Colorectal cancer is the third leading cause of cancer death in both males and females in the U.S. The overall, long-term goal of the Chemoprevention of Colon Cancer 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 in subjects at increased risk for colon cancer and to define the fundamental epigenetic and genetic mechanisms of polyp genesis and recurrence. Our Program Project consists of three highly interactive scientific research components and will complete two large cancer control phase III studies in 2800 participants as follows: 1. A phase III randomized, placebo-controlled, double-blind cancer control study of the effect of ursodeoxycholic acid on recurrence of adenomatous polyps, with emphasis on proving the bile acid hypothesis that colon carcinogenesis is a progressive disorder of signal transduction involving the interaction of fat, bile acids and bacteria; 2. A phase II randomized, placebo-controlled, double-blind study of factorial design of the effect of celecoxib, a COX-2 inhibitor, and selenium (formulated in backer's yeast), a nutritional supplement, and their combination on adenoma recurrence. These agents were selected because of their different mechanistic effects on the colon carcinogenesis signal transduction pathway, well-documented activity in animal models and safety profiles established in human studies; 3. An examination of CpG island methylator phenotype (CIMP) abnormalities, specific genetic alterations (APC, Ki-ras, p53), and biologic perturbations (PCNA, COX, apoptosis) in baseline adenomas and age-related DNA methylation and nuclear chromatin patterns in rectal mucosal biopsies, as predictors of adenomas recurrence; and 4. Project of factors enhancing susceptibility to colon carcinogenesis, including environmental/lifestyle characteristics and high prevalence polymorphisms in enzymes involved in folate metabolism and metabolism of heterocyclic amines, and their interaction with genetic and epigenetic mechanisms in relation to risk of adenoma recurrence. To accomplish our goals, we have brought together a group of outstanding cancer researchers who have developed a highly integrated, hypothesis-driven research proposal with a strong likelihood of success that was grafted so that will Projects and Core Services within six large universities depend scientifically and operationally on each other.
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