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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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Presentation Transcript
slide1

Molecular Targets for Nutrients in

Prostate Cancer Prevention

Nutritional Science Research Group

Prostate and Urologic Cancer Research Group

slide2

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
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

slide4

Processes Influenced by Nutrients

Carcinogen Metabolism

Hormonal Regulation

Cell Signaling

Nutrients

Differentiation

Cell Cycle

Apoptosis

slide5

Goal of the RFA Concept

To promote

genetic and epigenetic research

to define molecular targets for nutrients

in prostate cancer prevention.

slide6

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

slide7

Models for Prostate Cancer

  • Animals
  • Rodents
      • Chemically induced
      • Transgenics
      • Knockouts
      • Xenografts
  • Canine
  • Spontaneously induced
  • Culture
  • Tumor cells
slide8

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

slide9

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)

slide10

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)

slide11

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?

slide12

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)

slide13

Mechanism for Concept

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

fy00 extramural portfolio analysis

%

#

$ (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)