Evaluation of Novel Radiation Modifiers

许多代理商已经开始为这个项目进行测试。一种名为MEK抑制剂的试剂已被评估为体外和体内的辐射增敏剂。该试剂被发现在体外使三个组织对辐射敏感，并在皮下异种移植中使两个受试细胞系对辐射敏感。更多的机制研究表明，这种敏感化的原因似乎与辐射后G2检查点的废除有关。该化合物的其他工作集中在可能的生物标志物上，以确定临床翻译疗效的候选标志物。此外，我们目前正在测试该试剂与其他靶向药物或化疗的联合应用。另外两种试剂目前正在接受作为辐射敏感剂的有效性测试。其中包括一种小分子聚(ADP-核糖)聚合酶(PARP)抑制剂和一种多靶点酪氨酸激酶抑制剂。初步的体外克隆试验对这两个化合物具有良好的应用前景。其他的体外工作、体内工作和机械工作将继续进行。这些化合物的最终目标是将其作为辐射增敏剂转化为临床试验。

A number of agents have begun testing for this project. One agent, a MEK inhibitor, has been evaluated as a radiation sensitizer both in vitro and in vivo. The agent was found to sensitize three histologies to radiation in vitro and to sensitize two tested cell lines to radiation in subcutaneous xenografts. Additional mechanistic work has revealed that the cause of this senstization appears to be related to abrogation of the G2 checkpoint after irradiation. Additional work with this compound is focusing on possible biomarkers of effect to identify candidate markers of efficacy for clinical translation. In addition, we are currently testing the agent in compbination with other targeted agents or with chemotherapy. Two additional agents are currently undergoing testing for efficacy as radiation sensitizers. These include a small molecule poly(ADP-ribose) polymerase (PARP) inhibitor and a multi-target tyrosine kinase inhibitor. The preliminary in vitro clonogenic assays have been promising for these two compounds. Additional in vitro work, in vivo work, and mechanistic work will be ongoing. The eventual goal for these compounds is clinical translation into trials as radiation sensitizers.