Molecular Targets for Nutrients in Prostate Cancer Prevention Nutritional Science Research Group Prostate and Urologic Cancer Research Group
30 25 20 15 Age-Adjusted Death Rates (per 100,000 population) 10 5 0 Philippines Bulgaria United States Iceland Japan Greece Switzerland 1996 Global Prostate Cancer Mortalities http://www-depdb.iarc.fr/who/detail.asp?cancer
Nutrient Modifiers of Prostate Cancer Probable Potential Selenium Vitamin D Vitamin E Vitamin A Genistein EGCG Fatty Acids Calcium Indole 3-carbinol Resveratrol However, the Specific Mechanism is Not Defined
Processes Influenced by Nutrients Carcinogen Metabolism Hormonal Regulation Cell Signaling Nutrients Differentiation Cell Cycle Apoptosis
Goal of the RFA Concept To promote genetic and epigenetic research to define molecular targets for nutrients in prostate cancer prevention.
Effective Nutrients(Relative Effectiveness, Dose Dependency, Temporality, Consistency, Specificity) Criteria for Molecular Targets • Linkage to a significant proportion of prostate tumors • Tissue specificity across various genetic backgrounds • Modification influences tumor risk and/or behavior
Models for Prostate Cancer • Animals • Rodents • Chemically induced • Transgenics • Knockouts • Xenografts • Canine • Spontaneously induced • Culture • Tumor cells
Approaches for Defining Molecular Targets for Nutrients Expression Level In Vitro In Vivo Transfection Adenoviral Infection Transgene Antisense Nucleotide Metabolic Inhibitors Conditional Knockout Metabolic Inhibitors
Plausible Targets Nutrient ?? ?? ?? Apoptosis (e.g. bcl2) Signaling Pathways (e.g.CDKs) Cell Senescence (e.g. Telomerase) p27 Tumor Suppressor Genes (e.g. pRb) Oncogenes (e.g. c-myc) Survival Pathways (e.g. IGF-1/PI3K/Akt) Inflammation (e.g. NF kappa B)
Model Application Might Include Nutrient-Molecular Target In Vitro In Vivo Transgenic or KO Mice (PTEN, p27) Transfection (p27, CDK2) Nutrient Pharmokinetics (Absorption and Metabolism)
Overarching Topics of Interest • Can IGF-1, PI3K, and Akt account for the effect of dietary fatty acids on prostate tumor growth promotion? • Can variation in AR or ER explain the ability of soy isoflavones to retard prostate cancer? • Can GSTP1 methylation be influenced by dietary methyl donors and ultimately modify prostate cancer risk?
Supports for the RFA Concept • National Cancer Institute Prostate Cancer Progress Review Group (1998) • Nutrition Implementation Group (1999) • DCP/NCI Molecular Targets for Dietary Prevention of Prostate Cancer (2000) • National Cancer Institute’s Extraordinary Opportunities (2002)
Mechanism for Concept This RFA mechanism with set-aside funds is needed to stimulate submission of innovative applications, primarily R01s.
% # $ (M) Total 2,204 100.0 Cancer Prevention 662 222 10.1 Prostate Cancer 2,231 170 7.7 Nutrition 606 156 7.1 Combination 15 5 0.2 FY00 Extramural Portfolio Analysis (10 R01, 2 R03, 2 U01, 1 R21)