Henry J. Thompson
No Relevant Financial Relationship: none_________________________
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Name of conflicting business, organization or individuals:
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“Education is not about the filling of a pail; it is
about the lighting of a fire” Yates
This presentation is intended to
stimulate thinking and discussion
and create the opportunity for
epiphanies
• Understanding of food, nutrition, and physical activity (LIFESTYLE) in cancer risk (using preclinical models).
• Thinking about the strengths and limitations of preclinical models in
mechanism‐based research Nutrition/Diet/ Food-Cancer
Conundrum
Eat mostly foods of plant origin for cancer prevention
WCRF‐AICR: Food, Nutrition, Physical Activity and the Prevention of Cancer: a Global Perspective. Nov.1‐2, 2007
No convincing epidemiological evidence that any specific type of plant food (V,F,G) or nutrient inhibits cancer of any type
Is it realistic to expect that diet and nutrition
can have any impact on a genetically driven
process like carcinogenesis?
Nutrition and Cancer: How Much Does It
Really Matter? (AACR 2012 Forum)
Is there any value of animal/cell-based
models in this debate?
Beware! (Challenge) If your interest is lifestyle and cancer
• Current literature on preclinical model relevance: heavily weighted toward the failure in translating drug development to cancer therapy.
• There is a tendency to confuse to concepts and questions in cancer chemopreventive with the questions relevant to lifestyle interventions & cancer: they are not the same. – The chemoprevention literature on preclinical model relevance is older because there is currently a strong negative bias against chemoprevention.
Relevance of animal & cell‐based models: it depends on the purpose in their use.
(And here, word definitions matter).
For lifestyle factors:
• Predict (or screen) versus understand?
• Eliminate hypotheses versus establish causality?
• The perfect story: select positive results: publication bias.
• Where are the problems: we need better models
– are the models flawed or is the way we use them flawed? (Models are just fine is used wisely)
• The pressures of science: costs, selection bias etc.
– Call to reign‐in animal per diems. •
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All models illuminate one or more aspects of the heterogenous disease process referred to as cancer
What does success look like?
How have animals and cells been used well?
Use animals models to take you where you cannot easily go with people.
There is enough known in people that you can wisely choose a model with a specific set of characteristics to permit you to address a clearly stated human relevant question (global relevance of a model is not required).
Use cell culture as an external (secondary) source of validation
Your primary objective is to eliminate hypotheses and in order to determine what’s left standing
Feed human diets in rodent studies:CARB: Effect of glycemic load
on biomarkers…rat: on breast cancer endpoints
Thompson, Lampe, Neuhouser, McTiernan
Strengths & Weaknesses of Preclinical Models
Strengths
• Cancer endpoints
Weaknesses
Statistically significant vs
translationally meaningful
Under powered /pick & choose
• Statistical power
Too defined (at times)
• Defined conditions
• In depth tissue analyses Ignore when things work differently Temporal pattern of use within • Manipulable
Ho testing (when to use in vitro vs in vivo approaches)
Opportunities: The Future?
(Models illuminate specifics aspects of the carcinogenic process)
•Personalized medicine (lifestyle): Move from
broad population based assessment and
recommendations to functional subgroups (Kaput
J. et al; Rodriquez, A. et al; Nicholson’s group)
• Lifestyle interventions based on knowledge of
requirements, status, and genotype (i.e.,
"personalized lifestyle") can be used to prevent,
mitigate or cure chronic disease.
Next generation mechanisms:
(where preclinical models are essential)
• Consider the effects of lifestyle interventions
under three contexts:
• 1. homeostasis challenge tests (normal diagnostics)
• 2. failed homeostasis (abnormal diagnostics)
• 3. overt disease (responses in “diseased cells” likely to
differ from those in “uninvolved” cells/tissues)
Identify characteristics of responders and non
responders