The goal of this program has been to elucidate mechanisms by which loss of DNA mismatch repair (MMR) function leads to genesis of human colon cancers with microsatellite instability (MSI), with particular emphasis on understanding MSI colon cancers that arise as sporadic non-familial disease (at a minimum, non-classical HNPCC). Based on extensive work accomplished during the initial funding period, this continuation will focus on understanding mechanisms that give rise to aberrant methylation of the hMLH1 promoter, and will exploit the specific DNA repair defect present in MSI colon cancers to develop new diagnostic and therapeutic strategies that target these tumors. There are 5 specific aims. First, to determine whether methylation of hMLH1 is due to an aberration that works in cis or in trans, and whether the underlying cellular defect is dominant or recessive. Second, to determine if the hMLH1 methylation is an initiation or progression event in colon cancer, and whether it occurs in tandem or independent of methylation of other genes. Third, to develop an assay for circulating methylated hMLH1 DNA as a diagnostic test for early detection of sporadic MSI colon cancer. Fourth, to determine what derivatives of ICR191 have optimal selectivity for killing MSI colon cancers both in cell culture and in vivo. Fifth, to develop a novel assay for recognizing individuals with germ line MMR mutations, by increasing genomic instability in their cultured lymphocytes that induces loss of the wild-type allele, thus generating MMR deficiency and MNNG resistence.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA067409-06
Application #
6286892
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Okano, Paul
Project Start
1996-04-15
Project End
2006-01-31
Budget Start
2001-04-11
Budget End
2002-01-31
Support Year
6
Fiscal Year
2001
Total Cost
$439,209
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Sun, Xiyuan; Liu, Yiding; Lutterbaugh, Jim et al. (2006) Detection of mononucleotide repeat sequence alterations in a large background of normal DNA for screening high-frequency microsatellite instability cancers. Clin Cancer Res 12:454-9
Chen, Wei-Dong; Han, Z James; Skoletsky, Joel et al. (2005) Detection in fecal DNA of colon cancer-specific methylation of the nonexpressed vimentin gene. J Natl Cancer Inst 97:1124-32
Coady, Michael J; Chang, Min-Hwang; Charron, Francois M et al. (2004) The human tumour suppressor gene SLC5A8 expresses a Na+-monocarboxylate cotransporter. J Physiol 557:719-31
Traicoff, June L; De Marchis, Laura; Ginsburg, Britten L et al. (2003) Characterization of the human polymeric immunoglobulin receptor (PIGR) 3'UTR and differential expression of PIGR mRNA during colon tumorigenesis. J Biomed Sci 10:792-804
Traicoff, June L; Periyasamy, Sumudra; Brattain, Michael G et al. (2003) Reconstitution of TGF-beta sensitivity in the VACO-411 human colon carcinoma line by somatic cell fusion with MCF-7. J Biomed Sci 10:253-9
Fink, Stephen P; Mikkola, Debra; Willson, James K V et al. (2003) TGF-beta-induced nuclear localization of Smad2 and Smad3 in Smad4 null cancer cell lines. Oncogene 22:1317-23
Brunschwig, Elaine B; Wilson, Keith; Mack, David et al. (2003) PMEPA1, a transforming growth factor-beta-induced marker of terminal colonocyte differentiation whose expression is maintained in primary and metastatic colon cancer. Cancer Res 63:1568-75
Li, Hui; Myeroff, Lois; Smiraglia, Dominic et al. (2003) SLC5A8, a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers. Proc Natl Acad Sci U S A 100:8412-7
Meyers, Mark; Hwang, Arlene; Wagner, Mark W et al. (2003) A role for DNA mismatch repair in sensing and responding to fluoropyrimidine damage. Oncogene 22:7376-88
Moinova, Helen R; Chen, Wei-Dong; Shen, Lanlan et al. (2002) HLTF gene silencing in human colon cancer. Proc Natl Acad Sci U S A 99:4562-7

Showing the most recent 10 out of 26 publications