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）是美国筛查高风险个体以早期发现结肠病变的第二主要原因，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型的内窥镜和蛋白质组学方法，用于评估癌前异常的隐窝灶（ACF）和腺瘤息肉。该方法旨在建立分子特征，以预测特定化学预防剂的功效并可能赋予。我们将使用Sulindac，目前正在NCI多中心试验性化学预防临床试验（CPN）中进行测试，作为一种模型化学预防剂来开发这种方法。我们提出的研究将解决以下问题：（1）Sulindac针对ACF和腺瘤的功效将使用小鼠中新型的内窥镜成像/病变映射方案进行原位跟踪；（2）将确定腺瘤的蛋白质组学和基因组特征，以预测和/或赋予其对苏琳克的反应；（3）在一项为期六周的Sulindac Pilot研究中，将在人类结肠组织中评估这些分子靶标的预测值。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疗效。最终，我们设想产生结肠病变的分子概况，以作为评估风险，设计为个人定制的癌症预防策略的基础，并确定未来化学预防剂的发展目标。尽管我们提出的研究集中于对苏琳克的反应，但这种一般策略可以适应通过不同作用模式起作用的化学预防剂。对个体结肠病变的分子概况的更全面的了解最终可以使用其对特定化学预防剂的反应，以制定安全有效的策略，以充分实现化学预防的承诺，以降低与结肠癌相关的死亡率和发病率。公共卫生相关性：我们正在开发一种方法来查看“实时”中结肠癌发生和化学预防的事件。在本金中，有可能确定哪些早期结肠病变的亚群发展为肿瘤，以及化学预防剂是抑制ACF形成速率还是促进其退化。我们预计我们的方法可以概括潜在的临床情况，其中可以使用蛋白质标记来鉴定具有“高风险” ACF或腺瘤的个体。此外，我们方法的长期目标是根据预测蛋白或癌前病变中发现的预测蛋白或基因的表达来自定义人群中的化学预防。尽管我们提出的研究集中于对苏琳克的反应，但这种一般策略可以适应通过不同作用模式起作用的化学预防剂。对个体结肠病变的分子概况的更全面的了解最终可以使用其对特定化学预防剂的反应，以制定安全有效的策略，以充分实现化学预防的承诺，以降低与结肠癌相关的死亡率和发病率。