BIOMARKERS AND METABOLIC PATHWAYS IN GLIOMAS AND BRAIN METASTASIS

神经胶质瘤和脑转移中的生物标志物和代谢途径

• 批准号: 8171674
• 负责人: Robert M. Bachoo
• 金额: $ 4.18万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8171674
• 关键词: Acetates; Address; Astrocytes; Biological Markers; Blood; Brain; Brain Neoplasms; Breast; Characteristics; Citric Acid Cycle; Common Neoplasm; Complex; Computer Retrieval of Information on Scientific Projects Database; Disseminated Malignant Neoplasm; Environment; Excision; Funding; Generations; Genetic; Genotype; Glioblastoma; Glioma; Glucose; Glycolysis; Grant; Growth; Histology; Human; Implant; Institution; Kidney; Label; Lung; Malignant Neoplasms; Measures; Metabolic; Metabolic Pathway; Metabolism; Metastatic malignant neoplasm to brain; Modeling; Mus; NMR Spectroscopy; Neoplasm Metastasis; Neuraxis; Neuroglia; Neurons; Non-Small-Cell Lung Carcinoma; Oligodendroglia; Organ; Pathway interactions; Patients; Pattern; Pentosephosphate Pathway; Phenotype; Primary Neoplasm; Production; Property; Proto-Oncogene Proteins c-akt; Relative (related person); Renal Cell Carcinoma; Research; Research Personnel; Resources; Skin; Source; TP53 gene; Time; Tissue Extracts; Tracer; Tumor-Derived; United States National Institutes of Health; Variant; base; cancer cell; cell type; gamma-Aminobutyric Acid; kidney cell; lung melanoma; melanoma; mouse model; oxidation; research study; response; therapeutic development; therapy design; tumor; tumor growth

