Using Mouse Endoscopy for Evaluating 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，筛查高危人群以早期发现结肠病变是提高治疗和生存率的重要途径。本应用程序旨在开发和完善一种新的内镜和蛋白质组学联合方法来评估癌前异常隐窝灶（ACF）和腺瘤性息肉。该方法旨在建立分子特征，预测和潜在地授予特定化学预防剂的功效。我们将使用目前正在NCI多中心试点化学预防临床试验（CPN）中进行测试的舒林达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)使用一种新的内窥镜成像/病变定位方案在小鼠中原位跟踪舒林酸对ACF和腺瘤的疗效；(2)将确定预测和/或赋予其对舒林达反应的腺瘤的蛋白质组学和基因组特征；(3)这些分子靶点对舒林达克疗效的预测价值将在为期6周的舒林达克中试研究中在人结肠组织中进行评估。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有效性。最终，我们设想生成结肠病变的分子图谱，作为评估风险的基础，设计针对个体的癌症预防策略，并确定未来化学预防药物开发的目标。虽然我们提出的研究重点是对舒林达的反应，但这种一般策略可以适用于通过不同作用模式起作用的化学预防剂。更全面地了解个体结肠病变的分子特征与他们对特定化学预防药物的反应之间的关系，最终可以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”观察结肠癌发生和化学预防事件的方法。原则上有可能确定早期结肠病变的哪些亚群发展成肿瘤，以及化学预防药物是否抑制ACF的形成速度，还是促进其消退。我们的方法预计将概括潜在的临床情况，其中蛋白质标记物可用于识别“高风险”ACF或腺瘤患者。此外，我们方法的一个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类的化学预防。虽然我们提出的研究重点是对舒林达的反应，但这种一般策略可以适用于通过不同作用模式起作用的化学预防剂。更全面地了解个体结肠病变的分子特征与他们对特定化学预防药物的反应之间的关系，最终可以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。

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.