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抑制剂p27/Kip 1的表达减少经常在广泛的人类肿瘤中观察到，并且这与不良预后相关。在本申请中，我们建议使用本地小鼠肿瘤模型来检查p27/Kip 1在肿瘤对全身给药的化疗和放疗的反应中的作用。p27是细胞周期蛋白/cdk抑制剂，其介导细胞周期阻滞以响应细胞外信号和细胞-细胞接触。我们的实验室，使用小鼠模型，是第一个证明p27作为一个肿瘤抑制基因的功能。p27抑制肿瘤的一种机制是减少肿瘤细胞增殖，从而减少肿瘤生长。新的数据表明，p27缺陷也会导致DNA损伤后的细胞周期检查点缺陷，并增加对诱变的敏感性。据我们所知，这是第一个将p27与诱变和细胞对DNA损伤的反应联系起来的证据。大多数癌症治疗药物具有遗传毒性，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的缺失损害了细胞对常用化疗剂和放疗剂的反应，导致诱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检验。首先，将确定p27在调节cdk活性和启动响应DNA损伤的S和G2/M细胞周期检查点中的作用。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缺陷对自体肿瘤对化疗和放疗的反应的影响。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，这些知识可以应用于改善临床环境中的治疗设计和方案。

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.