# Presentation: 121014

## Molecular Targets for Nutrients in

**Prostate Cancer Prevention **

**Nutritional Science Research Group**
**Prostate and Urologic Cancer Research Group**

## 1996 Global Prostate Cancer Mortalities

**http://www-depdb.iarc.fr/who/detail.asp?cancer**

##  Nutrient Modifiers of Prostate Cancer

**However, the Specific Mechanism is Not Defined**

_**Probable**_

**Selenium Vitamin D Vitamin E **

_**Potential**_

**Vitamin A Genistein**
**EGCG**
**Fatty Acids**
**Calcium**
**Indole 3-carbinol**
**Resveratrol **

## Processes Influenced by Nutrients

**Carcinogen Metabolism**

**Hormonal Regulation**

**Cell Signaling**

** ****Apoptosis**

**Nutrients**

**Differentiation**

**Cell Cycle**

## Goal of the RFA Concept

**To promote**
*** *****genetic and epigenetic research**** **
**to define molecular targets for nutrients **
**in prostate cancer prevention.**

## 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**

**Effective Nutrients****                                           ****(Relative Effectiveness, Dose Dependency, Temporality, Consistency, Specificity)**** **

## 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**

## p27

**Plausible Targets**

**p27**

**Signaling Pathways            (****e.g.**** ****CDKs)**

**Apoptosis ****(e.g. bcl2)**

**Cell Senescence ****(e.g. Telomerase)**

**Survival Pathways ****(e.g. IGF-1/PI3K/Akt)**

**Oncogenes ****(e.g. c-myc)**

**Tumor Suppressor Genes ****(e.g. pRb)**

**Inflammation ****(e.g. NF kappa B)**

**Nutrient**

**??**

**??**

**??**

## Model Application Might Include

**Nutrient-Molecular**
**Target**

**Nutrient**
**Pharmokinetics**
**(Absorption and Metabolism)**

**In Vitro**

**In Vivo**

**Transfection          ****(p27, CDK2)**

**Transgenic or KO Mice      ****(PTEN, p27)**

## 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?**

**Overarching Topics of Interest**

## 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****.**

## Proposed Budget (M) (4 to 6 Awards)

|    2003 |    2004 |    2005 |    Total |
| --- | --- | --- | --- |
|  $ 1.50 |  $ 1.55 |  $ 1.60 |   $ 4.65 |

## FY00 Extramural Portfolio Analysis

**(10 R01, 2 R03,**
**       ****2 U01, 1 R21)**