Our Center has been involved in developing and analyzing a large number of genetically modified mouse models for colon cancer. Study of these models provided valuable information about the initiation and progression of colorectal cancer and the roles of many different genes in that process. More recently we have developed floxed alleles of three genes;Ape, Mlh1 and Msh2. When adeno-cre is introduced into the rectum of the floxed allele of Ape, the mice develop one tumor at the site of injection. We have developed a novel colonoscope for mice that allows us to examine the onset and progression of the tumors without sacrificing the mice. We now propose a series of experiments to establish the different mouse models that we have already developed for translational research. We have used our mouse models to identify protein based biomarkers that enable us to distinguish between normal and tumor bearing mice at an early stage. In a parallel effort we have collaborated with the Women's Health Initiative and the NCI's early detection research network (EDRN) to identify a similar set of protein markers based on examination of plasma samples from women prior to diagnosis with colon cancer. There is a significant overlap between the proteins identified from the mouse model and the human samples. We will use mouse models to bring these markers into the clinical setting. The Apc-Adeno-cre model described above is an excellent model for human sporadic colorectal cancer. We will use our models to evaluate a large number of drugs that might be effective in colon cancer. All of these studies are going to be facilitated by the use of novel imaging methodologies that allow us to follow the progression of tumors in individual mice in a non-invasive fashion. Germline mutations in human mismatch repair genes MLH1 and MSH2 result in a cancer predisposition syndrome, termed hereditary non-polyposis colorectal cancer (HNPCC). Mismatch repair (MMR) deficiency is also observed in a large number of sporadic tumors in different tissues. Understanding how tumors with MMR deficiency respond to chemotherapeutic regimens and other drugs is critical in developing new therapeutic approaches. We propose such experiments. Mismatch repair genes function within large DNA binding complexes. All of the critical members of these complexes have not been identified. Using novel models and mass spectrometry we propose to identify all of the members of the complex. These efforts will significantly advance the use of mouse models for human cancer translational efforts.

Public Health Relevance

The RFA is seeking the use of mouse models to directly address relevant to human cancer. We have developed novel mouse models that mimic both human colon cancer predisposition and sporadic cancer. The use of these models would accelerate early detection and therapeutic intervention strategies in human colorectal cancer

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA084301-14
Application #
8329717
Study Section
Special Emphasis Panel (ZCA1-SRLB-Q (M1))
Program Officer
Marks, Cheryl L
Project Start
1999-09-30
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
14
Fiscal Year
2012
Total Cost
$770,255
Indirect Cost
$159,879
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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Habibollahi, Peiman; Waldron, Todd; Heidari, Pedram et al. (2014) Fluorescent nanoparticle imaging allows noninvasive evaluation of immune cell modulation in esophageal dysplasia. Mol Imaging 13:1-11
Li, Xingnan; Nadauld, Lincoln; Ootani, Akifumi et al. (2014) Oncogenic transformation of diverse gastrointestinal tissues in primary organoid culture. Nat Med 20:769-77
Turker, N Selcan; Heidari, Pedram; Kucherlapati, Raju et al. (2014) An EGFR targeted PET imaging probe for the detection of colonic adenocarcinomas in the setting of colitis. Theranostics 4:893-903
Kucherlapati, Melanie H; Esfahani, Shadi; Habibollahi, Peiman et al. (2013) Genotype directed therapy in murine mismatch repair deficient tumors. PLoS One 8:e68817

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