Mouse Models of Tumor Progression and Therapy Response

描述(由申请人提供)：了解肿瘤对治疗的不同反应的分子基础是分子肿瘤学的主要目标。CDK抑制因子p27/Kip1的低表达常见于多种人类肿瘤中，这与预后不良有关。在这一应用中，我们建议使用固有的小鼠肿瘤模型来研究p27/Kip1在全身化疗和放射治疗的肿瘤反应中的作用，p27是一种细胞周期蛋白/cdk抑制物，它介导细胞外信号和细胞-细胞接触反应中的细胞周期停滞。我们的实验室利用小鼠模型，首次证明了p27作为肿瘤抑制基因的功能。P27抑制肿瘤的机制之一是抑制肿瘤细胞的增殖，从而抑制肿瘤的生长。新的数据显示，p27缺乏还会导致DNA损伤后细胞周期检查点的缺陷，并增加对突变的敏感性。据我们所知，这是将p27与突变和细胞对DNA损伤的反应联系起来的第一个证据。大多数癌症治疗药物具有基因毒性，这表明p27与肿瘤治疗反应之间存在联系。这项应用的目的是检验一种假设，即p27的丢失会损害细胞对常用的化疗和放射治疗药物的反应，导致突变和遗传不稳定性的增加。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细胞周期检查点以应对DNA损伤中的作用。其次，将在体内测量p27减少对突变和染色体不稳定性的影响。第三，将直接测量p27缺乏对原发肿瘤化疗和放疗反应的影响。最后，将确定恢复p27表达对肿瘤消退的影响。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。这些知识随后可用于改进临床环境中的治疗设计和治疗方案。

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.