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来预防散发性腺瘤性息肉的复发，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部分：1.在1600名参与者中，对环氧合酶-2抑制剂塞来昔布和营养补充剂硒及其组合对腺瘤复发的影响进行了第三阶段的随机、安慰剂对照、双盲因子设计研究。这些药物之所以被选中，是因为它们在结肠癌发生中的不同机制作用，在 临床前模型，以及在人体研究中建立的安全性概况。作为次要目标，将在六个基因中分析单核苷酸多态变异的影响，这些基因有证据表明塞来昔布、阿司匹林或硒干预措施的基因效应改变，或它们的毒性。2.高危结直肠腺瘤表型的病理、分子、遗传和流行病学鉴定，包括对锯齿状腺瘤致癌途径的深入分析，这最终将有助于更好地理解风险分层、面向公共健康的筛查和化学预防策略；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)与复发和高危结直肠腺瘤和癌变的关系，包括参与胰岛素产生、清除和作用的基因的候选基因型/单倍型以及胰岛素抵抗的血浆生物标志物之间的关系。我们将利用从6,000多名参与者的多个时间点获得的冷冻血浆、血清、外周血白细胞和档案息肉组织，这些参与者被随机分为四项结直肠息肉预防试验(即，我们计划的麦麸纤维、熊去氧胆酸、塞来昔布/硒试验和NCI息肉预防试验)，以及来自结肠癌家族登记的2000多名参与者的血液样本。为了实现我们的目标，我们聚集了一群杰出的癌症研究人员，他们在大多数情况下共同工作了10-15年，并开发了一个高度集成和互动的、以假设为导向的研究方案，该方案具有很大的成功可能性，其精心设计的方案使五个大型大学医疗中心和一个研究机构(翻译基因组研究所-菲尼克斯)内的所有项目和核心服务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.