Of somatic genome alterations in human solid organ cancers, only changes in DNA methylation occur consistently (>90% of cases), arise early (first appearing in preneoplastic lesions), and can be reversed (the DNA sequence remains intact). Hypermethylation of CpG island sequences, which encompass the 5' transcriptional regulatory regions of many genes, can lead to repression of gene transcription via the recruitment of 5-mCpG-binding domain (MBD) family proteins. Of the MBD family proteins, MBD2 is a very attractive target for cancer prevention and treatment: Apc Mm/+ mice, prone to intestinal tumorigenesis, develop some 10-fold fewer intestinal adenomas when bred to an Mbd2 -/- background. The therapeutic strategy to be explored in this Project features the selective targeting of the MBD2 transcriptional repression pathway. To discover small molecule MBD2 pathway inhibitors, a novel staged """"""""highthroughput"""""""" screen will be used, featuring the CpG island of GSTP1, known to be """"""""silenced"""""""" in prostate, breast, and liver cancers via somatic hypermethylation and MBD2-mediated repression. New """"""""lead"""""""" compounds will then be characterized for potency and efficacy at """"""""silenced"""""""" gene reactivation, and for therapeutic index in animal model studies of cancer prevention and treatment.
The Specific Aims to be pursued are: (i) the screening of 100,000 compounds for selective activation of transcription from hypermethylated GSTP1 promoter sequences, (ii) the characterization of """"""""lead"""""""" compounds for molecular mechanisms of action, and (iii) the evaluation of preclinical anti-cancer efficacy and toxicity in mouse models.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA113374-01
Application #
6899546
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Crowell, James A
Project Start
2005-06-01
Project End
2008-05-31
Budget Start
2005-06-01
Budget End
2006-05-31
Support Year
1
Fiscal Year
2005
Total Cost
$289,510
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218