Molecular Targets for Drug and Radiation Sensitivity

描述（由申请人提供）：本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标，并确定导致这种敏感性改变的分子机制。在其首次提交的申请中，该资助的标题是“操纵药物和辐射敏感性的细胞周期目标”。在这篇新提交的论文中，标题被稍微修改为“药物和辐射敏感性操纵的分子靶标”。这个新标题反映了这样一个事实，即在过去的五年里，我们已经意识到，我们预期的一些仅通过细胞周期调节事件起作用的因素实际上必须在更广泛的背景下理解，包括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时代。传统的方法是对各种肿瘤进行非特异性和经验性的细胞毒性药物测试，希望偶然发现合适的候选药物，而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，很可能这种方法也将在寻找提高放射治疗疗效的策略方面证明是富有成效的。ras和p53基因的特性与肿瘤细胞的一些突变变化会改变它们对常规疗法的反应的观点是一致的。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活性的基础。另外两个项目继续在分子水平上确定影响G2和细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对细胞毒性应激的反应。该应用程序中的四个项目涵盖了从研究已经处于临床试验中的靶向药物的信号转导途径；对于那些明显与药物和辐射敏感性有关的途径，但药物尚未准备好进入临床试验，但可能很快就会准备好在动物身上进行试验；到非常新的原创研究，旨在确定额外的目标。

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.