Colorectal cancer is the second leading cause of cancer death in the U.S. The overall, long-term goal of our Program Project is to reduce the incidence, morbidity and mortality of colorectal cancer. To accomplish this goal, we seek to develop highly effective intervention strategies to prevent the recurrence of sporadic adenomatous polyps, and to define the fundamental epidemiologic, epigenetic and genetic mechanisms of polyp genesis and recurrence. Our Program Project consists of three highly interactive scientific research components as follows: 1. a phase III randomized, placebo-controlled, double-blind study of factorial design of the effect of celecoxib, a COX-2 inhibitor, and selenium, a nutritional supplement, and their combination on adenoma recurrence in 1600 participants. These agents were selected because of their different mechanistic effects on the colon carcinogenesis, well-documented activity in preclinical models, and safety profiles established in human studies. As secondary objectives, the influence of single nucleotide polymorphism variations will be analyzed in six genes for which there is evidence of genotypic effect modification of the celecoxib, aspirin or selenium interventions, or their toxicities 2. a pathologic, molecular, genetic and epidemiologic identification of a high risk colorectal adenoma phenotype, including an in-depth analysis of the serrated adenoma carcinogenesis pathway that ultimately will contribute to an improved comprehension of risk stratification, public health oriented screening, and chemoprevention strategies;and 3. an in-depth analysis of associations between diet and lifestyle factors that promote chronic hyperinsulinemia/insulin resistance (e.g. obesity, excess energy intake, glycemic index) and recurrent and high risk colorectal adenomas and carcinogenesis, including associations between candidate genotypes/haplotypes in genes involved in insulin production, clearance, and action as well as plasma biomarkers of insulin resistance. We will utilize frozen plasma, serum, peripheral blood leukocytes and archival polyp tissue obtained at multiple time points from more than 6,000 participants randomized into four colorectal polyp prevention trials (i.e., our Program Project's wheat bran fiber, ursodeoxycholic acid, and celecoxib/selenium trials and the NCI polyp prevention trial), as well as blood samples from over 2000 participants in the Colon Cancer Family Registry. To accomplish our goals, we have brought together a group of outstanding cancer researchers who have in most cases worked together for 10-15 years and have developed a highly integrated and interactive, hypothesis-driven research proposal with a strong likelihood of success that was crafted so that all Projects and Core Services within five large university medical centers and a research institute (Translational Genomics Research Institute - Phoenix) depend scientifically and operationally on each other.
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