Metabolic Regulators of Tumor Growth and Progression

肿瘤生长和进展的代谢调节因子

• 批准号: 10238924
• 负责人: RALPH J DEBERARDINIS
• 金额: $ 94.38万
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10238924
• 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; 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.

项目总结/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 将重新编程的活动转化为新的疗法是有限的，因为绝大多数知识 在肿瘤代谢中的作用来源于对培养细胞的研究，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， 消除文化的人工制品。我们的方法将肿瘤的多参数成像与肿瘤内成像相结合， 手术输注同位素标记的营养物，如13 C-葡萄糖。我们利用术前成像的信息 以指导组织取样，从而我们可以评估相关生物特征（葡萄糖摄取， 灌注、组织密度）对肿瘤代谢的影响。手术后，我们进行了一个片段一个片段的分析， 测量肿瘤和邻近肺的流量，并检查它们与组织学、遗传学和基因的关系 表情我们在人类非小细胞肺癌（NSCLC）中发表的工作表明，a）与 长期以来的预期，这些肿瘤氧化葡萄糖过量相比，相邻的肺; B）肿瘤氧化 除了葡萄糖之外的其他燃料，并且通过手术前成像预测区域燃料选择;以及c）广泛的 代谢异质性存在于人肺肿瘤之间，甚至存在于同一肿瘤的不同区域内。 据我们所知，我们的多学科方法将临床成像与代谢通量分析相结合， 定量组织病理学和分子特征是独特的。在这里，我们建议扩大我们的计划， 人类NSCLC代谢，以解决未来几年出现的紧迫问题。我们 建立新的计算方法，以更好地报告整个复杂代谢过程中的变化通量， 人NSCLC的网络。我们正在建立一系列的NSCLC异种移植物， 研究，为我们提供了一个生物试验床的假设刺激的观察，在临床 问题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，包括通过在常规和靶向治疗之前和之后采样代谢通量。我们 已经确定了一些候选燃料，现在正在为患者注入一系列13 C和15 N标记的 测试哪些营养素被肿瘤消耗，以及它们的代谢在体内是如何调节的。最后我们 正在建立方法来解开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 在完整的肿瘤微环境中的基质细胞是最艰巨的技术挑战之一， 这是一个新的领域，也是做出新发现的最佳机会。这些努力将 以前所未有的详细程度、生物学准确性和 与人类疾病有关。它们有可能在代谢调节和代谢调节中建立新的范式。 肿瘤异质性，并预测哪些患者将对代谢疗法有反应。