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. All malignancies require well-organized metabolic activities to support growth and proliferation. Since tumor metabolism is essential to growth, an understanding of the metabolic properties of a tumor offers the opportunity to 1) identify critical steps that may be exploited in therapeutic development and 2) to develop well-defined noninvasive biomarkers of the status of a tumor and its response to treatment. Although the overall network of metabolic pathways is complex, the fundamental pathways are clearly defined and include oxidation of blood-borne substrates in the citric acid cycle, oxidation of glucose to lactate, and flux through the pentose phosphate pathway. In this Project we will examine metabolic and genetic features of human tumors implanted in the mouse brain as a model of primary and metastatic cancers of the central nervous system. We have already shown that superb-quality 13C NMR spectra can be obtained from tissue extracts of the mouse brain and implanted tumors. Since the brain is composed of both glia (astrocytes and oligodendrocytes) and neurons and the metabolic activities of each cell type may differ, these experiments will use the rich information content of a 13C NMR spectrum plus judicious selection of labeling patterns and substrates to assess fluxes in each compartment separately. Two central questions in cancer metabolism can be addressed. The first is whether the metabolic pathways required for tumor growth in the brain are common among the cancer subtypes or are subtype-specific. For example, the metabolic features of normal breast, skin, lung and kidney are quite distinct, yet it is not known whether these characteristic features are preserved in tumors that derive from these organs and metastasize to the brain. The second question is whether the metabolic phenotype of a malignancy in the brain is a consequence of its interaction with the local microenvironment or, alternatively, is a consequence of the genotype of the primary tumor. Designing therapies as well as biomarkers of response based on metabolism hinges on understanding these fundamental properties of cancer cells. To address these questions, we will use our human orthotopic brain tumor mouse models, which include glioblastoma (GBM) and the four most common tumors which metastasize to the brain (melanoma, lung, breast and renal cell cancer) which were derived from patients at the time of tumor resection, have been passaged exclusively in mouse brain, and are fully characterized molecularly. They provide an unprecedented opportunity to compare cancer subtypes directly in a common microenvironment using 13C NMR spectroscopy to measure relative fluxes in the pentose phosphate pathway, the citric acid cycle and glycolysis. There are three aims: Aim 1. To measure the metabolic phenotype of glioblastoma. Presumably these tumors are derived from mature glial cells with the implication that the two characteristics of glial metabolism (compared to neurons) are preserved: oxidation of acetate and absence of production of GABA from the citric acid cycle. Since gliomas grow in the environment of neurons, metabolism of tracers by neurons must be separated from metabolism of glial cells. The relative rates of glucose and acetate oxidation and generation of GABA from the citric acid cycle will be measured by 13C NMR isotopomer analysis of the malignancy during metabolism of 13C-enriched acetate, 13C enriched glucose, or both. Aim 2. To examine intermediary metabolism in brain metastases and determine the variation in pathway activity based on histological subtype. The four most common types of brain metastases will be used for these studies. These include non-small cell lung cancer, breast, renal cell, melanoma. Aim 3. To compare and contrast the metabolic phenotype of brain metastases with GBM and determine the impact of the underlying status of the common cancer pathways, RAS-MAPK, AKT, and p53 pathways relative to the underlying histology. We will determine whether the genotype or cell type is more important in determining the metabolic phenotype.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 所有恶性肿瘤都需要组织良好的代谢活动来支持生长和增殖。由于肿瘤代谢对于生长至关重要，因此对肿瘤的代谢特性的理解为1）确定在治疗性发育中可能利用的关键步骤，以及2）2）开发出明确定义的肿瘤状态的非侵入性生物标志物及其对治疗的反应。尽管代谢途径的总体网络很复杂，但基本途径已明确定义，包括在柠檬酸周期中血液传播底物的氧化，葡萄糖氧化为乳酸盐以及通过五磷酸五磷酸五磷酸五磷酸途径的通量。在这个项目中，我们将检查植入小鼠脑的人类肿瘤的代谢和遗传特征，作为中枢神经系统的原发性和转移性癌症的模型。我们已经表明，可以从小鼠脑和植入的肿瘤的组织提取物获得出色的13C NMR光谱。由于大脑由神经胶质（星形胶质细胞和少突胶质细胞）和神经元组成，并且每种细胞类型的代谢活性可能有所不同，因此这些实验将使用13C NMR光谱的丰富信息含量，以及明智的标记模式和底物选择的13C NMR选择，以分别评估每个隔段中的磁通量。 可以解决癌症代谢中的两个核心问题。首先是大脑肿瘤生长所需的代谢途径在癌症亚型中是常见的还是亚型特异性的。例如，正常乳房，皮肤，肺和肾脏的代谢特征是完全不同的，但尚不清楚这些特征是否保留在源自这些器官并转移到大脑的肿瘤中。第二个问题是大脑中恶性肿瘤的代谢表型是否是其与局部微环境相互作用的结果，或者是原发性肿瘤基因型的结果。设计疗法以及基于新陈代谢的反应的生物标志物，取决于了解癌细胞的这些基本特性。为了解决这些问题，我们将使用人类的骨脑肿瘤小鼠模型，其中包括胶质母细胞瘤（GBM）和四个最常见的肿瘤，这些肿瘤在肿瘤切除时从患者中转移到大脑（黑色素瘤，肺，肺，乳腺癌和肾脏细胞癌），在小鼠大脑中独家释放，并在小鼠大脑中独立地传递。他们提供了前所未有的机会，可以使用13C NMR光谱法直接在常见的微环境中比较癌症亚型，以测量五磷酸五磷酸途径，柠檬酸循环和糖酵解中的相对通量。有三个目标： 目的1。测量胶质母细胞瘤的代谢表型。据推测，这些肿瘤来自成熟的神经胶质细胞，这意味着保留了神经胶质代谢的两个特征（与神经元相比）：乙酸盐的氧化和柠檬酸周期中GABA产生的缺乏。由于神经胶质瘤在神经元的环境中生长，因此必须将神经元的示踪剂代谢与神经胶质细胞的代谢分离。柠檬酸周期的葡萄糖和乙酸盐氧化的相对速率以及GABA的产生将通过13C NMR同位素分析在13c富集乙酸，13C富集葡萄糖或两者兼有的13C NMR同位素分析中测量。 目标2。检查脑转移中的中间代谢，并根据组织学亚型确定途径活性的变化。这些研究将使用四种最常见的脑转移类型。这些包括非小细胞肺癌，乳腺癌，肾细胞，黑色素瘤。 目的3。要比较和对比脑转移的代谢表型与GBM，并确定相对于基础组织学相对于基础的癌症途径，RAS-MAPK，AKT和p53途径的基础状态的影响。我们将确定基因型或细胞类型在确定代谢表型中是否更重要。