Mechanisms of glioma growth and invasion novel therapeutic strategies

神经胶质瘤生长和侵袭的机制新的治疗策略

• 批准号: 8480082
• 负责人: Pedro R Lowenstein
• 金额: $ 34.02万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8480082
• 关键词: Accounting; Adenovirus Vector; Affect; Animals; Atrophic; Binding Proteins; Blood Vessels; Brain; Brain Drains; Brain Neoplasms; Caliber; Cells; Clinical; Clinical Treatment; Clinical Trials; Data; Diagnosis; Diffuse; Down-Regulation; Edema; Electrons; FDA approved; Functional disorder; Galectin 1; Glioma; Growth; HRAS gene; Human; Human Characteristics; Immune; Immune response; In Vitro; Indolent; Infiltration; Institutional Review Boards; Knowledge; Laboratories; Lead; Lentivirus Vector; Lymph; Malignant Neoplasms; Mediating; Michigan; Microscopy; Mitosis; Molecular; Obstruction; Operative Surgical Procedures; Pathway interactions; Patient Recruitments; Patients; Pattern; Phase; Platelet-Derived Growth Factor; Polysaccharides; Positioning Attribute; Radiation therapy; Recurrence; Research; Resistance; Rodent; Staging; Stem cells; Symptoms; T cell response; TK Gene; Testing; Therapeutic; Translating; Travel; Tumor Cell Invasion; Universities; Work; brain tissue; brain volume; chemotherapy; cytotoxic; gene therapy; gene therapy clinical trial; in vivo; inhibitor/antagonist; killings; knock-down; migration; neoplastic cell; novel; novel therapeutics; public health relevance; small hairpin RNA; treatment strategy; tumor; tumor growth; tumor microenvironment

DESCRIPTION (provided by applicant): High grade gliomas are uniformly lethal, and resistant to surgery, chemotherapy and radiotherapy. The precise cellular and molecular mechanisms by which glioma cells disperse through the brain and grow to form macroscopic symptomatic tumor masses remains poorly understood. Herein we propose to test novel cellular, molecular and mechanistic hypotheses concerning glioma growth, and how to translate this knowledge into new anti-glioma therapeutics. Preliminary work from my laboratory, using confocal, electron and multiphoton microscopy has shown that glioma cells and human glioma stem cells disperse through the brain in vivo by traveling preferentially along the perivascular compartment, a potential migration network surrounding the brain microvasculature. As glioma cells move throughout the perivascular network they dislodge glial endfeet from blood vessels and compromise adjacent brain tissue; this is later replaced by tumor cells. We have also generated preliminary data that a glycan binding protein, galectin-1, is essential for this growth mechanism. Down regulation of galectin-1 abolishes glioma growth in the brain in vivo, without affecting growth in vitro. These new data have several clinical consequences: (i) lymph drains from the brain through the perivascular compartment; its obstruction by gliomas would contribute to glioma-induced edema; (ii) human glioma tumors grow to large size before causing symptoms; glioma cell replacement of atrophied brain tissue could explain protracted and indolent tumor growth, and the delayed changes in total brain volume; (iii) inhibition of galectin-1 could represent a novel treatment of human gliomas. This proposal will (I) test the hypothesis that rodent and human glioma cells, and glioma stem cells grow preferentially along the perivascular space; (II) test the hypothesis that galectin-1 mediates glioma perivascular invasion and growth, and that inhibition of galectin-1 can be used as a novel therapeutic strategy; and (III) test the hypothesis that inhibition of galectin-1 will enhance specific anti-glioma immune responses. By progressing from glioma pathophysiology to molecular mechanisms of glioma migration to experimental therapeutics, we aim for our work to lead to novel early phase clinical translational trials for the treatment of human gliomas. Of note, our first clinical trial for gene therapy of human gliomas is approaching the start of patient recruitment (it was approved by FDA on 4/7/11 [IND 14574] and very recently by the University of Michigan IBC and IRB). Therefore, our laboratory is in a strong and realistic position to guide our research towards the translational implementation of novel clinical trials for this currently deadly human cancer.

描述(由申请人提供)：高级别胶质瘤具有一致的致命性，对手术、化疗和放射治疗耐药。胶质瘤细胞在脑内扩散并生长形成宏观症状性肿块的确切细胞和分子机制仍然知之甚少。在这里，我们建议测试关于胶质瘤生长的新的细胞、分子和机制假说，以及如何将这些知识转化为新的抗胶质瘤疗法。我的实验室使用共聚焦显微镜、电子显微镜和多光子显微镜进行的初步工作表明，胶质瘤细胞和人类胶质瘤干细胞在体内通过优先沿着血管周围的间隔室传播，血管周围是一个围绕脑微血管系统的潜在迁移网络。当胶质瘤细胞在血管周围网络中移动时，它们会从血管中移走神经胶质末梢，并损害邻近的脑组织；这后来被肿瘤细胞取代。我们还产生了初步数据，即糖链结合蛋白Galectin-1对这种生长机制是必不可少的。 Galectin-1的下调可以在体内消除脑内胶质瘤的生长，而不会影响体外的生长。这些新数据有几个临床后果：(I)淋巴管通过血管周围的腔室流出大脑；(Ii)胶质瘤的阻塞可导致胶质瘤引起的水肿；(Ii)人脑胶质瘤在出现症状之前会生长到很大程度；(Ii)萎缩的脑组织中的胶质瘤细胞替换可以解释肿瘤的长期、缓慢生长以及脑总体积的延迟变化；(Iii)抑制Galectin-1可能代表着一种治疗人脑胶质瘤的新方法。这一建议将(I)检验啮齿动物和人类胶质瘤细胞以及胶质瘤干细胞优先沿着血管周围空间生长的假设；(Ii)检验Galectin-1介导胶质瘤血管周围侵袭和生长的假设，以及Galectin-1的抑制可以作为一种新的治疗策略的假设；以及(Iii)检验Galectin-1的抑制将增强特异性抗胶质瘤免疫反应的假设。通过从胶质瘤病理生理学到胶质瘤迁移的分子机制再到实验治疗学的进展，我们的工作旨在引导新的早期临床翻译试验用于治疗人脑胶质瘤。值得注意的是，我们的第一个人类胶质瘤基因治疗的临床试验即将开始招募患者(FDA于2011年4月7日[IND 14574]批准了这项试验，最近又获得了密歇根大学国际BC和IRB的批准)。因此，我们的实验室处于一个强大和现实的地位，以指导我们的研究朝着翻译实施这种目前致命的人类癌症的新临床试验的方向发展。