Pathway Modeling of Complex Toxin Response and Energy Balance Systems in Cancer

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DESCRIPTION (provided by applicant): This Cancer Prevention, Control and Population Sciences Career Development Award is being requested to support the further development of Dr. Nora L. Nock into an independent investigator focusing on pathway modeling of energy balance and toxin response systems to help define exercise and diet interventions that will improve cancer control and prevention. Toxins such as polycyclic aromatic hydrocarbons (PAHs), which are ubiquitous and can create direct (PAH-DNA adduct) and indirect oxidative (8-oxo-dG) DNA damage, and genetic polymorphisms in their metabolism, conjugation and DNA repair have been equivocally associated with several cancers including prostate and colon. Physical activity (PA), a component of energy balance, has been consistently associated with colon cancer but reports in other cancers are inconsistent. Moreover, because exercise of sufficient intensity can upregulate antioxidant and other toxin defense mechanisms and lipophilic toxins (PAHs) can bioaccumulate in body fat, physical activity and other components of energy balance may modify effects of toxin exposure. To advance our knowledge of the role these systems play in carcinogenesis, biological systems-based modeling methods that incorporate genotype, phenotype (gene expression) and other epidemiological data are needed. Dr. Nock has been trained in genetic epidemiology but requires additional mentored training in statistical frameworks that solve systems of linear and non-linear equations including structural equation modeling (SEM) and physiologically-based toxico-kinetic/dynamic (PBTK/TD) modeling to undertake this pathway modeling. Dr. Nock would also benefit from explicit training in nutritional and exercise sciences. The proposed training program includes mentored research, graduate coursework and presentations at relevant national meetings. In the research plan, Dr. Nock proposes to integrate genotype-phenotype and biomarker measures into SEM and PBTK/TD statistical frameworks; and, apply these methods to modeling energy balance and toxin response systems using data from two cancer studies. The prostate cancer case-control study is unique because it includes biomarkers of effective PAH dose, candidate genes in PAH metabolism, conjugation and DNA repair and energy balance measures. The colon polyps case-control study is part of the Transdisciplinary Research on Energetics and Cancer program and enables evaluation of biomarkers and candidate genes in energy balance and toxin response systems.