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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：
10494106
负责人：
Luis Fernando Parada
金额：
$ 41.45万
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/10494106
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 Persons 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2）我们的中心假设是NF 1突变型胶质瘤构成了一个独特的胶质瘤亚组，分子发病机制、肿瘤微环境和肿瘤细胞脆弱性。我们的方法包括各种胶质瘤模型，包括GEM、患者来源的异种移植物（PDX）、原代培养物和人胶质瘤模型，肿瘤活检。我们将同时考虑胚系和体细胞NF 1沉默，最近在靶向其他器官系统中与NF 1相关的肿瘤发生方面取得了相当大的进展（项目1 （3）最大限度地发挥这项工作的翻译影响。为了发展NF 1基因型特异性假说，同系GEM和衍生GBM原代培养物是我们发现细胞内在特性，以及免疫微环境和一线治疗测试。我们会利用老鼠我们开发的模型，通过灭活三个关键肿瘤，抑制基因（NF 1，Tp 53和Pten），并设计成模拟生殖系与体细胞NF 1 疾病驱动在一种情况下，小鼠携带杂合种系NF 1突变（NF 1-/flox或-/+），而在另一种情况下，小鼠将仅发生体细胞NF 1突变（NF 1 flox/+或NF 1 flox/flox）。小鼠发育由于QKi、Tp 53和Pten基因突变的GBM（QPP小鼠）将在这些实验中用作对照。实验，并代表NF 1野生型GBM的亚组。原代培养和扩增肿瘤同种异体移植物将用于体外和体内临床前研究。由于散发性GBM的遗传复杂性在GEM中没有充分代表人类，我们将确认和扩展PDX模型中的关键结果，基因型不同，但NF 1基因是突变型或野生型。NF 1突变体和NF 1野生型在MSKCC开发的患者源性原位异种移植物（PDX）将与项目1一致进行研究第三，测试NF 1/Ras通路定制和该领域出现的其他疗法。人肿瘤样本与免疫浸润评估最相关，将在独特的背景下进行检查。生殖系NF 1 GBM患者的临床表现。目标3将侧重于系统的临床注释与常规收集的详细组织学和分子分析配对的生殖系NF 1 GBM患者中，来自NF 1相关GBM患者的福尔马林固定和石蜡包埋的肿瘤活检。这些研究将与核心C（生物标本/病理学）合作进行，并将用于验证关键结果关于TME的NF 1相关特征。我们将与Core B（Omics）合作，对GEM、PDX和人体组织样品进行详细的基因组和蛋白质组学表征，在NF 1突变GBM中特异性的可操作的信号传导途径。将创建一个面向患者的门户网站，并系统地记录NF 1相关GBM的临床表现和病程， GEM和PEX临床前模型中NF 1驱动的胶质瘤的组织学、分子和临床数据， NF 1 GBM患者