Effect of Bone Marrow Cells on the Radiosensitivity of Brain and Mouth Cancers

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）和头颈部肿瘤的治愈率：目前的治疗方法是放疗（伴或不伴手术和化疗）的人类癌症，导致患者死亡的治疗失败主要是无法控制原发肿瘤的结果。为了做到这一点，我们将利用新的假设，即尽管高剂量放射治疗，但未能治愈这些肿瘤是放射治疗过程后骨髓来源的细胞（BMDCs）的肿瘤血管再生的结果。我们已经获得了这一假说有效性的有力证据，表明MMP-9表达的CD 11b+单核细胞在照射后被募集到肿瘤中，没有MMP-9肿瘤不能在照射部位生长，照射后CD 11b+细胞的耗竭增强了肿瘤对照射的反应，并且抑制SDF-1与CXCR 4的相互作用，单核细胞上的一种关键受体，将它们募集到肿瘤血管系统，使GBM对分次照射敏感。为了确定该假设是否可以用于临床益处，我们将分别使用颅内植入的小鼠和人GBM以及皮下植入Rag 1敲除小鼠中的FaDu人头颈部肿瘤。我们将评估MMP-9对肿瘤放射敏感性和宿主细胞浸润的影响，使用肿瘤细胞和BMDC的适当组合，有和没有MMP-9移植到野生型和MMP-9敲除小鼠。我们还将使用适当的中和抗体和抑制剂评估VEGF和SDF信号传导和周细胞祖细胞的贡献。我们还将测试甲磺酸伊马替尼（GleevecTM）通过抑制骨髓细胞上的受体c-kit来阻断BMDC的动员。为了确定照射后BMDC对肿瘤生长的贡献，我们将用来自同基因actin-EGFP转基因小鼠的骨髓替换宿主小鼠中的骨髓，并使用FACS分析和免疫组织化学评估肿瘤中的宿主细胞。靶向局部肿瘤和骨髓来源的细胞是一种新的范例，并可能导致通过放射疗法治疗肿瘤的可治愈性的大幅增加。我们的项目结合了两个实验室的专业知识，一个是肿瘤放射生物学专家Brown博士，另一个是肿瘤血管生成和肿瘤骨髓源细胞专家Bergers博士。公共卫生相关性：该项目的总体目标是提高多形性胶质母细胞瘤（GBM）和头颈部肿瘤的治愈率：目前的治疗方法是放疗（伴或不伴手术和化疗），导致患者死亡的治疗失败主要是无法控制原发肿瘤的结果。为了做到这一点，我们计划利用新的假设，即尽管高剂量放射治疗，但未能治愈这些肿瘤是放射治疗过程后骨髓来源的细胞（BMDC）的肿瘤血管再生长的结果。我们将开发策略来抑制BMDC对肿瘤血管的这种贡献，这些策略可以立即在癌症患者中进行测试，因为所有要使用的药物都是临床批准的。靶向局部肿瘤和骨髓来源的细胞是一种新的范例，并且可以通过放射治疗显著提高GBM和头颈部肿瘤的可治愈性。

DESCRIPTION (provided by applicant): Our overall goal is to improve the cure rates of glioblastoma multiforme (GBM) and of head and neck tumors: human cancers for which the current treatment is radiotherapy (with or without surgery and chemotherapy) and for which treatment failure leading to patient death is largely the result of inability to control the primary tumor. To do this we will exploit the novel hypothesis that the failure to cure these tumors despite high dose radiotherapy is the result of regrowth of the tumor vasculature from bone marrow derived cells (BMDCs) following the course of radiotherapy. We have obtained strong evidence for the validity of this hypothesis by showing that MMP-9 expressing CD11b+ monocytes are recruited to tumors following irradiation, that tumors cannot grow in an irradiated site without MMP-9, that depletion of CD11b+ cells following irradiation enhances tumor response to irradiation, and that inhibition of the interaction of SDF-1 with CXCR4, a key receptor on the monocytes that recruits them to the tumor vasculature, sensitizes GBM to fractionated irradiation. To determine if this hypothesis can be exploited for clinical benefit we will use both mouse and human GBM implanted intracranially and the FaDu human head and neck tumor inplanted subcutaneously in Rag1 knockout mice respectively. We will evaluate the influence of MMP-9 on tumor radiosensitivity and host cell infiltration using appropriate combinations of tumor cells and BMDCs with and without MMP-9 transplanted into wild type and MMP-9 knockout mice. We will also evaluate the contribution of VEGF and SDF-signaling and pericyte progenitors using appropriate neutralizing antibodies and inhibitors. We will also test imatinib mesylate (GleevecTM) to block the mobilization of BMDCs by inhibition of the receptor c-kit on bone marrow cells. To determine the contribution of BMDCs to tumor growth after irradiation we will replace the bone marrow in the host mice with bone marrow from syngeneic actin-EGFP transgenic mice and evaluate the host cells in the tumor using FACS analysis and immunohistochemistry. Targeting both the local tumor and the bone marrow derived cells is a novel paradigm and could lead to a major increase in the curability of tumors by radiotherapy. Our project combines the expertise of two laboratories, that of Dr. Brown, an expert in tumor radiation biology, and that of Dr. Bergers, an expert in tumor angiogenesis and bone marrow derived cells in tumors. PUBLIC HEALTH RELEVANCE: The overall goal of this project is to improve the cure rates of glioblastoma multiforme (GBM) and of head and neck tumors: human cancers for which the current treatment is radiotherapy (with or without surgery and chemotherapy) and for which treatment failure leading to patient death is largely the result of inability to control the primary tumor. To do this we plan to exploit the novel hypothesis that the failure to cure these tumors despite high dose radiotherapy is the result of regrowth of the tumor vasculature from bone marrow derived cells (BMDCs) following the course of radiotherapy. We will develop strategies to inhibit this contribution of BMDCs to the tumor vascular that can be tested immediately in cancer patients as all the drugs to be used are clinically approved. Targeting both the local tumor and the bone marrow derived cells is a novel paradigm and could lead to a major increase in the curability of GBM and head and neck tumors by radiotherapy.