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。在广泛的人类肿瘤中经常观察到CDK抑制剂P27/KIP1的表达降低，这与预后不良有关。在此应用中，我们建议使用自毒鼠肿瘤模型来检查p27/Kip1在肿瘤对系统施用的化学疗法和放射性治疗中的作用，p27是一种细胞周期抑制剂，可介导细胞周期对细胞外信号和细胞细胞接触的响应。我们的实验室使用小鼠模型是第一个证明p27充当肿瘤抑制基因的。 p27抑制肿瘤的一种机制是减少肿瘤细胞增殖并因此减少肿瘤生长。新数据表明，p27缺乏还会导致DNA损伤后的细胞周期检查点有缺陷，并增加了对诱变的敏感性。据我们所知，这是第一个证据，将p27与诱变以及与DNA损伤的细胞反应联系起来。大多数癌症治疗剂都是遗传毒性的，这表明P27与肿瘤对治疗的反应之间有联系。该应用的目的是检验以下假设：p27的丧失损害了对常用化学和放射性治疗剂的细胞反应，从而导致诱变和遗传不稳定性的增加。反过来，这可能导致肿瘤细胞对这些药物的敏感性改变。这些想法将在四个阶段进行测试。首先，将确定p27在调节CDK活性和启动S和G2/M细胞周期检查点对DNA损伤的作用。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缺乏症对自我调节性肿瘤对化学疗法和放射疗法的反应的影响。最后，将确定p27表达对肿瘤回归的影响。这些实验将揭示与P27缺乏肿瘤相关的临床结果不良的分子和细胞基础。然后，可以将这些知识用于改善临床环境中的治疗设计和方案。