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改善治疗和生存的重要方法。本申请旨在开发和完善一种新的内镜和蛋白质组学联合方法，用于评估癌前异常隐窝病灶（ACF）和腺瘤性息肉。这种方法的目的是建立分子特征，预测，并可能赋予特定的化学预防剂的疗效。我们将使用舒林酸，目前正在测试中的NCI多中心试点化学预防临床试验（CPN），作为一个模型化学预防剂开发这种方法。我们提出的研究将解决以下问题：（1）舒林酸对ACF和腺瘤的疗效将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;（2）预测和/或赋予它们对舒林酸反应的腺瘤的蛋白质组学和基因组学特征将被鉴定;（3）这些分子靶标对舒林酸功效的预测价值将在六周舒林酸初步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和潜在地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，作为评估风险的基础，设计针对个人的癌症预防策略，并确定未来化学预防剂开发的目标。虽然我们提出的研究重点是对舒林酸的反应，但这种一般策略可以适用于通过不同作用模式发挥作用的化学预防剂。一个更全面的了解如何一个人的结肠病变的分子特征涉及到他们的反应特定的化学预防剂，最终可以用来开发安全有效的策略，充分实现化学预防的承诺，降低死亡率和发病率相关的结肠癌。公共卫生相关性：我们正在开发一种方法来查看结肠癌发生和化学预防的“实时”事件。原则上可以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。我们的方法被预测为概括潜在的临床情况，其中蛋白质标记物可用于识别具有“高风险”ACF或腺瘤的个体。此外，我们方法的长期目标是基于癌前病变中发现的预测蛋白或基因的表达来定制人群中的化学预防。虽然我们提出的研究重点是对舒林酸的反应，但这种一般策略可以适用于通过不同作用模式发挥作用的化学预防剂。一个更全面的了解如何一个人的结肠病变的分子特征涉及到他们的反应特定的化学预防剂，最终可以用来开发安全有效的策略，充分实现化学预防的承诺，降低死亡率和发病率相关的结肠癌。

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.