Molecular Targets for Drug and Radiation Sensitivity

描述（由申请人提供）：本授权申请的假设是，有可能确定癌细胞中改变细胞对药物或辐射的反应的分子靶点，并确定导致这种敏感性改变的分子机制。在第一次提交时，这项赠款的标题是“操纵药物和辐射敏感性的细胞周期目标”。在这个新的提交的标题已略有改变，以“分子靶操纵药物和辐射敏感性。”“这个新标题反映了这样一个事实，即当我们在过去五年中致力于资助时，我们已经意识到，我们预期的一些因素完全通过细胞周期调节事件起作用，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凋亡的过程。我们正在进入癌症治疗的新时代。与传统的非特异性和经验性地测试细胞毒性药物对各种肿瘤的作用，希望通过偶然发现合适的候选药物的方法不同，新的方法是描述促进肿瘤生存的分子机制，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，并且很可能这种方法也将证明在寻找提高放射治疗疗效的策略方面富有成效。ras和p53基因的特性与肿瘤细胞中的一些突变改变了它们对常规疗法的反应的想法一致。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确定影响G2期和胞质分裂的细胞周期检查点的机制，因为这些是最高度保守的，因此可能是最重要的细胞毒性应激反应。该申请中的四个项目涵盖了一系列研究，从研究靶向药物已经在临床试验中的信号转导途径;到明确涉及药物和辐射敏感性的途径，但药物尚未准备好进行临床试验，但可能很快准备好进入动物体内;到旨在识别其他靶点的非常新的原始研究。

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.