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:
- 金额:$ 41.45万
- 依托单位:
- 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:
- 关键词:AddressAllograftingBiopsyCell LineCellsCharacteristicsClinicalClinical DataCollaborationsCommunitiesDevelopmentDiseaseDrug ScreeningEngineeringEquilibriumEvolutionExperimental ModelsFormalinGene MutationGeneticGenetically Engineered MouseGenomicsGenotypeGerm LinesGlioblastomaGliomaGoalsHistologicHumanImmune responseImmune systemImmunologicsImmunotherapyIn VitroIncidenceIndividualInflammatoryInflammatory ResponseInfrastructureInternationalLinkMalignant NeoplasmsMalignant neoplasm of brainMemorial Sloan-Kettering Cancer CenterMicrogliaModelingMolecularMolecular AnalysisMolecular ProfilingMusMutateMutationNF1 geneNF1 mutationNF1 related tumorigenesisNatural HistoryPTEN geneParaffin EmbeddingPathogenesisPathologicPathologyPathway interactionsPatientsPenetrancePersonsPharmaceutical PreparationsPhenotypePre-Clinical ModelPredispositionPropertyProteomicsPublished CommentResearch PersonnelResourcesRoleSamplingSignal PathwaySiteStratificationSubgroupSuggestionTP53 geneTestingTherapeuticTimeTissuesTumor Cell LineTumor Suppressor GenesTumor-infiltrating immune cellsWorkXenograft procedurebasebody systemcohesiondrug sensitivityeffective therapyefficacy testingexperienceexperimental studyhuman tissuehyperactive Rasin vivomembermouse modelmutantneoplastic cellpatient advocacy grouppatient derived xenograft modelpreclinical studyrecruitresearch clinical testingresponsetargeted treatmenttherapeutic evaluationtranslational impacttumortumor microenvironmenttumor-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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Luis Fernando Parada其他文献
Luis Fernando Parada的其他文献
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{{ truncateString('Luis Fernando Parada', 18)}}的其他基金
Isolation, characterization and translational development of glioma stem cells
神经胶质瘤干细胞的分离、表征和转化发育
- 批准号:
10555234 - 财政年份:2017
- 资助金额:
$ 41.45万 - 项目类别:
Isolation, characterization and translational development of glioma stem cells
神经胶质瘤干细胞的分离、表征和转化发育
- 批准号:
10337037 - 财政年份:2017
- 资助金额:
$ 41.45万 - 项目类别:
Isolation, characterization and translational development of glioma stem cells
神经胶质瘤干细胞的分离、表征和转化发育
- 批准号:
10090574 - 财政年份:2017
- 资助金额:
$ 41.45万 - 项目类别:
The ability of BDNF in the NAc an VTA in to regulate mood & motivational
NAc 和 VTA 中的 BDNF 调节情绪的能力
- 批准号:
8114142 - 财政年份:2010
- 资助金额:
$ 41.45万 - 项目类别:
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