Using Mouse Endoscopy for Evaluating Colon Cancer

使用小鼠内窥镜评估结肠癌

基本信息

批准号：
8267088
负责人：
Daniel William Rosenberg
金额：
$ 35.01万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8267088
关键词：
A/J Mouse Aberrant crypt foci Address Adenomatous Polyps Arachidonic Acids Biopsy Specimen Cancer Etiology Cessation of life Chemoprevention Chemopreventive Agent Clinic Clinical Clinical Trials Colon Colon Carcinoma Colonic Adenoma Colorectal Cancer Development Dose Early Diagnosis Endoscopy Event Future Genes Genomics Goals Growth Health Human Image In Situ Individual Intervention Laboratories Lesion Maps Methodology Methods Modeling Molecular Molecular Analysis Molecular Profiling Molecular Target Monitor Morbidity - disease rate Mucous Membrane Mus Pathway interactions Patients Pilot Projects Predictive Value Premalignant Prevention strategy Proteins Proteomics Protocols documentation Relative (related person)Resistance Risk Screening procedure Site Sulindac Testing Time Tissues adenoma base cancer prevention cancer risk colon carcinogenesis design high risk improved mortality novel population based response tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the second leading cause of cancer deaths in the U.S. Screening high-risk individuals for the early detection of colon lesions is an important approach to improving treatment and survival. This application is intended to develop and refine a novel combined endoscopic and proteomic method for evaluating precancerous aberrant crypt foci (ACF) and adenomatous polyps. This methodology aims to establish molecular features that predict, and potentially confer, the efficacy of specific chemoprevention agents. We will use sulindac, currently being tested in an NCI multi-center pilot chemoprevention clinical trial (CPN), as a model chemopreventive agent to develop this methodology. Our proposed studies will address the following issues: (1) The efficacy of sulindac against ACF and adenomas will be tracked in situ using a novel endoscopic imaging/lesion mapping protocol in mice; (2) The proteomic and genomic features of adenomas that predict and/or confer their response to sulindac will be identified; (3) The predictive value of these molecular targets for sulindac efficacy will be evaluated in human colon tissues in a six-week sulindac pilot study. Our hypothesis is that the molecular features of early precancerous lesions and adenomas will predict and potentially confer the efficacy of chemoprevention. Ultimately we envision generating a molecular profile of colon lesions to serve as the basis for assessing risk, designing cancer- prevention strategies customized to the individual and identifying targets for the development of future chemopreventive agents. Although our proposed studies focus on the response to sulindac, this general strategy could be adapted to chemoprevention agents that function through different modes of action. A more comprehensive understanding of how the molecular profile of an individual's colon lesions relates to their response to specific chemopreventive agents could ultimately be used to develop safe and effective strategies that fully realize the promise of chemoprevention for reducing mortality and morbidity related to colon cancer. PUBLIC HEALTH RELEVANCE: We are developing an approach to view the events of colon carcinogenesis and chemoprevention in 'real-time'. It will be possible in principal to determine which subpopulations of early colon lesions develop into tumors, and whether chemoprevention agents suppress the rate of ACF formation, or promote their regression. Our approach is predicted to recapitulate potential clinical situations, in which protein markers can be used to identify individuals with 'high-risk' ACF or adenomas. In addition, a long-term goal of our approach is to customize chemoprevention in human populations based on expression of predictive proteins or genes uncovered in precancerous lesions. Although our proposed studies focus on the response to sulindac, this general strategy could be adapted to chemoprevention agents that function through different modes of action. A more comprehensive understanding of how the molecular profile of an individual's colon lesions relates to their response to specific chemopreventive agents could ultimately be used to develop safe and effective strategies that fully realize the promise of chemoprevention for reducing mortality and morbidity related to colon cancer.

描述（由申请人提供）：结直肠癌（CRC）是美国癌症死亡的第二大原因。筛查高危个体以及早发现结肠病变是改善治疗和生存的重要方法。该应用旨在开发和完善一种新颖的内窥镜和蛋白质组学组合方法，用于评估癌前异常隐窝灶（ACF）和腺瘤性息肉。该方法旨在建立预测并可能赋予特定化学预防剂功效的分子特征。我们将使用目前正在 NCI 多中心试点化学预防临床试验 (CPN) 中进行测试的舒林酸作为模型化学预防剂来开发该方法。我们提出的研究将解决以下问题：（1）将使用新型内窥镜成像/病变绘图方案在小鼠中原位追踪舒林酸对抗 ACF 和腺瘤的功效； (2) 将鉴定预测和/或赋予其对舒林酸反应的腺瘤的蛋白质组学和基因组学特征； (3) 将在为期六周的舒林酸试点研究中评估这些分子靶点对舒林酸功效的预测价值。我们的假设是，早期癌前病变和腺瘤的分子特征将预测并可能赋予化学预防的功效。最终，我们设想生成结肠病变的分子谱，作为评估风险、设计针对个体的癌症预防策略以及确定未来化学预防药物开发目标的基础。尽管我们提出的研究重点是对舒林酸的反应，但这一总体策略可以适用于通过不同作用模式发挥作用的化学预防药物。更全面地了解个体结肠病变的分子特征与其对特定化学预防药物的反应之间的关系，最终可用于制定安全有效的策略，充分实现化学预防降低结肠癌相关死亡率和发病率的承诺。公共卫生相关性：我们正在开发一种“实时”查看结肠癌发生和化学预防事件的方法。原则上将有可能确定早期结肠病变的哪些亚群发展成肿瘤，以及化学预防剂是否抑制 ACF 形成的速率，或促进其消退。我们的方法预计将重现潜在的临床情况，其中蛋白质标记可用于识别患有“高风险”ACF 或腺瘤的个体。此外，我们方法的长期目标是根据癌前病变中发现的预测蛋白或基因的表达来定制人群的化学预防。尽管我们提出的研究重点是对舒林酸的反应，但这一总体策略可以适用于通过不同作用模式发挥作用的化学预防药物。更全面地了解个体结肠病变的分子特征与其对特定化学预防药物的反应之间的关系，最终可用于制定安全有效的策略，充分实现化学预防降低结肠癌相关死亡率和发病率的承诺。