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Mammalian models for integrated metabolic and molecular profiling of malignant glioma

Mammalian models for integrated metabolic and molecular profiling of malignant glioma
恶性胶质瘤综合代谢和分子分析的哺乳动物模型
批准号:
10405088
负责人:
THOMAS G GRAEBER
金额:
$54.3万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-06-06 至 2023-05-31

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中文摘要
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英文摘要
PROJECT SUMMARY/ABSTRACT Translational cancer research requires robust preclinical models to most effectively investigate the underlying biology of disease and develop new therapeutics. While all models are imperfect, it is essential to understand the degree by which each model system (e.g., cell culture, xenograft) recapitulates specific molecular and functional characteristics of human tumors. This may be particularly relevant for studying altered metabolism, a hallmark of cancer, as even subtle changes to the environment can greatly impact the metabolic phenotype of a tumor. Moreover, as cancer metabolism is tightly regulated by oncogenic signaling, the diversity of molecular alterations within a given malignancy may elicit unique metabolic characteristics; which, may greatly influence metabolic pathway dependencies for tumor proliferation and growth. To best determine the fidelity of preclinical models in preserving the metabolic features of human cancer, this requires cross-comparing matched patient tissue and preclinical models across tumors with various genetic alterations. However, such a comprehensive investigation has yet to be undertaken. This proposal will perform an integrated metabolic and molecular characterization of matched human tumors, direct-from-patient orthotopic xenografts (GliomaPDOX), and cell lines from patients with glioblastoma (GBM) – one of the most lethal human malignancies that also reside within the unique brain metabolic milieu. In Aim 1, stable isotope-labeled metabolic tracing and liquid chromatography- mass spectrometry (LC-MS) will be used to cross-compare the metabolic phenotypes of prospectively matched GBM patient tumors, GliomaPDOX, and cell lines to determine the metabolic characteristics that are preserved and/or lost from patient to preclinical model. Aim 2 proposes to determine, in genetically diverse preclinical GliomaPDOX models, whether specific metabolic phenotypes align with distinct molecular signatures. Finally, in Aim 3, in vivo genetic knockdown experiments will be performed to assess whether measured metabolic phenotypes represent targetable dependencies for GliomaPDOX growth, invasion, and survival. Collectively, the studies proposed in this application will provide critical insight into the translatability of preclinical GBM models for studying tumor metabolism; which, may ultimately have important implications for developing new therapeutics against metabolic dependencies in GBM, and potentially, other malignancies.
期刊论文(5)
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会议论文
DOI: 10.1007/s00234-020-02585-8
发表时间: 2021-06
期刊: Neuroradiology
影响因子: 2.8
作者: [Oughourlian TC, Yao J, Hagiwara A, Nathanson DA, Raymond C, Pope WB, Salamon N, Lai A, Ji M, Nghiemphu PL, Liau LM, Cloughesy TF, Ellingson BM]
通讯作者: Ellingson BM
Project 2: Targeting differentiation-linked redox sensitivity in melanoma
Project 2: Targeting differentiation-linked redox sensitivity in melanoma
Project 2: Targeting differentiation-linked redox sensitivity in melanoma
Project 2: Targeting differentiation-linked redox sensitivity in melanoma
国内基金
海外基金
层出镰刀菌氮代谢调控因子AreA 介导伏马菌素 FB1 生物合成的作用机理
  • 批准号:
    2021JJ40433
  • 项目类别:
    省市级项目
  • 资助金额:
    --
  • 批准年份:
    2021
  • 负责人:
    孙磊
  • 依托单位:
寄主诱导梢腐病菌AreA和CYP51基因沉默增强甘蔗抗病性机制解析
  • 批准号:
    32001603
  • 项目类别:
    青年科学基金项目
  • 资助金额:
    24.0万元
  • 批准年份:
    2020
  • 负责人:
    段真珍
  • 依托单位:
AREA国际经济模型的移植.改进和应用
  • 批准号:
    18870435
  • 项目类别:
    面上项目
  • 资助金额:
    2.0万元
  • 批准年份:
    1988
  • 负责人:
    史树中
  • 依托单位: