A Mouse Model for FAP Polyp Progression and Prevention

James M. Ford, MD, FASCO

• Professor of Medicine and Genetics

• Division of Oncology Director

• Clinical Cancer Genetics and Genomics

• Stanford University School of Medicine

A Mouse Model for FAP Polyp Progression and Prevention

Familial Adenomatous Polyposis (FAP) patients have a very high rate of polyp progression to colon adenocarcinomas unless undergoing a prophylactic colectomy. However, to date there is little that can be done clinically to prevent this in patients at high risk. We propose to develop a mouse model of FAP polyp progression to colon cancer and to use this to test the hypothesis that mutagenesis, and ultimately tumorigenesis, can be suppressed by activating specific DNA repair enzymes that recognize the most highly mutagenic lesions that arise in DNA. Our research team is the first to propose upregulating DNA repair as a targeted strategy for chemoprevention as there are currently no clinical strategies for directly suppressing mutagenesis. In Aim 1, we will feed ApcMin/+ mice, which have been genetically modified to develop intestinal polyps, with damaged deoxynucleosides that we have shown to introduce DNA damage and result in enhanced mutagenesis in cell lines, to accelerate the progression of polyps to invasive colon cancers in mice and thus more accurately mimic the physiologic condition of human FAP patients. In the second aim, we will test whether small-molecule activators of specific DNA repair enzymes that we have disovered will enhance DNA repair and suppress mutagenesis in our animal model of FAP. We hypothesize that FAP patients and others can benefit from the development of DNA repair targeted strategies for preventing the mutations that lead to malignancies, and thus serve as clinical prevention agents that might be exploited for FAP patients.