Targeting the Tumor Matrix as Anti-Invasive and Sensitizing Strategy for Glioma

靶向肿瘤基质作为胶质瘤的抗侵袭和增敏策略

基本信息

批准号：
8473672
负责人：
Mariano Sebastian Viapiano
金额：
$ 26.04万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-03 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8473672
关键词：
Animals Apoptotic Binding Biological Assay Brain Brain Neoplasms Caring Cell Adhesion Cell Death Cell Survival Cells Cytotoxic Chemotherapy Data Development Distant Down-Regulation Environment Experimental Models Extracellular Matrix Extracellular Matrix Degradation Extracellular Matrix Proteins Genes Glioma Goals In Vitro Lead Lentivirus Vector Malignant Glioma Malignant neoplasm of brain Mediating Mediator of activation protein Metalloproteases Molecular NF-kappa B Names Neoplasm Metastasis Notch Signaling Pathway Pathway interactions Patients Peptide Hydrolases Pharmaceutical Preparations Process Proteins Proteoglycan Proteolysis RNA Interference Radiation Radiation therapy Reagent Recurrence Research Resistance Role S1-5 protein Signal Transduction Site Source Stimulus System TIMP3 gene TNF-alpha converting enzyme Testing Therapeutic Tissues Translating Treatment Efficacy Tumor Cell Invasion Work brain tissue cancer type cell motility chemotherapy cytotoxic effective therapy fibulin improved in vivo inhibitor/antagonist insight neoplastic neoplastic cell notch protein novel novel strategies outcome forecast public health relevance relating to nervous system research study response scaffold temozolomide tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): Malignant gliomas are the most common and deadly type of brain cancer, highly invasive and resistant to radiation and chemotherapy. Our goal is to understand and target the mechanisms that drive tumor invasion and promote survival in glioma cells. In recent work we identified and characterized a novel extracellular matrix (ECM) protein named fibulin-3, which is absent in normal brain but is abundant in gliomas and promotes tumor growth and invasion. From our preliminary results, we hypothesize that fibulin-3 acts as a diffusible factor in the ECM, promoting invasion and cell survival by mechanisms that may include activation of anti-apoptotic Notch signaling and the NF-kappaB pathway, increased expression of pro-invasive genes, and controlled degradation of the extracellular matrix. Accordingly, inhibition of fibulin-3 may reduce tumor invasion and make gliomas more sensitive to chemotherapeutics. To test these hypotheses, in Specific Aim 1 we propose to investigate the mechanisms by which fibulin-3 promotes tumor cell migration and survival. We will analyze the mechanisms of activation of the Notch pathway by fibulin-3, and the requirement of Notch signaling to mediate the effects of fibulin-3 on cell invasion and survival. In Specific Aim 2 we propose to analyze the mechanisms by which fibulin-3 may promote ECM degradation. We will analyze if fibulin-3 increases metalloprotease activity and degradation of the ECM by activating the pro-invasive NF-kappaB pathway and inhibiting the metalloprotease inhibitor TIMP3. Finally, in Specific Aim 3 we propose to evaluate the impact of suppressing fibulin-3 on tumor progression and response to chemotherapy. We will assay a novel system to induce the downregulation of fibulin-3 in the tumor and will analyze the effect this downregulation on tumor growth, invasion, animal survival, and sensitization of gliomas to a standard-of-care anti-neoplastic drug. Successful completion of these studies will establish the role of fibulin-3 in brain tumors and will provide new insights into the mechanisms that support brain tumor progression. These results may translate into novel strategies to disrupt tumor invasion and achieve more effective therapies.

描述（由申请人提供）：恶性神经胶质瘤是最常见和致命的脑癌类型，对放射线和化学疗法具有高度侵入性和抗性。我们的目标是了解和靶向驱动肿瘤侵袭并促进神经胶质瘤细胞存活的机制。在最近的工作中，我们确定并表征了一种新型的细胞外基质（ECM）蛋白，称为fibulin-3，该蛋白在正常脑中不存在，但在神经胶质瘤中很丰富，可促进肿瘤的生长和侵袭。从我们的初步结果中，我们假设Fibulin-3是ECM中的一个扩散因素，通过可能包括激活抗凋亡Notch信号的激活和NF-KAPPAB途径的机制促进侵袭和细胞存活，增加了侵入性基因的表达，并受控降解额外的Matrix。因此，抑制腓蛋白-3可能会降低肿瘤侵袭并使神经胶质瘤对化学治疗剂更敏感。为了检验这些假设，在特定的目标1中，我们提出了研究斐库蛋白3促进肿瘤细胞迁移和存活的机制。我们将通过fibulin-3分析Notch途径激活的机制，并要求Notch信号传导介导Fibulin-3对细胞浸润和存活的影响。在特定的目标2中，我们建议分析斐杜蛋白3可能促进ECM降解的机制。我们将通过激活促侵入性NF-kappab途径并抑制金属蛋白酶抑制剂timp3来分析Fibulin-3是否增加了金属蛋白酶活性和ECM的降解。最后，在特定的目标3中，我们建议评估抑制斐库蛋白3对肿瘤进展和对化学疗法反应的影响。我们将分析一个新的系统，以诱导肿瘤中腓蛋白3的下调，并将分析这种对肿瘤生长，侵袭，动物存活和神经胶质瘤对标准护理抗肿瘤药物的敏感的影响。这些研究的成功完成将确定腓蛋白-3在脑肿瘤中的作用，并将为支持脑肿瘤进展的机制提供新的见解。这些结果可能转化为破坏肿瘤入侵并实现更有效疗法的新型策略。