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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 中心，不一定是研究者的机构。 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，因此了解肿瘤的代谢特性提供了机会：1）确定可用于治疗开发的关键步骤，2）开发明确的肿瘤状态的非侵入性生物标志物和它对治疗的反应。尽管代谢途径的整体网络很复杂，但基本途径是明确定义的，包括柠檬酸循环中血源性底物的氧化、葡萄糖氧化为乳酸以及通过戊糖磷酸途径的通量。在这个项目中，我们将检查植入小鼠大脑中的人类肿瘤的代谢和遗传特征，作为中枢神经系统原发性和转移性癌症的模型。我们已经证明，可以从小鼠大脑和植入肿瘤的组织提取物中获得高质量的 13C NMR 谱。由于大脑由神经胶质细胞（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动可能有所不同，因此这些实验将使用 13C NMR 谱的丰富信息内容以及明智选择的标记模式和底物来评估通量分别在每个隔间中。 癌症代谢的两个核心问题可以得到解决。首先是脑部肿瘤生长所需的代谢途径在癌症亚型中是否常见，或者是亚型特异性的。例如，正常乳腺、皮肤、肺和肾的代谢特征是非常独特的，但尚不清楚这些特征是否在源自这些器官并转移到大脑的肿瘤中保留。第二个问题是大脑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，或者是原发肿瘤基因型的结果。基于新陈代谢设计治疗方法和反应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，我们将使用我们的人类原位脑肿瘤小鼠模型，其中包括胶质母细胞瘤 (GBM) 和转移到大脑的四种最常见的肿瘤（黑色素瘤、肺癌、乳腺癌和肾细胞癌），这些肿瘤来自于患者肿瘤切除时，仅在小鼠大脑中传代，并且具有完全的分子特征。它们提供了前所未有的机会，可以使用 13C NMR 光谱法直接在常见微环境中比较癌症亚型，以测量戊糖磷酸途径、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，这些肿瘤源自成熟的神经胶质细胞，这意味着神经胶质细胞代谢的两个特征（与神经元相比）被保留：乙酸盐氧化和柠檬酸循环中不产生 GABA。由于神经胶质瘤在神经元环境中生长，神经元示踪剂的代谢必须与神经胶质细胞的代谢分开。在富含 13C 的乙酸盐、富含 13C 的葡萄糖或两者的代谢过程中，通过对恶性肿瘤进行 13C NMR 同位素异构体分析来测量葡萄糖和乙酸盐氧化以及柠檬酸循环中 GABA 生成的相对速率。 目标 2. 检查脑转移瘤的中间代谢并根据组织学亚型确定通路活性的变化。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、肾细胞癌、黑色素瘤。 目标 3. 比较和对比脑转移瘤与 GBM 的代谢表型，并确定常见癌症通路、RAS-MAPK、AKT 和 p53 通路的潜在状态相对于潜在组织学的影响。我们将确定基因型或细胞类型在确定代谢表型时更重要。