METABOLIC REGULATORS OF TUMOR CELL GROWTH

肿瘤细胞生长的代谢调节因子

• 批准号: 9102445
• 负责人: RALPH J DEBERARDINIS
• 金额: $ 38.44万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9102445
• 关键词: Accounting; Acetates; Address; Area; Award; Bioenergetics; Biological; Cancer Etiology; Cancer Patient; Cancer cell line; Carbon; Cell Line; Cell Proliferation; Cells; Cessation of life; Citric Acid Cycle; Clinical Research; Data; Enzymes; Fatty Acids; Gene Expression; Glucose; Glutamine; Gold; Grant; Heterogeneity; Histology; Histopathology; Human; Image; Imaging Techniques; Individual; Infusion procedures; Intrinsic factor; Investigation; Isotope Labeling; Knowledge; Label; Life; Lung; Lung Neoplasms; Magnetic Resonance Imaging; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Metabolic; Metabolic Pathway; Metabolism; Methods; Molecular; Mouse Cell Line; Mus; Non-Small-Cell Lung Carcinoma; Nutrient; Operative Surgical Procedures; Organ; Pathway interactions; Patients; Perfusion; Positioning Attribute; Process; Proliferating; Property; Regulation; Reporting; Resolution; Role; Sampling; Site; Solid Neoplasm; Source; Staging; Survival Rate; System; Techniques; Testing; Tissue Sample; Tissues; Waste Products; Work; Xenograft procedure; addiction; anticancer research; cancer cell; cell growth; fluorodeoxyglucose positron emission tomography; glucose metabolism; human data; human disease; imaging modality; improved; in vivo; innovation; insight; metabolic phenotype; metabolomics; neoplastic cell; new therapeutic target; novel; novel strategies; oxidation; preference; programs; public health relevance; regional difference; tandem mass spectrometry; targeted cancer therapy; tumor; tumor heterogeneity; tumor metabolism

 DESCRIPTION (provided by applicant): Metabolic reprogramming is considered to be a hallmark of malignancy and source of novel therapeutic targets. However, the vast majority of knowledge so far established for tumor cell metabolism is derived from studies in cultured cell lines rather than intact tumors. Our work over the previous five years of this Award demonstrated that a) tumor cells contain a diversity of metabolic programs to support survival and proliferation, with many distinct configurations of the tricarboxylic acid (TCA) cycle regulate by combinations of cell-intrinsic and extrinsic factors; b) intra-operative infusions of 13C-glucos and other isotope-labeled fuels can be used to probe the metabolism of intact tumors in mice and humans; c) important metabolic differences exist between tumor cells in culture and in vivo, indicating a need to improve techniques for in vivo analysis, particularly in humans; d) human lung tumors support their bioenergetics by oxidizing glucose and a variety of other substrates in vivo; and e) pre-operative MRI, FDG-PET and other imaging techniques can be used to predict informative aspects of tumor metabolism and identify areas of metabolic heterogeneity within individual human lung tumors. We are now poised to use a unique and highly innovative combination of approaches to test hypotheses about the metabolism of intact tumors in humans and mice, focusing on the drivers of metabolic heterogeneity in vivo. We propose three Specific Aims to address these issues in non-small cell lung cancer (NSCLC), the most common cause of cancer-related deaths worldwide. In Aim 1, we will implement a novel technique to derive positional assignment of 13C by mass spectrometry. This will enable us to maximize the information content derived from very small samples, potentially as little as 1% the size of fragments currently required by standard approaches. This will greatly enhance our ability to map regional metabolic heterogeneity within individual tumors in vivo. In Aim 2, we will use pre-surgical imaging, 13C infusions and metabolomics to examine the metabolism of glucose and other fuels in intact tumors. We will determine how tissue perfusion alters nutrient preferences in vivo and test the hypothesis that enhanced glucose oxidation in the TCA cycle is a specific hallmark of proliferating tumor cells. This aim will use xenografts derived from NSCLC cell lines, patient-derived NSCLC xenografts, and a clinical study featuring intra-operative 13C infusions in human NSCLC patients. In Aim 3, we will test the hypothesis that lactate, an abundant circulating fuel long considered a waste product of tumor metabolism, is also used as a fuel source for the TCA cycle in a subset of well-perfused NSCLC tumors. We will use infusions of 13C-labeled lactate to identify and localize pathways of lactate utilization within intact tumors i humans and mice. Altogether, these Aims will generate a unique view of NSCLC metabolism with an unprecedented level of detail, biological accuracy and relevance to human disease. They have the potential to establish new paradigms in metabolic regulation and heterogeneity in cancer and in predicting which tumors will respond to metabolic therapies.

 描述（由申请人提供）：代谢重编程被认为是恶性肿瘤的标志和新治疗靶点的来源。然而，迄今为止建立的肿瘤细胞代谢的绝大多数知识都来自对培养细胞系而不是完整肿瘤的研究。我们在该奖项前五年的工作表明：a) 肿瘤细胞包含多种代谢程序来支持生存和增殖，并通过细胞内在和外在因素的组合调节三羧酸 (TCA) 循环的许多不同配置； b) 术中输注 13C-葡萄糖和其他同位素标记的燃料可用于探测小鼠和人类完整肿瘤的代谢； c) 培养物和体内肿瘤细胞之间存在重要的代谢差异，表明需要改进体内分析技术，特别是在人类中； d) 人类肺部肿瘤通过氧化体内葡萄糖和各种其他底物来支持其生物能； e) 术前 MRI、FDG-PET 和其他成像技术可用于预测肿瘤代谢的信息方面并识别个体人类肺部肿瘤内代谢异质性的区域。我们现在准备使用一种独特且高度创新的方法组合来测试有关人类和小鼠完整肿瘤代谢的假设，重点关注体内代谢异质性的驱动因素。我们提出了三个具体目标来解决非小细胞肺癌 (NSCLC) 中的这些问题，非小细胞肺癌是全球癌症相关死亡的最常见原因。在目标 1 中，我们将实施一种新技术，通过质谱法推导 13C 的位置分配。这将使我们能够最大限度地从非常小的样本中获取信息内容，这些样本可能只有目前标准方法所需片段大小的 1%。这将极大地增强我们在体内绘制单个肿瘤内区域代谢异质性的能力。在目标 2 中，我们将使用术前成像、13C 输注和代谢组学来检查完整肿瘤中葡萄糖和其他燃料的代谢。我们将确定组织灌注如何改变营养偏好 体内并检验了 TCA 循环中葡萄糖氧化增强是肿瘤细胞增殖的特定标志这一假设。该目标将使用源自 NSCLC 细胞系的异种移植物、患者来源的 NSCLC 异种移植物以及一项以人类 NSCLC 患者术中 13C 输注为特色的临床研究。在目标 3 中，我们将检验以下假设：乳酸是一种丰富的循环燃料，长期以来被认为是肿瘤代谢的废物，在灌注良好的 NSCLC 肿瘤中也被用作 TCA 循环的燃料来源。我们将使用 13C 标记的乳酸输注来识别和定位人类和小鼠完整肿瘤内乳酸利用的途径。总而言之，这些目标将产生非小细胞肺癌代谢的独特观点，其细节、生物学准确性和与人类疾病的相关性达到前所未有的水平。他们有潜力在癌症的代谢调节和异质性以及预测哪些肿瘤将对代谢疗法产生反应方面建立新的范例。