Metabolic Regulators of Tumor Growth and Progression

肿瘤生长和进展的代谢调节因子

• 批准号: 10472535
• 负责人: RALPH J DEBERARDINIS
• 金额: $ 92.43万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-04 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10472535
• 关键词: Address; Beds; Biochemical Pathway; Biological; Biological Testing; Biology; Cancer Etiology; Cell Line; Cessation of life; Clinical Research; Complex; Computing Methodologies; Consumption; Cultured Cells; Disease; Evolution; Gene Expression; Genetic; Glucose; Heterogeneity; Histology; Histopathology; Human; Image-Guided Surgery; Infusion procedures; Isotope Labeling; Knowledge; Label; Lung; Lung Neoplasms; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of thorax; Measures; Metabolic; Metabolism; Methods; Molecular; Morphologic artifacts; Mus; Non-Small-Cell Lung Carcinoma; Nutrient; Operative Surgical Procedures; Oxides; Patient Recruitments; Patients; Perfusion; Publishing; Regulation; Reporting; Sampling; Series; Source; Stromal Cells; Survival Rate; Testing; Tissue Sample; Tissues; Translating; Work; Xenograft procedure; cancer cell; cancer imaging; cell type; clinical imaging; conventional therapy; density; expectation; glucose uptake; human disease; human subject; improved; in vivo; interdisciplinary approach; metabolic phenotype; multiparametric imaging; novel; novel therapeutics; programs; targeted treatment; therapeutic target; tumor; tumor growth; tumor heterogeneity; tumor metabolism; tumor microenvironment; tumor progression

Project Summary/Abstract Metabolic reprogramming is a hallmark of malignancy and a source of therapeutic targets. Progress in translating reprogrammed activities into new therapies is limited by the fact that the vast majority of knowledge in tumor metabolism is derived from studies in cultured cells with unknown relevance to disease biology. We developed methods to assess metabolic flux directly in tumors from human subjects and mice, thereby eliminating artifacts of culture. Our approach integrates multi-parametric imaging of the tumor with intra- operative infusions of isotope labeled nutrients like 13C-glucose. We use information from pre-surgical imaging to guide tissue sampling, so that we can assess the effects of relevant biological features (glucose uptake, perfusion, tissue density) on tumor metabolism. After surgery, we perform a fragment-by-fragment analysis of tumor and adjacent lung to measure fluxes and examine their relationship to histology, genetics and gene expression. Our published work in human non-small cell lung cancer (NSCLC) demonstrated that a) contrary to long-held expectations, these tumors oxidize glucose in excess compared to adjacent lung; b) tumors oxidize other fuels in addition glucose, and regional fuel choice is predicted by pre-surgical imaging; and c) extensive metabolic heterogeneity exists among human lung tumors and even within distinct regions of the same tumor. As far as we know, our multidisciplinary approach integrating clinical imaging with metabolic flux analysis, quantitative histopathology and molecular features is unique. Here we propose to expand our program in human NSCLC metabolism to address emerging, pressing questions over the next several years. We are establishing novel computational methods to better report altered fluxes throughout the complex metabolic networks of human NSCLC. We are establishing a series of NSCLC xenografts from patients recruited to the study, providing us with a biological test bed for hypotheses stimulated by observations made in the clinical studies. In patients and mice, we will examine the evolution of metabolic phenotypes during cancer progression, including by sampling metabolic flux before and after conventional and targeted therapies. We have identified a number of candidate fuels and are now infusing patients with a series of 13C and 15N-labeled nutrients to test which ones are consumed by tumors and how their metabolism is regulated in vivo. Finally, we are establishing methods to disentangle the metabolic contributions of distinct cell types comprising the tumor microenvironment in patients and mice. We believe that understanding metabolic crosstalk between cancer and stromal cells in the intact tumor microenvironment is one of the most daunting technical challenges in the field, but also the best opportunity to make fundamentally new discoveries. Altogether, these efforts 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 tumor heterogeneity and to predict which patients will respond to metabolic therapies.

项目概要/摘要 代谢重编程是恶性肿瘤的标志，也是治疗靶点的来源。进展情况 将重新编程的活动转化为新疗法受到以下事实的限制：绝大多数知识 肿瘤代谢中的作用源自对培养细胞的研究，与疾病生物学的相关性未知。我们 开发了直接评估人类受试者和小鼠肿瘤中代谢通量的方法，从而 消除文化文物。我们的方法将肿瘤的多参数成像与内部 手术输注同位素标记的营养物质，如 13C-葡萄糖。我们使用来自术前成像的信息 指导组织取样，以便我们能够评估相关生物学特征（葡萄糖摄取、 灌注、组织密度）对肿瘤代谢的影响。手术后，我们对以下内容进行逐片段分析： 肿瘤和邻近的肺部，测量通量并检查它们与组织学、遗传学和基因的关系 表达。我们发表的关于人类非小细胞肺癌 (NSCLC) 的研究表明：a) 与 长期以来的预期是，与邻近的肺相比，这些肿瘤会过量氧化葡萄糖； b) 肿瘤氧化 除葡萄糖外的其他燃料，并且通过术前成像预测区域燃料选择； c) 广泛的 人类肺部肿瘤之间甚至同一肿瘤的不同区域内都存在代谢异质性。 据我们所知，我们的多学科方法将临床成像与代谢流分析相结合， 定量组织病理学和分子特征是独一无二的。在此，我们建议将我们的计划扩展至 人类非小细胞肺癌代谢解决未来几年新出现的紧迫问题。我们是 建立新颖的计算方法，以更好地报告整个复杂代谢过程中变化的通量 人类非小细胞肺癌网络。我们正在从招募的患者中建立一系列非小细胞肺癌异种移植物 研究为我们提供了一个生物试验台，用于根据临床观察结果激发假设 研究。在患者和小鼠中，我们将检查癌症期间代谢表型的演变 进展，包括通过对常规和靶向治疗之前和之后的代谢通量进行采样。我们 已经确定了一些候选燃料，现在正在为患者输注一系列 13C 和 15N 标记的燃料 营养物质来测试哪些营养物质被肿瘤消耗以及它们的代谢在体内是如何调节的。最后，我们 正在建立方法来理清构成肿瘤的不同细胞类型的代谢贡献 患者和小鼠的微环境。我们相信，了解癌症之间的代谢串扰 完整肿瘤微环境中的基质细胞是该领域最艰巨的技术挑战之一 领域，也是做出全新发现的最佳机会。总而言之，这些努力将 生成非小细胞肺癌代谢的独特视图，具有前所未有的细节水平、生物学准确性和 与人类疾病的相关性。他们有潜力在代谢调节和 肿瘤异质性并预测哪些患者将对代谢疗法产生反应。