Colon Cancer Prevention Program Project Grant

结直肠癌是美国癌症死亡的第二大原因。我们计划项目的总体长期目标是降低结直肠癌的发病率、发病率和死亡率。为了实现这一目标，我们寻求开发高效的干预策略，以防止复发的散发性腺瘤性息肉，并确定息肉发生和复发的基本流行病学，表观遗传学和遗传学机制。我们的计划项目包括以下三个高度互动的科学研究组成部分：1。 一项III期、随机、安慰剂对照、双盲、析因设计的研究，在1600名受试者中研究塞来昔布（一种考克斯-2抑制剂）和硒（一种营养补充剂）及其联合用药对腺瘤复发的影响。选择这些药物是因为它们对结肠癌发生的不同机制作用，在结肠癌中有充分记录的活性。 临床前模型和人体研究中建立的安全性特征。作为次要目的，将在6个基因中分析单核苷酸多态性变异的影响，这些基因有证据表明塞来昔布、阿司匹林或硒干预的基因型效应改变或其毒性2。高风险结肠直肠腺瘤表型的病理学、分子学、遗传学和流行病学鉴定，包括锯齿状腺瘤致癌途径的深入分析，其最终将有助于改善对风险分层、公共卫生导向的筛查和化学预防策略的理解;以及3.深入分析促进慢性高胰岛素血症/胰岛素抵抗的饮食和生活方式因素（例如肥胖、过量能量摄入、血糖指数）与复发性和高风险结直肠腺瘤和癌发生之间的关联，包括参与胰岛素产生、清除和作用的基因中候选基因型/单倍型之间的关联，以及胰岛素抵抗的血浆生物标志物。我们将利用在多个时间点从6,000多名参与者中获得的冷冻血浆、血清、外周血白细胞和存档息肉组织，这些参与者被随机分配到四项结肠直肠息肉预防试验中（即，我们计划项目的麦麸纤维、熊去氧胆酸和塞来昔布/硒试验以及NCI息肉预防试验），以及结肠癌家族登记处2000多名参与者的血液样本。为了实现我们的目标，我们汇集了一批优秀的癌症研究人员，他们在大多数情况下一起工作了10-15年，并开发了一个高度集成和互动的，一个假设驱动的研究提案，具有很大的成功可能性，该提案经过精心设计，使五个大型大学医学中心和一个研究机构内的所有项目和核心服务（翻译基因组学研究所-凤凰城）在科学上和操作上相互依赖。

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.