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2）我们的中心假设是NF1突变粒胶质瘤构成一个独特的胶质瘤亚组分子发病机理，肿瘤微环境和肿瘤细胞脆弱性。我们的方法包括各种神经胶质瘤模型，包括宝石，患者衍生的异种移植（PDX），原发性培养物和人类肿瘤活检。我们将考虑种系和躯体NF1沉默，也基于针对其他器官系统中NF1相关肿瘤发生的最新进展（项目1） 3）最大程度地提高了这项工作的翻译影响。为了发展NF1基因型特异性假设，合成宝石和衍生的GBM原发性培养物是我们发现细胞内在的发现方面的首选特性以及免疫微环境和第一线治疗测试。我们将利用鼠标我们开发的模型通过使三个关键肿瘤灭活而自发发展具有完全渗透的GBM 该疾病中的抑制基因（NF1，TP53和PTEN），并设计为模仿种系与体细胞NF1 驱动疾病。在一种情况下，小鼠携带杂合种系NF1突变（nf1-/flox或 - /+），而在另一种情况下，小鼠将仅开发体细胞NF1突变（NF1FLOX/+或NF1FLOX/FLOX）。发展的小鼠 GBM由于QKI，TP53和PTEN基因（QPP小鼠）的突变引起实验并表示NF1野生型GBM的亚组。原发性培养和扩大肿瘤同种异体移植将用于体外和体内临床前研究。由于零星GBM的遗传复杂性在人类中，在GEM中没有充分代表，我们将在PDX模型中确认并扩展关键结果在基因型中有所不同，但NF1基因是突变的或野生型的。 NF1突变体和NF1野生型在MSKCC上开发的患者衍生的原位异种移植物（PDX）将与项目1对齐1 和3，测试现场出现的NF1/RAS途径和其他疗法。人肿瘤样本与评估免疫浸润最相关，将在独特的背景下进行检查种系NF1 GBM患者的临床表现。 AIM 3将重点放在系统的临床注释上种系NF1 GBM的患者与经常收集的详细组织学和分子分析配对来自NF1相关GBM患者的福尔马林固定和石蜡嵌入了肿瘤活检。这些研究将与Core C（Biospecimen/Pathology）合作进行，并将用于验证关键结果关于TME的NF1相关特性。我们将与Core B（OMIC）合作进行执行来自宝石，PDX和人体组织样品的详细基因组和蛋白质组学表征，以鉴定在NF1突变体GBM中专门可操作的信号通路。将创建面向患者的门户以招募并系统地记录NF1相关GBM的临床表现和过程，以允许整合 NF1驱动的神经胶质瘤的组织学，分子和临床数据，跨宝石和PEX临床前模型以及 NF1 GBM的人。