In Project 1 we will test the hypothesis in a novel interventional clinical trial that concurrent inhibition of cyclo-oxygenases and EGFR will induce duodenal and colorectal adenomatous polyp regression in a cohort of high-risk, familial adenomatous polyposis (FAP) and attenuated FAP subjects. The two protein classes inhibited in this trial were found in the previous funding cycle to mediate the oncogenic effects of mutant adenomatous polyposis coli (APC) gene. Examining adenoma regression and specific markers of these two pathways in a clinical trial will not only address specific clinical needs, but will also provide the human model for defining how these pathways are perturbed in carcinogenesis following loss of APC function. These same pathways will be addressed in the other projects of this Program in cell culture, zebrafish and mouse models, thereby forming a unified approach to determining downstream effects of APC function loss. The knowledge gained will serve to identify novel strategies for diagnosis, prevention and treatment of adenomatous polyps and colon cancer. FAP and attenuated FAP subjects will be studied both because of the multiple polyp phenotype, and because these conditions arise from inherited APC gene mutations, the same gene somatically mutated in the large majority of colon adenomas and cancers. Safe and effective chemoprevention for colon polyps and cancer would be of substantial benefit for both sporadic and high risk forms of colorectal neoplasia. Duodenal polyps and cancer are a particular problem for FAP and attenuated FAP patients, as present treatments are far from satisfactory. We will specifically enroll 100 FAP and attenuated FAP subjects in a double blind, placebo controlled trial to examine the combinatorial effect of sulindac (a general COX inhibitor) and erlotinib (an EGFR inhibitor) to induce regression of duodenal and colorectal adenomatous polyps. We will draw from a combined cohort of approximately 300 local FAP and attenuated FAP subjects in our high-risk familial colon cancer registry. Secondary endpoints that complement the studies of other projects of this Program include: the change in aberrant crypt foci before and after treatment;and, changes in expression of WNT, EGFR and KRAS cellular signaling pathways in both adenomatous polyp and normal tissue biopsy samples. Finally, appropriate samples obtained in this project will be utilized by Projects 2-4.

Public Health Relevance

Two agents (COX inhibitors and EGFR inhibitors) that are used alone to inhibit or treat colon polyps and cancer will be given together to high risk colon cancer patients who form multiple polyps. It is expected that this combination of medication will cause polyps to significantly regress. Results of this study will not only suggest better ways to prevent colon polyps and cancer, but will provide an understanding of how the function of the cell is perturbed in the formation of cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA073992-11A1
Application #
7786712
Study Section
Special Emphasis Panel (ZCA1-RPRB-7 (O1))
Project Start
2010-03-12
Project End
2015-02-28
Budget Start
2010-03-12
Budget End
2011-02-28
Support Year
11
Fiscal Year
2010
Total Cost
$1,315,004
Indirect Cost
Name
University of Utah
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Jewel Samadder, N; Valentine, John F; Guthery, Stephen et al. (2017) Colorectal Cancer in Inflammatory Bowel Diseases: A Population-Based Study in Utah. Dig Dis Sci 62:2126-2132
Gan, Meng; Boothe, Dustin; Neklason, Deborah W et al. (2017) Outcomes and complications of radiation therapy in patients with familial adenomatous polyposis. J Gastrointest Oncol 8:643-649
Bice, Benjamin D; Stephens, Megan R; Georges, Stephanie J et al. (2017) Environmental Enrichment Induces Pericyte and IgA-Dependent Wound Repair and Lifespan Extension in a Colon Tumor Model. Cell Rep 19:760-773
Kanth, Priyanka; Bronner, Mary P; Boucher, Kenneth M et al. (2016) Gene Signature in Sessile Serrated Polyps Identifies Colon Cancer Subtype. Cancer Prev Res (Phila) 9:456-65
Burt, Randall W (2016) Screening and Survival in Familial Adenomatous Polyposis. J Clin Gastroenterol 50:3-4
Samadder, N Jewel; Smith, Ken Robert; Hanson, Heidi et al. (2016) Familial Risk in Patients With Carcinoma of Unknown Primary. JAMA Oncol 2:340-6
Neklason, Deborah W; VanDerslice, James; Curtin, Karen et al. (2016) Evidence for a heritable contribution to neuroendocrine tumors of the small intestine. Endocr Relat Cancer 23:93-100
Li, Jun; Woods, Susan L; Healey, Sue et al. (2016) Point Mutations in Exon 1B of APC Reveal Gastric Adenocarcinoma and Proximal Polyposis of the Stomach as a Familial Adenomatous Polyposis Variant. Am J Hum Genet 98:830-842
Samadder, N Jewel; Curtin, Karen; Pappas, Lisa et al. (2016) Risk of Incident Colorectal Cancer and Death After Colonoscopy: A Population-based Study in Utah. Clin Gastroenterol Hepatol 14:279-86.e1-2
Samadder, N Jewel; Neklason, Deborah W; Boucher, Kenneth M et al. (2016) Effect of Sulindac and Erlotinib vs Placebo on Duodenal Neoplasia in Familial Adenomatous Polyposis: A Randomized Clinical Trial. JAMA 315:1266-75

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