Discovering New Targets for Chemoprevention in Familial Adenomatous Polyposis

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DESCRIPTION (provided by applicant): It has been shown that chemopreventive strategies involving nonsteroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors reduce the polyp burden in the colorectum of patients with Familial Adenomatous Polyposis (FAP). However, the same effect has not been observed on lesions arising in the duodenum. This fact indicates that there is a fundamental gap in understanding the molecular differences between polyps arising in the duodenum and the colorectum of patients with FAP. This knowledge is essential to develop new chemo- preventive agents in this disease. The long-term goal is to develop new chemopreventive therapies for patients with FAP. The objective in this particular application is to generate preliminary data to identify new targets that are amenable to drug intervention in duodenal adenomas of patients with FAP by fully characterizing the exome and transcriptome of these lesions. The central hypothesis is that duodenal adenomas, compared with colorectal adenomas, have distinct molecular alteration profiles, although both types of lesions arise on a common genetic basis (i.e. APC alterations). Therefore, a comprehensive annotation of the exome and transcriptome of duodenal polyps in FAP will be critical to identify new chemoprevention drugs targeting these lesions. The rationale that underlines this proposal is based on the observation in different clinical studies that chemoprevention with NSAIDs, proven effective in reducing the number of polyps and delaying adenoma progression in the colon and rectum, has had almost negligible effect on duodenal lesions. In addition, the natural history of duodenal polyps is notable for a slow and prolonged course of the adenoma-to-carcinoma sequence. This hypothesis will be tested by pursuing two specific aims: 1) To compare the genomic and gene expression profiles of duodenal adenomas with those of patient-matched colorectal adenomas and normal surrounding mucosa from both locations in patients with FAP; 2) To identify molecular pathways and candidate compounds for targeting duodenal adenomas in FAP patients by using systems biology tools. Under the first aim, next generation sequencing techniques will be used to characterize the exome and transcriptome of duodenal and colorectal polypoid lesions in 10 patients with FAP. Under the second aim, bioinformatics tools will be developed to integrate the data generated with both next-generation sequencing tools into existing publicly available data sets using systems biology tools. These bioinformatic tools will be exploited to discover new targets and com- pounds to be developed as chemopreventive agents. The approach is innovative because is combining the use of next-generation sequencing technologies and systems biology tools for the first time to study premalignant gastrointestinal lesions in a genetic disease and to identify new targeted chemopreventive agents. The proposed research is significant because is expected to lead to the development of new pharmacologic strategies for prevention in FAP. This will ultimately lead to the reduction of the mortality secondary to duodenal carcinomas, and morbidity of prophylactic surgeries performed in patients with duodenal adenomatosis.