Mouse Models of Tumor Progression and Therapy Response

肿瘤进展和治疗反应的小鼠模型

• 批准号: 6588223
• 负责人: CHRISTOPHER J KEMP
• 金额: $ 38.49万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6588223
• 关键词: DNA damage; antineoplastics; cell cycle; cell cycle proteins; chromosome aberrations; cyclin dependent kinase; cyclins; disease /disorder model; drug resistance; enzyme inhibitors; fluorescence microscopy; genetically modified animals; laboratory mouse; molecular oncology; neoplasm /cancer genetics; neoplasm /cancer remission /regression; neoplastic process; radiation resistance; terminal nick end labeling; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): Understanding the molecular basis for the differential response of tumors to therapy is a primary goal of molecular oncology. Reduced expression of the cdk inhibitor p27/Kip1 is frequently observed in a wide range of human tumors and this correlates with poor prognosis. In this application, we propose to use autochthonous murine tumor models to examine the role of p27/Kip1 in tumor response to systemically administered chemo- and radio-therapy, p27 is a cyclin/cdk inhibitor that mediates cell cycle arrest in response to extracellular signals and cell-cell contact. Our laboratory, using mouse models, was the first to demonstrate that p27 functions as a tumor suppressor gene. One mechanism of tumor suppression by p27 is to reduce tumor cell proliferation and hence tumor growth. New data shows that p27 deficiency also results in defective cell cycle checkpoints following DNA damage, and increases the sensitivity to mutagenesis. This is the first evidence, to our knowledge, linking p27 to mutagenesis and the cellular response to DNA damage. Most cancer therapy agents are genotoxic, suggesting a link between p27 and tumor response to therapy. The objective of this application is to test the hypothesis that loss of p27 compromises the cellular response to commonly used chemo- and radio-therapeutic agents, leading to an increase in mutagenesis and genetic instability. This in turn may result in altered tumor cell sensitivity to these agents. These ideas will be tested in four stages. First, the role of p27 in regulating cdk activity and initiating the S and G2/M cell cycle checkpoints in response to DNA damage will be determined. Second, the effect of p27 reduction on mutagenesis and chromosomal instability will be measured in vivo. Third, the impact of p27 deficiency on the response of autochthonous tumors to chemo- and radiotherapy will be directly measured. Finally, the effect of restoration of p27 expression on tumor regression will be determined. These experiments will reveal the molecular and cellular basis for the poor clinical outcome associated with p27 deficient tumors. This knowledge can then be applied to improve treatment design and regimen in the clinical setting.

描述（由申请人提供）：了解肿瘤对治疗的差异反应的分子基础是分子肿瘤学的主要目标。在多种人类肿瘤中经常观察到 cdk 抑制剂 p27/Kip1 表达的减少，这与不良预后相关。在本申请中，我们建议使用本地小鼠肿瘤模型来检查 p27/Kip1 在肿瘤对全身化疗和放疗的反应中的作用，p27 是一种细胞周期蛋白/cdk 抑制剂，可响应细胞外信号介导细胞周期停滞以及细胞与细胞的接触。我们的实验室使用小鼠模型，首先证明了 p27 作为肿瘤抑制基因的功能。 p27 抑制肿瘤的机制之一是减少肿瘤细胞增殖，从而减少肿瘤生长。新数据表明，p27 缺陷还会导致 DNA 损伤后细胞周期检查点出现缺陷，并增加对突变的敏感性。据我们所知，这是第一个将 p27 与突变和细胞对 DNA 损伤的反应联系起来的证据。大多数癌症治疗药物都具有基因毒性，这表明 p27 与肿瘤对治疗的反应之间存在联系。本申请的目的是检验以下假设：p27 缺失会损害细胞对常用化疗和放疗药物的反应，导致突变和遗传不稳定性增加。这反过来可能导致肿瘤细胞对这些药物的敏感性改变。这些想法将分四个阶段进行测试。首先，将确定 p27 在调节 cdk 活性和启动 S 和 G2/M 细胞周期检查点以响应 DNA 损伤中的作用。其次，将在体内测量 p27 减少对诱变和染色体不稳定性的影响。第三，将直接测量p27缺陷对本土肿瘤对化疗和放疗反应的影响。最后，将确定p27表达的恢复对肿瘤消退的影响。这些实验将揭示与 p27 缺陷肿瘤相关的不良临床结果的分子和细胞基础。然后可以应用这些知识来改进临床环境中的治疗设计和治疗方案。