Development of Clinical Strategies to Prevent GBM Recurrences After Radiotherapy
预防放疗后 GBM 复发的临床策略的制定
基本信息
- 批准号:8181978
- 负责人:
- 金额:$ 48.96万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-08-01 至 2016-05-31
- 项目状态:已结题
- 来源:
- 关键词:AMD3100BindingBiologicalBiological ModelsBlood VesselsBone MarrowBrain NeoplasmsCXCR4 ReceptorsCXCR4 geneCellsCessation of lifeClinicClinicalClinical ResearchCranial IrradiationDataDetectionDevelopmentDoseEndothelial CellsEthylnitrosoureaFailureGlioblastomaGoalsHeadHumanHypoxiaITGAM geneImplantLaboratoriesLeadMalignant neoplasm of brainMarrowMediatingModelingMusPathway interactionsPatientsPharmaceutical PreparationsPlasmaPrimary NeoplasmProcessRadiationRadiation therapyRadiobiologyRattusRecurrenceResearch PersonnelSiteSkin TransplantationSkin graftSolid NeoplasmSourceStem cellsStromal Cell-Derived Factor 1TechniquesTestingTimeTreatment FailureU251Up-RegulationWorkbasecancer recurrencechemokine receptorcytokineimprovedinhibitor/antagonistinstrumentirradiationmonocytemouse modelnovelpre-clinicalpreventreceptorresearch clinical testingresponserestorationtumoruptakevasculogenesis
项目摘要
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. )
PUBLIC HEALTH RELEVANCE: Our goal is to improve the cure rates of glioblastoma multiforme (GBM), a devastating brain cancer. Radiotherapy is a key part of the treatment of GBM, but despite the high doses of radiation that are given the tumors invariably recur within the radiation field. We have shown that we can prevent, or markedly delay, the recurrence of experimental GBM in mice and rats by preventing the accumulation within the irradiated tumors of circulating cells that can form blood vessels. This application proposes using three drugs that inhibit these circulating cells to determine their optimum use for subsequent clinical studies.
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。为此,我们计划利用一种假设,即尽管进行了高剂量放射治疗,但未能治愈这些肿瘤,这是放射治疗过程中肿瘤血管从循环细胞中再生的结果(这一过程被称为“血管生成”)。以CD11b+骨髓单核细胞和循环内皮细胞(ECs)为主的局部肿瘤靶向和血管生成靶向是一种新的治疗模式,可通过放射治疗显著提高肿瘤的治愈率。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抑制物,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。)
公共卫生相关性:我们的目标是提高多形性胶质母细胞瘤(GBM)的治愈率,GBM是一种毁灭性的脑癌。放射治疗是GBM治疗的关键部分,但尽管给予高剂量的照射,肿瘤总是在照射野内复发。我们已经证明,我们可以通过防止照射后的肿瘤中形成血管的循环细胞的积聚,来防止或显著延缓实验性GBM在小鼠和大鼠中的复发。这项申请建议使用三种抑制这些循环细胞的药物来确定它们在后续临床研究中的最佳使用。
项目成果
期刊论文数量(0)
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JOHN MARTIN BROWN其他文献
JOHN MARTIN BROWN的其他文献
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{{ truncateString('JOHN MARTIN BROWN', 18)}}的其他基金
Development of Clinical Strategies to Prevent GBM Recurrences After Radiotherapy
预防放疗后 GBM 复发的临床策略的制定
- 批准号:
8305505 - 财政年份:2011
- 资助金额:
$ 48.96万 - 项目类别:
Development of Clinical Strategies to Prevent GBM Recurrences After Radiotherapy
预防放疗后 GBM 复发的临床策略的制定
- 批准号:
8850819 - 财政年份:2011
- 资助金额:
$ 48.96万 - 项目类别:
Development of Clinical Strategies to Prevent GBM Recurrences After Radiotherapy
预防放疗后 GBM 复发的临床策略的制定
- 批准号:
8464667 - 财政年份:2011
- 资助金额:
$ 48.96万 - 项目类别:
Development of Clinical Strategies to Prevent GBM Recurrences After Radiotherapy
预防放疗后 GBM 复发的临床策略的制定
- 批准号:
8677772 - 财政年份:2011
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8208642 - 财政年份:2011
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Nanoparticle-based Sensitizer for Radiation Therapy of Glioblastoma
用于胶质母细胞瘤放射治疗的纳米颗粒敏化剂
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8715571 - 财政年份:2010
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7800584 - 财政年份:2010
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Effect of Bone Marrow Cells on the Radiosensitivity of Brain and Mouth Cancers
骨髓细胞对脑癌和口腔癌放射敏感性的影响
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8077235 - 财政年份:2008
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$ 48.96万 - 项目类别:
Effect of Bone Marrow Cells on the Radiosensitivity of Brain and Mouth Cancers
骨髓细胞对脑癌和口腔癌放射敏感性的影响
- 批准号:
8267090 - 财政年份:2008
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$ 48.96万 - 项目类别:
Effect of Bone Marrow Cells on the Radiosensitivity of Brain and Mouth Cancers
骨髓细胞对脑癌和口腔癌放射敏感性的影响
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7523818 - 财政年份:2008
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$ 48.96万 - 项目类别:
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