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Project 4- Targeting the neuronal microenvironment in gliomas (Monje/Suva)

项目 4 - 针对神经胶质瘤的神经元微环境 (Monje/Suva)

基本信息

批准号：
10696103
负责人：
Mario Luca Suva
金额：
$ 34.54万
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：
2013
资助国家：
美国
起止时间：
2013-09-19 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10696103
关键词：
Acute Adult Adult Glioblastoma Allografting Brain Brain Neoplasms Brain-Derived Neurotrophic Factor Cell Communication Cells Cessation of life Childhood Childhood Glioblastoma Childhood Glioma Clinical Clinical Trials Complement Coupled Data Dependence Development Dissociation Ecosystem Enzymes Exhibits FRAP1 gene Future Genetic Genetic Transcription Genome Genomics Glioblastoma Glioma Growth Immunocompetent In Vitro Knock-out Knockout Mice Malignant Neoplasms Malignant neoplasm of brain Measures Mediating Mitogens Modeling Molecular Mus Nature Neuroglia Neuronal Plasticity Neurons Oncogenic Oncologist PIK3CG gene Pathology Pathway interactions Patients Pediatric Brain Tumor Consortium Penetration Peptide Hydrolases Pharmaceutical Preparations Phase Phase I Clinical Trials Phase I/II Clinical Trial Phase I/II Trial Primary Neoplasm Proteins Quantitative Microscopy Recurrence Research Resolution Rest Role Sampling Science Signal Transduction Synapses Testing Therapeutic Time Treatment Efficacy Tumor Burden Tumor Tissue Wild Type Mouse Work Xenograft Model Xenograft procedure bioluminescence imaging cancer cell cell type efficacy testing experimental study in vivo inhibitor insight malignant breast neoplasm mouse model neurodevelopment neuroligin 3 neuromechanism novel novel therapeutic intervention novel therapeutics patient derived xenograft model patient subsets pre-clinical preclinical efficacy research clinical testing safety testing single-cell RNA sequencing targeted treatment therapeutic evaluation transcriptome tumor tumor growth tumor microenvironment

项目摘要

High-grade gliomas are the leading cause of brain tumor-related death, underscoring the urgent need for a deeper understanding of high-grade glioma pathobiology and novel avenues for therapy. We have recently discovered that neuronal activity robustly promotes high-grade glioma growth and that a synaptic molecule called neuroligin-3 is a crucial activity-regulated mechanism for glioma growth. Activity-regulated cleavage and release of neuroligin-3 from synapses, mediated by the protease ADAM10, is required for glioma growth, although it is not yet clear what mediates this striking dependency. Further, we have found that a subset of xenografted gliomas evolve in vivo to circumvent neuroligin-3 dependency over a period of 6 months in the context of a neuroligin-3 deficient brain microenvironment. In the present proposal, we seek to leverage single cell genomics together with patient-derived glioblastoma orthotopic xenografts and immunocompetent murine glioblastoma allografts in neuroligin-3 knockout or wild type mice to dissect neuroligin-3 signaling within the intact glioma ecosystem. Using a similar strategy, we will also uncover the mechanisms by which some xenografted gliomas circumvent neuroligin-3 dependency, findings that will inform not only neuron-glioma interactions but also fundamental mechanisms of glioma progression. Finally, we will perform preclinical efficacy and safety testing of ADAM10 inhibition to block neuroligin-3 release into the tumor microenvironment in an effort to provide sufficient preclinical evidence to bring this novel therapeutic strategy to a clinical trial for adult high-grade gliomas. This future trial will complement our Pediatric Brain Tumor Consortium-sponsored phase 1 clinical trial of ADAM10 inhibition for pediatric high grade glioma. Taken together, the proposed experiments will elucidate fundamental mechanisms of glioma growth and progression and advance a promising new therapeutic approach for these lethal brain cancers.

高级别胶质瘤是脑肿瘤相关死亡的主要原因，因此迫切需要对其进行治疗