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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.

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Molecular Targets for Nutrients in

Prostate Cancer Prevention

Nutritional Science Research Group

Prostate and Urologic Cancer Research Group


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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


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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


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Processes Influenced by Nutrients

Carcinogen Metabolism

Hormonal Regulation

Cell Signaling

Nutrients

Differentiation

Cell Cycle

Apoptosis


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Goal of the RFA Concept

To promote

genetic and epigenetic research

to define molecular targets for nutrients

in prostate cancer prevention.


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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


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Models for Prostate Cancer

  • Animals

  • Rodents

    • Chemically induced

    • Transgenics

    • Knockouts

    • Xenografts

  • Canine

  • Spontaneously induced

  • Culture

  • Tumor cells


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    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


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    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)


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    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)


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    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?


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    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)


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    Mechanism for Concept

    This RFA mechanism with set-aside funds is needed to stimulate submission of innovative applications, primarily R01s.


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    Proposed Budget (M)(4 to 6 Awards)


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    %

    #

    $ (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)


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