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: 9250229
• 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 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9250229
• 关键词: Adenovirus Vector; Affect; Anatomy; Animals; 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; FLT3LG gene; Functional disorder; Galectin 1; Glioma; Growth; HRAS gene; Human; Human Characteristics; Immune; Immune response; In Vitro; Indolent; Infiltration; Institutional Review Boards; Investigational Therapies; 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; Stem cells; Symptoms; T cell response; TK Gene; Testing; Therapeutic; Translating; Travel; Tumor Cell Invasion; Universities; Work; brain parenchyma; brain tissue; brain volume; cerebral atrophy; cerebral microvasculature; 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; translational clinical trial; 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）：高级别神经胶质瘤均具有致死性，并且对手术、化疗和放疗具有抵抗力。神经胶质瘤细胞在大脑中分散并生长形成宏观症状肿瘤块的精确细胞和分子机制仍然知之甚少。在此，我们建议测试有关神经胶质瘤生长的新细胞、分子和机制假设，以及如何将这些知识转化为新的抗神经胶质瘤疗法。我的实验室使用共焦、电子和多光子显微镜进行的初步工作表明，神经胶质瘤细胞和人类神经胶质瘤干细胞在体内分散在大脑中，优先沿着血管周围室（围绕大脑微血管系统的潜在迁移网络）移动。当神经胶质瘤细胞在血管周围网络中移动时，它们会将神经胶质末足从血管中移出并损害邻近的脑组织；随后被肿瘤细胞取代。我们还生成了初步数据，表明聚糖结合蛋白 galectin-1 对于这种生长机制至关重要。 下调半乳糖凝集素-1可消除体内脑胶质瘤的生长，而不影响体外生长。这些新数据有几个临床后果：（i）淋巴液从大脑通过血管周围室排出；神经胶质瘤的阻塞会导致神经胶质瘤引起的水肿； (ii) 人类神经胶质瘤在出现症状之前会长到很大；萎缩脑组织的神经胶质瘤细胞替代可以解释肿瘤长期且惰性的生长以及总脑体积的延迟变化； (iii) 半乳糖凝集素-1 的抑制可能代表人类神经胶质瘤的一种新治疗方法。该提案将（I）检验啮齿动物和人类神经胶质瘤细胞以及神经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，并且抑制galectin-1可以作为一种新的治疗策略； (III) 检验抑制半乳糖凝集素-1 将增强特异性抗神经胶质瘤免疫反应的假设。通过从神经胶质瘤病理生理学进展到神经胶质瘤迁移的分子机制再到实验治疗，我们的目标是我们的工作为人类神经胶质瘤的治疗带来新的早期临床转化试验。值得注意的是，我们的第一个人类神经胶质瘤基因治疗临床试验即将开始患者招募（该试验于 2011 年 4 月 7 日获得 FDA 批准 [IND 14574]，最近获得密歇根大学 IBC 和 IRB 批准）。因此，我们的实验室处于强有力且现实的地位，可以指导我们的研究针对这种目前致命的人类癌症进行新型临床试验的转化实施。