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: 7523818
• 负责人: JOHN MARTIN BROWN
• 金额: $ 50.63万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7523818
• 关键词: AMD3100; Actins; Antibodies; Bone Marrow; Bone Marrow Cells; Bone Marrow Neoplasms; Bone Marrow Transplantation; Brain; CXCR4 gene; Cancer Patient; Cells; Cessation of life; Clinical; Dose; Failure; Gelatinase B; Glioblastoma; Goals; Head and Neck Cancer; Head and Neck Neoplasms; Human; ITGAM gene; Imatinib mesylate; Immunohistochemistry; Implant; Infiltration; Knock-out; Knockout Mice; Laboratories; Lead; Malignant Neoplasms; Marrow; Mus; Neoplasms in Vascular Tissue; Normal tissue morphology; Operative Surgical Procedures; PDGFRB gene; Patients; Pericytes; Pharmaceutical Preparations; Primary Neoplasm; Protein Tyrosine Kinase; Proto-Oncogene Protein c-kit; Public Health; Radiation Tolerance; Radiation therapy; Radiobiology; Radiosensitization; Rag1 Mouse; Rate; Receptor Inhibition; Recruitment Activity; Signal Transduction; Site; Stromal Cell-Derived Factor 1; Testing; Transgenic Mice; Transplantation; Treatment Failure; Tumor Angiogenesis; Vascular Endothelial Growth Factors; antibody inhibitor; chemotherapy; clinically relevant; improved; inhibitor/antagonist; irradiation; malignant mouth neoplasm; monocyte; neoplastic cell; neutralizing antibody; novel; prevent; progenitor; receptor; response; small molecule; tumor; tumor growth; vasculogenesis

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.

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（包括或不包括手术和化疗），治疗失败导致患者死亡的主要原因是无法控制原发肿瘤。为了做到这一点，我们将利用一个新的假设，即尽管高剂量放疗仍无法治愈这些肿瘤是由于肿瘤血管在放疗过程后从骨髓来源细胞（bmdc）再生的结果。我们已经为这一假设的有效性获得了强有力的证据，表明表达CD11b+单核细胞的MMP-9在照射后被招募到肿瘤中，肿瘤不能在没有MMP-9的照射部位生长，照射后CD11b+细胞的消耗增强了肿瘤对照射的反应，抑制SDF-1与CXCR4的相互作用，CXCR4是单核细胞上的一个关键受体，将它们招募到肿瘤血管中。使GBM对分步辐照致敏。为了确定这一假设是否可以用于临床，我们将分别在Rag1敲除小鼠中植入小鼠和人颅内GBM，并在皮下植入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，方法是将肿瘤细胞和携带或不携带MMP-9的BMDCs适当组合移植到野生型和MMP-9敲除小鼠体内。我们还将使用适当的中和抗体和抑制剂评估VEGF和sdf信号和周细胞祖细胞的贡献。我们还将测试甲酸伊马替尼（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BMDCs对照射后肿瘤生长的贡献，我们将用同源actin-EGFP转基因小鼠的骨髓替代宿主小鼠的骨髓，并使用FACS分析和免疫组织化学评估肿瘤中的宿主细胞。同时靶向局部肿瘤和骨髓源性细胞是一种新的模式，可能导致肿瘤放疗治愈率的显著提高。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博士的实验室，一个是肿瘤血管生成和肿瘤骨髓衍生细胞专家Bergers博士的实验室。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），治疗失败导致患者死亡的主要原因是无法控制原发肿瘤。为了做到这一点，我们计划利用新的假设，即尽管高剂量放疗仍无法治愈这些肿瘤是由于肿瘤血管在放疗过程后从骨髓来源细胞（bmdc）再生的结果。我们将制定策略来抑制BMDCs对肿瘤血管的贡献，这些策略可以立即在癌症患者中进行测试，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源性细胞是一种新的治疗模式，可以显著提高GBM和头颈部肿瘤的放疗治愈率。