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PROJECT 2: NF1-associated Glioblastoma

项目 2：NF1 相关胶质母细胞瘤

基本信息

批准号：
10270582
负责人：
Luis Fernando Parada
金额：
$ 43.38万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10270582
关键词：
Address Allografting Biopsy Cell Line Cells Characteristics Clinical Clinical Data Collaborations Communities Development Disease Drug Screening Engineering Equilibrium Evolution Experimental Models Formalin Gene Mutation Genetic Genetically Engineered Mouse Genomics Genotype Germ Lines Glioblastoma Glioma Goals Histologic Human Immune response Immune system Immunologics Immunotherapy In Vitro Incidence Individual Inflammatory Inflammatory Response Infrastructure International Link Malignant Neoplasms Malignant neoplasm of brain Memorial Sloan-Kettering Cancer Center Microglia Modeling Molecular Molecular Analysis Molecular Profiling Mus Mutate Mutation NF1 gene NF1 mutation NF1 related tumorigenesis Natural History PTEN gene Paraffin Embedding Pathogenesis Pathologic Pathology Pathway interactions Patients Penetrance Pharmaceutical Preparations Phenotype Pre-Clinical Model Predisposition Property Proteomics Published Comment Research Personnel Resources Role Sampling Signal Pathway Site Stratification Subgroup Suggestion TP53 gene Testing Therapeutic Time Tissues Tumor Cell Line Tumor Suppressor Genes Tumor-infiltrating immune cells Work Xenograft procedure base body system cohesion drug sensitivity effective therapy efficacy testing experience experimental study human tissue hyperactive Ras in vivo member mouse model mutant neoplastic cell patient advocacy group patient derived xenograft model preclinical study recruit research clinical testing response targeted treatment therapeutic evaluation translational impact tumor tumor microenvironment tumor-immune system interactions

项目摘要

ABSTRACT (Project 2) Our central hypothesis is that NF1 mutant gliomas constitute a distinct glioma subgroup with a unique molecular pathogenesis, tumor microenvironment, and tumor cell vulnerabilities. Our approach includes a variety of glioma models, including GEMs, patient-derived xenografts (PDX), primary cultures, and human tumor biopsies. We will consider both germline and somatic NF1 silencing, and also build upon the considerable recent progress with targeting NF1 associated tumorigenesis in other organ systems (Projects 1 and 3) to maximize the translational impact of this work. To develop NF1 genotype-specific hypotheses, syngeneic GEM and derived GBM primary cultures are our first choice for discovery aspects of cell intrinsic properties, as well as the immune microenvironment and first line therapeutic testing. We will exploit mouse models developed by us that spontaneously develop GBM with full penetrance by inactivating three key tumor suppressor genes in this disease (NF1, Tp53 and Pten) and engineered to mimic germline versus somatic NF1 driven disease. In one setting the mice harbor a heterozygous germline NF1 mutation (NF1-/flox or -/+), whereas in the other setting the mice will develop only somatic NF1 mutations (NF1flox/+ or NF1flox/flox). Mice that develop GBM due to mutations in the QKi, Tp53 and Pten genes (QPP mice) will serve as controls in these experiments and represent the subgroup of NF1 wild type GBM. Primary cultures and expanded tumor allografts will be used for in vitro and in vivo preclinical studies. Since the genetic complexity of sporadic GBM in humans is not adequately represented in GEM, we will confirm and extend key results in PDX models that vary in genotypes but for which the NF1 gene is either mutated or wildtype. NF1 mutant and NF1 wild type patient derived orthotopic xenografts (PDX) developed at MSKCC will be studied in alignment with Projects 1 and 3, to test NF1/Ras pathway-tailored and other therapies that have emerged in the field. Human tumor samples are most relevant for assessment of immune infiltration and will be examined in context of the unique clinical presentation of patients with germline NF1 GBM. Aim 3 will focus on the systematic clinical annotation of patients with germline NF1 GBM paired with detailed histologic and molecular analysis of routinely collected formalin-fixed and paraffin embedded tumor biopsies from people with NF1 associated GBM. These studies will be performed in collaboration with Core C (Biospecimen/Pathology) and will be used to validate key results regarding NF1 associated characteristics of the TME. We will collaborate with Core B (Omics) to perform detailed genomic and proteomic characterization of samples from GEM, PDX and human tissue to identify actionable signaling pathways specifically in NF1 mutant GBM. A patient-facing portal will be created to recruit and systemically document the clinical presentation and course of NF1 associated GBM to allow integration of histologic, molecular and clinical data for NF1 driven gliomas across GEM and PEX preclinical models and people with NF1 GBM.

摘要（项目二）