Revealing cancer metabolism via mass spectrometry and isotope tracers

通过质谱和同位素示踪剂揭示癌症代谢

• 批准号: 9762593
• 负责人: Wenyun Lu
• 金额: $ 10.84万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-19 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9762593
• 关键词: Autophagocytosis; Award; Cancer Center; Cancer Institute of New Jersey; Carbon; Cultured Cells; Data; Development; Diagnosis; Folic Acid; Folic Acid Antagonists; Freezing; Functional disorder; Genetically Engineered Mouse; Glutathione Metabolism Pathway; Goals; Growth; Human; Isotopes; Leadership; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Mass Spectrum Analysis; Measurement; Measures; Memorial Sloan-Kettering Cancer Center; Metabolic; Metabolism; Methionine Metabolism Pathway; Methods; Modernization; Mus; NADP; Neuroblastoma; Oncogenes; Oxidation-Reduction; Oxyphilic Adenoma; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Play; Positioning Attribute; Production; Protocols documentation; Regional Cancer; Research; Role; Selection for Treatments; Signal Transduction; Specialist; Specimen; Technology; Thyroid Gland; Tracer; analytical method; asparaginase; base; cancer cell; carbene; cofactor; fluorodeoxyglucose positron emission tomography; improved; in vivo; insight; metabolic abnormality assessment; metabolome; novel; novel diagnostics; novel therapeutics; success; tool; tumor; tumor metabolism; tumor microenvironment

Project Summary/Abstract Metabolism plays a fundamental role in cancer growth, diagnosis (e.g. FDG-PET), and treatment (e.g. antifolates, asparaginase). Over the past decade, research into cancer metabolism has flourished, contextualized by the realization that metabolic changes in cancer are triggered by oncogene signaling and accelerated by the emergence of new measurement tools. This NCI Research Specialist Award will study cancer metabolism using the most important modern tools: mass spectrometry and isotope tracers. Working together with Unit Director Joshua Rabinowitz and his lab, and a diverse set of collaborators from Rutgers Cancer Institute of New Jersey and other regional cancer centers (U Penn, MSKCC, NYU), I aim over the next 5 years to achieve the following: (1) Develop mass spectrometry-based analytical methods that enable more complete and accurate metabolome quantitation. I will focus in particular on developing analytical solutions for hard to measure metabolites of high relevance to cancer. These include unstable species such as redox cofactors (e.g., NADPH) and activated folates (e.g. 5,10-methylene-THF). (2) Apply these methods to measurement of the cancer metabolome, from cultured cells to human tumors. This will include studies on flash-frozen de-identified patient tumor specimens, from cancers where we already have a leadership position (pancreatic ductal adenocarcinoma, oncocytoma) and those that remain understudied for a metabolic perspective (thyroid, neuroblastoma). Building on our prior success in discovering the oncometabolite 2- hydroxyglutarate, a particular focus will be identifying unexpected or novel metabolites that are altered in cancer. (3) Combine these methods with isotope tracers to determine fluxes in cancer cells and in vivo tumors. We have a long-standing leadership position in developing isotope tracer methods for quantitating metabolic fluxes, including notable recent success in measuring NADPH production pathways using 2H-tracers. We have recently developed protocols for infusing a wide variety of 13C and 2H-tracers into mouse, with the goal of enabling quantitation of tumor metabolic flux. Collectively, these tracers cover central carbon metabolism, one- carbon metabolism, and methionine and glutathione metabolism. We will apply them to study metabolism in genetically engineered mouse models including of pancreatic cancer with and without Myc activation and lung cancer with and without autophagy deletion. Resulting data will provide critical insights into the actual metabolic pathophysiology of cancer in the native tumor microenvironment and will thereby inform treatment selection strategies and the development of novel therapeutics.

项目摘要/摘要 代谢在肿瘤生长、诊断(如FDG-PET)和治疗(如： 抗叶酸、天冬酰胺酶)。在过去的十年里，对癌症新陈代谢的研究蓬勃发展， 通过认识到癌症中的代谢变化是由癌基因信号和 新的测量工具的出现加速了这一进程。NCI研究专家奖将研究 使用最重要的现代工具：质谱仪和同位素示踪剂研究癌症新陈代谢。劳作 与单位主任Joshua Rabinowitz和他的实验室以及来自罗格斯大学的一组不同的合作者一起 新泽西癌症研究所和其他地区性癌症中心(宾夕法尼亚大学、MSKCC、纽约大学)，我的目标是下一个 5年来实现以下目标：(1)开发基于质谱学的分析方法，使更多 完整、准确的代谢组定量。我将特别专注于开发以下方面的分析解决方案 很难测量与癌症高度相关的代谢物。这包括不稳定的物种，如氧化还原 辅因子(如NADPH)和活化的叶酸(如5，10-亚甲基-四氢呋喃)。(2)将这些方法应用于 从培养细胞到人类肿瘤的癌症代谢物的测量。这将包括对以下方面的研究 快速冷冻去鉴定患者肿瘤标本，来自我们已经处于领先地位的癌症 (胰腺导管腺癌、嗜酸细胞瘤)和那些仍未被充分研究的代谢 视角(甲状腺、神经母细胞瘤)。在我们之前成功发现的新生物2的基础上- 羟基戊二酸，一个特别的重点将是识别意外或新的代谢物，这些代谢物在 癌症。(3)将这些方法与同位素示踪剂相结合，以确定癌细胞和体内肿瘤中的通量。 我们在开发定量代谢的同位素示踪方法方面长期处于领先地位。 通量，包括最近在使用2H示踪剂测量NADPH产生途径方面取得的显著成功。我们有 最近开发的用于向小鼠体内注入各种13C和2H示踪剂的方案，目标是 能够对肿瘤代谢流量进行量化。总体而言，这些示踪剂涵盖了中央碳代谢，一是- 碳代谢、蛋氨酸和谷胱甘肽代谢。我们将应用它们来研究新陈代谢。 基因工程小鼠模型，包括带有和不带有Myc激活的胰腺癌和肺 带有和不带有自噬缺失的癌症。由此产生的数据将提供对实际 在自然肿瘤微环境中癌症的代谢病理生理学，并因此将指导治疗 选择策略和新疗法的发展。