Metabolic Regulators of Tumor Growth and Progression

肿瘤生长和进展的代谢调节因子

• 批准号: 9389673
• 负责人: RALPH J DEBERARDINIS
• 金额: $ 96.17万
• 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/9389673
• 关键词: Address; Beds; Biochemical Pathway; Biological; Biological Testing; Biology; Cancer Etiology; Cell Line; Cessation of life; Clinical Research; Complex; Computing Methodologies; 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.

项目摘要/摘要 代谢重编程是恶性肿瘤的标志，也是治疗靶标的来源。进步 将重编程活动转换为新疗法的限制，这是绝大多数知识的限制 在肿瘤中，代谢是从与疾病生物学相关的培养细胞研究中得出的。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结合 同位素标记的营养素（如13c-葡萄糖）的手术输注。我们使用术前成像中的信息 为了指导组织采样，以便我们可以评估相关生物学特征的影响（葡萄糖摄取， 灌注，组织密度）在肿瘤代谢上。手术后，我们对 肿瘤和邻近的肺，以测量通量并检查其与组织学，遗传学和基因的关系 表达。我们在人类非小细胞肺癌（NSCLC）中发表的工作表明，a）与 与邻近的肺相比，这些肿瘤长期以来的预期会使葡萄糖过量氧化。 b）肿瘤氧化 其他燃料以及葡萄糖和区域燃料选择是通过手术前成像预测的。 c）广泛 代谢异质性存在于人肺肿瘤之间，甚至在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一无二的。在这里，我们建议扩大我们的计划 人类NSCLC代谢解决新兴的新陈代谢，在接下来的几年中提出问题。我们是 建立新的计算方法，以更好地报告整个复杂代谢中的变化的变化 人类NSCLC网络。我们正在建立一系列从招募到该患者的NSCLC异种移植物 研究，为我们提供了一个生物测试床，以通过临床观察结果刺激的假设 研究。在患者和小鼠中，我们将检查癌症中代谢表型的演变 进展，包括在常规和靶向疗法之前和之后对代谢通量进行采样。我们 已经确定了许多候选燃料，现在正在注入一系列13C和15N标签的患者 营养以测试哪些被肿瘤消耗的营养以及其代谢如何在体内调节。最后，我们 正在建立解开包含肿瘤的不同细胞类型的代谢贡献的方法 患者和小鼠的微环境。我们认为了解癌症之间的代谢串扰 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 现场，这也是从根本上进行新发现的最佳机会。这些努力总共 以前所未有的细节，生物准确性和 与人类疾病有关。他们有可能在代谢法规中建立新的范例和 肿瘤异质性并预测哪些患者将对代谢疗法有反应。