Molecular Targets for Drug and Radiation Sensitivity

描述(申请人提供)：这项资助申请的假设是，有可能确定癌细胞中改变细胞对药物或辐射反应的分子靶点，并确定导致这种改变敏感性的分子机制。在第一次提交时，这笔赠款的标题是“操纵药物和辐射敏感性的细胞周期目标”。在这份新提交的文件中，标题略有更改为“操纵药物和辐射敏感性的分子靶标”。这个新标题反映了这样一个事实，即随着我们在过去五年的拨款工作，我们开始意识到，我们预期的一些因素完全通过细胞周期调节事件发挥作用，实际上必须在更广泛的背景下理解，涉及信号转导的调节和调节细胞凋亡的过程。我们正在进入癌症治疗的新纪元。传统的方法是在各种肿瘤上进行非特异性和经验性的细胞毒药物测试，希望合适的候选药物可能会在偶然的情况下显现出来。新的方法是描绘促进肿瘤存活的分子机制，然后设计专门针对这些机制的药物和治疗方案。这种方法已经影响了医学肿瘤学的实践，而且这种方法很可能在寻找提高放射治疗疗效的策略方面也将被证明是卓有成效的。Ras和p53基因的性质与肿瘤细胞的某些突变改变了它们对传统疗法的反应的想法是一致的。我们提出的两个项目将在分子水平上进一步探索这些基因的活性基础。另外两个项目继续在分子水平上定义细胞周期检查点影响G2和胞质分裂的机制，因为这些是最保守的，因此可能是最重要的细胞对细胞毒应激的反应。这项应用中的四个项目涵盖了从研究靶向药物已经处于临床试验的信号转导途径；到明显涉及药物和辐射敏感性但药物尚未准备好进入临床试验，但可能很快就能进入动物体内的途径；从旨在识别更多靶点的非常新的原创性研究。

DESCRIPTION (provided by applicant): The hypothesis of this grant application is that is possible to identify molecular targets in the cancer cell that modify the response of the cell to drugs or radiation and to define the molecular mechanisms that result in such altered sensitivity. On its first submission this grant was entitled "Cell Cycle Targets for Manipulation of Drug and Radiation Sensitivity." On this new submission the title has been slightly altered to be "Molecular Targets for Manipulation of Drug and Radiation Sensitivity." This new title reflects the fact that as we have worked on the grant for the last five years we have come to realize that some factors that we anticipated worked exclusively through cell cycle regulated events in fact have to understood in a wider context involving the regulation of signal transduction and the processes that regulate apoptosis. We are entering a new era in cancer therapeutics. Instead of the traditional approach of nonspecifically and empirically testing cytotoxic agents on a wide variety of tumors, hoping that a suitable candidate might become apparent by serendipity, the new approach is to delineate the molecular mechanisms that promote tumor survival, and then design drugs and treatment regimens that specifically target these mechanisms. This approach has impacted the practice of medical oncology and it is likely that such an approach will also prove fruitful in finding strategies to enhance the efficacy of radiation therapy. The genes ras and p53 have properties that are consistent with the idea that some of the mutational changes in tumor cells alter their response to conventional therapies. Two of the projects we propose will further explore at the basis for the activity of these genes at the molecular level. Two additional projects continue to define at the molecular level the mechanisms of cell cycle checkpoints influencing G2 and cytokinesis since these are the most highly conserved, and thus likely to be the most important, cellular responses to cytotoxic stress. The four projects in this application span a spectrum from investigating signal transduction pathways where targeting agents are already in clinical trial; to pathways clearly involved in sensitivity to drugs and radiation but where agents are not yet ready to proceed to clinical trial, but may soon be ready to go into animals; to very new original studies aimed at identification of additional targets.