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

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)和头颈部肿瘤的治愈率：目前的治疗是放射治疗(包括或不包括手术和化疗)，并且治疗失败导致患者死亡的主要原因是无法控制原发肿瘤。要做到这一点，我们将利用一个新的假设，即尽管高剂量放疗仍未能治愈这些肿瘤，这是放射治疗过程中骨髓来源细胞(BMDCs)重新生长肿瘤血管的结果。我们已经获得了这一假说有效性的有力证据，证明了表达CD11b的单核细胞在照射后被招募到肿瘤中，肿瘤在没有MMP-9的情况下不能在照射部位生长，照射后CD11b细胞的枯竭增强了肿瘤对照射的反应，以及抑制SDF-1与CXCR4的相互作用，CXCR4是单核细胞上的关键受体，使它们招募到肿瘤血管系统，使GBM对分割照射敏感。为了确定这一假说是否可以用于临床，我们将分别使用小鼠和人的GBM植入脑内，以及将FaDu人头颈部肿瘤分别植入Rag1基因敲除小鼠的皮下。我们将使用合适的肿瘤细胞和骨髓基质细胞联合移植到野生型和基质金属蛋白酶-9基因敲除小鼠中来评价基质金属蛋白酶-9对肿瘤放射敏感性和宿主细胞浸润的影响。我们还将使用适当的中和抗体和抑制剂来评估血管内皮生长因子和SDF信号转导以及周细胞前体细胞的作用。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BMDCs的动员。为了确定照射后BMDCs对肿瘤生长的贡献，我们用同基因肌动蛋白-EGFP转基因小鼠的骨髓替换宿主小鼠的骨髓，并用FACS分析和免疫组织化学方法评估肿瘤中的宿主细胞。同时针对局部肿瘤和骨髓来源的细胞是一种新的范例，可以通过放射治疗大幅提高肿瘤的治愈率。我们的项目结合了两个实验室的专业知识，一个是布朗博士，他是肿瘤放射生物学专家，另一个是伯杰斯博士，他是肿瘤血管生成和肿瘤骨髓来源细胞方面的专家。与公共卫生相关：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，这些肿瘤目前的治疗是放射治疗(包括或不包括手术和化疗)，而且治疗失败导致患者死亡在很大程度上是由于无法控制原发肿瘤。为此，我们计划利用一种新的假设，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从骨髓来源的细胞(BMDCs)再生肿瘤血管的结果。我们将制定策略来抑制BMDCs对肿瘤血管的这种贡献，这种策略可以在癌症患者身上立即进行测试，因为所有使用的药物都已获得临床批准。同时靶向局部肿瘤和骨髓来源的细胞是一种新的范例，可以通过放射治疗大幅提高GBM和头颈部肿瘤的治愈率。

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.