Targeting the tumor matrix as anti-invasive and sensitizing strategy for glioma

靶向肿瘤基质作为神经胶质瘤的抗侵袭和增敏策略

• 批准号: 8616849
• 负责人: Mariano Sebastian Viapiano
• 金额: $ 18.05万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 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/8616849
• 关键词: Targeting; tumor; matrix; anti; invasive

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. PUBLIC HEALTH RELEVANCE: Malignant brain tumors, known as gliomas, are one of the types of cancer with worst prognosis. This situation has not improved even after decades of research because these tumors resist conventional chemotherapy and escape novel therapies, thanks, in large part, to their ability to infiltrate in the brain. We propose to characterize and target a novel protein that is secreted by glioma cells but is absent in normal brain. This protein promotes brain tumor invasion and tumor survival, which are the two key processes that reduce the efficacy of current treatments. Therefore, our proposed research is highly relevant because it may lead to effective disruption of tumor progression and increased sensitivity of the tumor to conventional chemotherapeutics. We believe that these studies will have relevance for the development of more effective strategies and therapeutic reagents against malignant brain tumors.

描述（由申请人提供）：恶性神经胶质瘤是最常见和最致命的脑癌类型，具有高度侵袭性，对放疗和化疗具有抗性。我们的目标是了解和靶向驱动肿瘤侵袭和促进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名为fibulin-3的新型细胞外基质（ECM）蛋白，该蛋白在正常脑中不存在，但在胶质瘤中丰富，并促进肿瘤生长和侵袭。根据我们的初步结果，我们假设纤蛋白-3在ECM中作为扩散因子，通过可能包括抗凋亡Notch信号传导和NF-κ B通路的激活、促侵袭基因的表达增加和细胞外基质的受控降解的机制促进侵袭和细胞存活。因此，抑制fibulin-3可以减少肿瘤侵袭并使胶质瘤对化疗药物更敏感。为了验证这些假设，在具体目标1中，我们提出研究fibulin-3促进肿瘤细胞迁移和存活的机制。我们将分析fibulin-3激活Notch通路的机制，以及Notch信号转导介导fibulin-3对细胞侵袭和存活的影响的必要性。在具体目标2中，我们建议分析fibulin-3可能促进ECM降解的机制。我们将分析纤蛋白-3是否通过激活促侵袭性NF-κ B通路和抑制金属蛋白酶抑制剂TIMP 3来增加金属蛋白酶活性和ECM降解。最后，在具体目标3中，我们建议评估抑制fibulin-3对肿瘤进展和化疗反应的影响。我们将检测一种新的系统来诱导肿瘤中fibulin-3的下调，并分析这种下调对肿瘤生长、侵袭、动物存活和胶质瘤对标准治疗抗肿瘤药物的敏感性的影响。这些研究的成功完成将确立fibulin-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。这些结果可能会转化为新的策略，以破坏肿瘤侵袭和实现更有效的治疗。 公共卫生相关性：恶性脑肿瘤，称为神经胶质瘤，是预后最差的癌症类型之一。即使经过几十年的研究，这种情况也没有得到改善，因为这些肿瘤抵抗常规化疗并逃避新疗法，这在很大程度上要归功于它们渗透大脑的能力。我们建议表征和靶向一种由胶质瘤细胞分泌但在正常脑中不存在的新蛋白。这种蛋白质促进脑肿瘤侵袭和肿瘤生存，这是降低当前治疗效果的两个关键过程。因此，我们提出的研究是高度相关的，因为它可能导致有效的肿瘤进展中断和增加肿瘤对常规化疗药物的敏感性。我们相信，这些研究将有针对恶性脑肿瘤的更有效的策略和治疗试剂的发展相关。