Colonoscopic Analysis of Response of Murine Colon Lesions to Drug Intervention

描述(申请人提供)：我们早期发现结直肠癌病变的能力方面的技术进步未能改变结直肠癌作为美国癌症相关死亡的第二大原因的地位。结直肠癌的零星性质，再加上普通公众缺乏对内窥镜监测指南的遵守，决定了为这种可预防的疾病开发有效的化学预防方案的必要性。该小组最近成功地建立了可靠的MRI和结肠镜检查方案，用于体内结肠腺瘤的可重现的基于图像的分析。将这项新技术应用于我们独特的多发性肠道肿瘤(Min)小鼠，它会自发地发展成多个结肠肿瘤，为在体内监测结肠腺瘤对化学预防干预的反应提供了一个新的机会。初步的结肠镜检查结果表明，Min模型重现了结肠腺瘤对非类固醇抗炎药(NSAID)舒林酸的异质抑制反应，就像在人类中看到的那样。建议研究的假设是，当舒林酸与最常开出的他汀类药物(降胆固醇药)阿托伐他汀(立普妥)联合使用时，舒林酸在抑制结肠腺瘤方面更有效。结肠镜检查和核磁共振成像将用于特定的目标1，以监测结肠腺瘤在一段时间内单独或与阿托伐他汀联合使用时对舒林酸的反应。可评估的终点包括肿瘤生长率、肿瘤潜伏期、大体形态和肿瘤发生率/多发性的变化。结肠腺瘤的相应基因表达分析(特定目标2)将提供对舒林酸和阿托伐他汀治疗靶点的一系列基因表达水平的洞察。定量实时聚合酶链式反应将被用来比较：1)来自对照和药物治疗动物的结肠腺瘤，以及2)每个治疗组中药物敏感和不敏感病变的亚组。这项拟议的研究是首次应用小动物结肠镜检查和核磁共振成像来分析单个结肠肿瘤对药物治疗的反应。这些新颖的研究结果预计将为未来制定提高非类固醇抗炎药对结肠癌的化学预防效果的策略做出重大贡献，因为它提供了对导致大体形态相关变化的基因表达变化的全面评估。这些数据可能导致建立第一个可耐受的结直肠癌化学预防方案。公共卫生相关性：通过在小鼠身上进行结肠镜检查，我们能够获得以前从未获得过的信息，即随着时间的推移，独立结肠肿瘤对药物治疗的反应或无反应。这项研究的发现可能为评估非类固醇抗炎药与降胆固醇药联合抑制人类肿瘤的能力提供基础。这些结果可能导致第一个被接受的预防结肠癌的治疗方法的建立。

DESCRIPTION (provided by applicant): Technological advancements in our ability to detect colorectal lesions early have failed to alter the status of colorectal cancer as the second leading cause of cancer-related deaths in the U.S. The sporadic nature of colorectal cancer, when combined with the lack of compliance of the general public with endoscopic surveillance guidelines, dictates the need to develop an efficacious chemopreventive regimen for this preventable disease. This group has recently succeeded in establishing reliable MRI and colonoscopic protocols for the reproducible image-based analysis of colon adenomas in vivo. Application of this new technology to our unique strain of Multiple Intestinal Neoplasia (Min) mice, which spontaneously develops multiple colon tumors, provides a novel opportunity to monitor the response of colon adenomas to chemopreventive intervention in vivo. Preliminary colonoscopic findings indicate that the Min model recapitulates the heterogeneous inhibitory response of colon adenomas to the nonsteroidal anti-inflammatory drug (NSAID) sulindac as seen in humans. The hypothesis of the proposed studies is that sulindac is more effective in inhibiting colon adenomas when administered in combination with the most frequently prescribed statin (cholesterol reducing agent), Atorvastatin (Lipitor). Colonoscopy and MRI will be used in Specific Aim 1 to monitor the response of colon adenomas to sulindac when given alone or in combination with Atorvastatin over time. Evaluable endpoints include changes in tumor growth rate, tumor latency, gross morphology and tumor incidence/multiplicity. Corresponding gene expression analyses of colon adenomas (Specific Aim 2) will provide insight into the level of expression of a battery of genes reported to be therapeutic targets of sulindac and Atorvastatin. Quantitative real-time PCR will be employed to compare the expression profile of: 1) colon adenomas from control and drug-treated animals and 2) subgroups of drug-responsive and -unresponsive lesions within each treatment group. The proposed studies represent the first application of small animal colonoscopy and MRI to an analysis of the response of individual colon tumors to drug therapy. The results of these novel studies are anticipated to contribute significantly to the future development of strategies to enhance the chemopreventive efficacy of NSAIDs against colon cancer by providing a comprehensive assessment of the underlying changes in gene expression responsible for associated alterations in gross morphology. These data could lead to the establishment of the first tolerable regimen for the chemoprevention of colorectal cancer. Public Health Relevance: By performing colonoscopies in the mouse, we are able to obtain information that we never had access to before regarding the responsiveness or unresponsiveness of independent colon tumors to drug treatment over time. Findings from this study could provide the basis for assessing the ability of nonsteroidal anti-inflammatory agents in combination with cholesterol-reducing agents to inhibit tumors in humans. These results could lead to the establishment of the first accepted therapy for the prevention of colon cancer.