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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

基本信息

批准号：
10165664
负责人：
THOMAS G GRAEBER
金额：
$ 55.41万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-06 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10165664
关键词：
Address Area Bioinformatics Biological Models Biology Brain Brain Neoplasms Carbon Cell Culture Techniques Cell Line Characteristics DNA DNA Sequence Alteration Data Dependence Disease Environment Enzymes Epidermal Growth Factor Receptor Exhibits Genetic Genetic Transcription Glioblastoma Glioma Goals Growth Heterogeneity Human Human Characteristics Hyperactivity In Vitro Investigation Isotope Labeling Libraries Malignant Glioma Malignant Neoplasms Measurement Measures Mesenchymal Metabolic Metabolic Pathway Metabolism Modeling Molds Molecular Molecular Genetics Molecular Profiling Mus Mutation NF1 gene Oncogenic Patients Phenotype Pre-Clinical Model Primary Brain Neoplasms Primary Cell Cultures Prognosis Public Health RNA Signal Transduction Stable Isotope Labeling Study models System Testing Therapeutic Human Experimentation Tissue Model Translational Research Tumor Cell Invasion Xenograft procedure cancer cell clinical translation conventional therapy experimental study high dimensionality human disease in vivo insight knock-down liquid chromatography mass spectrometry metabolic phenotype molecular subtypes neoplastic cell next generation sequencing novel therapeutics pre-clinical preservation prospective small hairpin RNA subcutaneous targeted treatment translational cancer research tumor tumor growth tumor metabolism

项目摘要

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.

项目总结/文摘