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

基本信息

批准号：
8606906
负责人：
Pedro R Lowenstein
金额：
$ 33.68万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
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/8606906
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

项目摘要

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）：高级神经胶质瘤均匀致死，对手术，化学疗法和放疗性有抵抗力。神经胶质瘤细胞通过大脑分散并成长形成宏观症状性肿瘤肿块的精确细胞和分子机制仍然很少了解。本文中，我们建议测试有关神经胶质瘤生长的新细胞，分子和机械假设，以及如何将这些知识转化为新的抗神经胶质瘤疗法。使用共聚焦，电子和多光子显微镜从我的实验室进行的初步工作表明，神经胶质瘤细胞和人神经胶质瘤干细胞通过优先沿着血管周围室室中的脑部传播，这是一个围绕脑大脑微举行的潜在迁移网络，从而在体内分散。随着神经胶质瘤细胞在整个血管周网中移动，它们会从血管中移动神经胶质末端，并妥协相邻的脑组织。后来被肿瘤细胞取代。我们还产生了初步数据，即聚糖结合蛋白Galectin-1对于这种生长机制至关重要。下调半乳糖素-1的下调可消除体内大脑中神经胶质瘤的生长，而不会影响体外的生长。这些新数据有几种临床后果：（i）通过血管周室从大脑排出的淋巴管；神经胶质瘤的阻塞会导致神经胶质瘤诱导的水肿。（ii）在引起症状之前，人神经胶质瘤肿瘤在大尺寸上生长；萎缩性脑组织的神经胶质瘤细胞替代可以解释旷日持久的肿瘤生长，以及总脑部量的延迟变化。（iii）抑制lectectin-1可以代表人神经胶质瘤的新型治疗方法。该建议将（i）检验以下假设：啮齿动物和人神经胶质瘤细胞以及胶质瘤干细胞沿着血管周空间优先生长；（ii）检验了lectectin-1介导神经胶质瘤周血管侵袭和生长的假设，并且抑制lectectin-1可以用作一种新型的治疗策略；（iii）检验了抑制lectectin-1将增强特定抗脱光瘤免疫反应的假设。通过从神经胶质瘤的病理生理学到神经胶质瘤迁移到实验疗法的分子机制，我们的目标是导致新的早期临床翻译试验，以治疗人神经胶质瘤。值得注意的是，我们对人神经胶质瘤基因治疗的首次临床试验正在接近患者招募的开始（它得到了FDA于4/7/11 [IND 14574]批准，最近由密歇根大学IBC和IRB大学批准）。因此，我们的实验室处于强大而现实的地位，可以指导我们的研究对当前致命的人类癌症进行新的临床试验的实施。