Development of Clinical Strategies to Prevent GBM Recurrences After Radiotherapy

描述(申请人提供)：我们的总体目标是提高多形性胶质母细胞瘤(GBM)的治愈率，对于这种疾病，治疗失败导致患者死亡是由于无法通过放射治疗控制原发肿瘤。为了做到这一点，我们计划利用这样一个假设，即尽管高剂量放疗仍未能治愈这些肿瘤，这是放疗过程中肿瘤血管从循环细胞重新生长的结果(这一过程被称为“血管生成”)。靶向局部肿瘤和血管生成，主要由CD11b骨髓单核细胞和循环内皮细胞(ECs)介导，是一种新的范式，可以通过放射治疗大幅提高肿瘤的治愈率。我们将在两个GBM模型系统中测试三种抑制血管生成途径的药物：1)AMD3100，一种基质衍生因子-1(SDF-1)与其受体CXCR4相互作用的特异性抑制剂。这种相互作用导致CD11b骨髓单核细胞在照射后保留在肿瘤中；2)CCX662，SDF-1与其第二受体CXCR7相互作用的特异性抑制剂，我们认为它负责在受照射的肿瘤中招募循环内皮细胞并捕获它们；以及3)NOX-A12，一种高度特异的SDF-1抑制剂，我们假设它将阻止CD11b单核细胞和循环内皮细胞在受照射的肿瘤中定植。我们将使用的两个基底膜模型系统是人U251基底膜植入小鼠体内和ENU诱导的大鼠基底膜。我们将对所有三种药物进行为期3-4周的测试，并在对每个肿瘤模型进行单次或分次照射后测试更长时间，并将确定它们在防止辐射增加的CD11b和ECs流入方面的有效性，以及它们在我们将使用的适度辐射剂量后防止肿瘤复发的能力。我们还将在小鼠模型中测试我们的策略在局部肿瘤照射而不是全脑照射下工作的能力。我们的项目结合了三个实验室的专业知识，即拥有肿瘤放射生物学专业知识的实验研究员Brown博士、治疗GBM患者的神经肿瘤学家Recht博士、其实验室在启动和检测ENU诱导的大鼠GBM模型方面的专业知识以及建造基于Micro-CT的辐照器的Graves博士。目标是提供必要的信息，以便对这一新策略进行临床测试。)

DESCRIPTION (provided by applicant): Our overall goal is to improve the cure rates of glioblastoma multiforme (GBM) for which treatment failure leading to patient death is the result of inability to control the primary tumor by radiotherapy. To do this we plan to exploit the hypothesis that the failure to cure these tumors despite high dose radiotherapy is the result of regrowth of the tumor vasculature from circulating cells (a process known as "vasculogenesis") following the course of radiotherapy. Targeting both the local tumor and vasculogenesis, primarily mediated by CD11b+ myelomonocytes and circulating endothelial cells (ECs), is a novel paradigm and could lead to a major increase in the curability of tumors by radiotherapy. We will test three drugs that inhibit vasculogenesis pathway, in two GBM model systems: 1) AMD3100, a specific inhibitor of the interaction of stromal derived factor-1 (SDF-1) with its receptor CXCR4. This interaction is responsible for the retention of the CD11b+ myelomonocytes in tumors after irradiation, 2) CCX662, a specific inhibitor of the interaction of SDF-1 with its second receptor, CXCR7, which we believe is responsible for the recruitment of circulating ECs and their capture in the irradiated tumor, and 3) NOX-A12, a highly specific inhibitor of SDF-1 which we hypothesize will prevent both the CD11b+ monocytes and circulating ECs from colonizing the irradiated tumor. The two GBM models systems we will use are the intracranially implanted human U251 GBM in the mouse and the ENU-induced GBM in the rat. We will test all three drugs given for 3-4 weeks, and for longer, following either single or fractionated irradiation to each of these tumors models and will determine their efficacy in preventing the radiation increased influx of CD11b+ and ECs and on for their ability to prevent recurrences of the tumors following the modest radiation doses that we will use. We will also test in the mouse model the ability of our strategy to work with focal tumor irradiation rather than whole brain irradiation. Our project combines the expertise of three laboratories, that of Dr. Brown, an experimental investigator with expertise in tumor radiation biology, that of Dr. Recht, a neurooncologist who treats GBM patients and whose laboratory has expertise with initiation and detection of the ENU-induced rat GBM model and Dr. Graves who built the micro-CT based irradiator. The goal is to provide the needed information to allow clinical testing of this new strategy. )