Development of Clinical Strategies to Prevent GBM Recurrences After Radiotherapy

描述（由申请人提供）：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GBM，治疗失败导致患者死亡是由于无法通过放疗控制原发肿瘤。为了做到这一点，我们计划利用这样的假设，即尽管进行了高剂量放射治疗，但这些肿瘤仍未能治愈，这是放射治疗过程后肿瘤血管系统从循环细胞中再生的结果（一个称为“血管发生”的过程）。靶向局部肿瘤和血管生成（主要由CD 11b+骨髓单核细胞和循环内皮细胞（EC）介导）是一种新的范例，可能会导致放射治疗肿瘤的可治愈性大幅增加。我们将在两种GBM模型系统中测试三种抑制血管生成途径的药物：1）AMD 3100，一种基质衍生因子-1（SDF-1）与其受体CXCR 4相互作用的特异性抑制剂。这种相互作用是照射后肿瘤中CD 11b+骨髓单核细胞保留的原因，2）CCX 662，SDF-1与其第二受体CXCR 7相互作用的特异性抑制剂，我们认为CXCR 7负责循环EC的募集和它们在照射的肿瘤中的捕获，和3）NOX-A12，一种高度特异性的SDF-1抑制剂，我们假设它将阻止CD 11b+单核细胞和循环EC在照射的肿瘤中定植。我们将使用的两种GBM模型系统是颅内植入小鼠中的人U251 GBM和大鼠中的ENU诱导的GBM。我们将在对这些肿瘤模型进行单次或分次照射后，对所有三种药物进行3-4周或更长时间的测试，并将确定它们在预防辐射增加的CD 11b+和EC流入方面的功效，以及它们在我们将使用的适度辐射剂量后预防肿瘤复发的能力。我们还将在小鼠模型中测试我们的策略与局灶性肿瘤照射而不是全脑照射一起工作的能力。我们的项目结合了三个实验室的专业知识，Brown博士，一位具有肿瘤辐射生物学专业知识的实验研究者，Recht博士，一位治疗GBM患者的神经肿瘤学家，他的实验室具有启动和检测ENU诱导的大鼠GBM模型的专业知识，以及Graves博士，他建立了基于微CT的辐照器。我们的目标是提供所需的信息，以允许这种新策略的临床测试。)

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. )