Exploiting metabolic reprogramming to target IDH1 mutated cholangiocarcinoma

利用代谢重编程来靶向 IDH1 突变的胆管癌

基本信息

批准号：
10115672
负责人：
Lei Shi
金额：
$ 17.82万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10115672
关键词：
Affect Automobile Driving Award Biochemical Biochemistry Biological Assay Biological Models Biology Cancer Center Cell Differentiation process Cell physiology Cells Chemicals Cholangiocarcinoma Citric Acid Cycle Clinical Oncology Clinical Trials Collection Complex Coupled DNA DNA Damage DNA Sequence Alteration DNA biosynthesis DNA damage checkpoint Data Defect Dependence Disease Disease model Drug Screening Electron Transport Environment Enzymes Epigenetic Process Equilibrium Foundations Future Gene Mutation General Hospitals Genes Genetic Genetic Predisposition to Disease Genetic Screening Genetically Engineered Mouse Goals Homeostasis Hot Spot Human Hypersensitivity Impairment In Vitro Incidence Intervention Intrahepatic Cholangiocarcinoma Isocitrate Dehydrogenase Isocitrates Isotope Labeling Knowledge Laboratories Lead Lesion Liver Malignant Neoplasms Massachusetts Mediating Mentors Mentorship Metabolic Metabolism Methods Mitochondria Modeling Molecular Mutate Mutation Nucleotides Oncogenes Oncogenic Orphan Outcome Oxidation-Reduction Pathway interactions Patients Pharmacology Pharmacotherapy Phase Physiological Production Prognosis Proteomics Public Health Pyrimidine Pyrimidine Nucleotides Reaction Research Resistance Respiration Role Series Solid Neoplasm System Testing Tetanus Helper Peptide Therapeutic Training Translational Research United States National Institutes of Health Work alpha ketoglutarate base bile duct biliary tract chemical genetics clinically relevant cytotoxic gain of function gene function histone demethylase improved in vivo in vivo Model inhibitor/antagonist innovation insight interest loss of function metabolomics mitochondrial metabolism mouse model mutant neoplastic cell novel nucleotide metabolism patient derived xenograft model pre-clinical programs pyrimidine metabolism respiratory response therapy development tool translational study tumor tumor metabolism

项目摘要

Project Summary Considerable interests in understanding and developing therapeutics for cancer have been to study oncogenic lesion reprogrammed metabolism that is the hallmark of cancer. Gain-of-function hot-spot mutations in the isocitrate dehydrogenase genes (IDH) are among the most common genetic alterations in intrahepatic cholangiocarcinoma (ICC). The IDH mutations lead to production of an oncometabolite 2-hydroxygluatrate that perturbs epigenetics and other cellular processes. However, it was not clear how oncogenic IDH1 mutations alter metabolism that could underlie novel vulnerabilities in ICC. To uncover novel insights in IDH1 mutant ICC, we have established and characterized an IDH1 mutant ICC mouse model (GEMM), as well as patient derived models for in vivo disease biology. Leveraging these models, we demonstrate that mutant IDH1 reprograms metabolism including suppression of mitochondrial function and selective hinderance of de novo pyrimidine synthesis, which underlie novel metabolic vulnerability. Coherently, we identified from large-scale screens selective and potent chemical and genetic vulnerabilities of IDH1 mutant cells that impinge on nucleotide metabolism. As such, an important scientific goal, and that of this NIH Pathway to Independence, are to further understand cellular and physiological basis underpinning the crosstalk between reprogrammed metabolism and vulnerabilities for future therapy development. I propose an innovative research program combining cutting-edge metabolomics, proteomics, as well as classic biochemistry, genetics and chemical biology approaches to obtain mechanistic and translational insights in the novel metabolic vulnerabilities of IDH1 mutant ICC using my human and GEMM models. I hypothesize that oncogenic IDH1 mutations lead to reprogrammed nucleotide synthesis that can be leveraged upon to target IDH1 mutant ICC. I will focus on three specific aims: 1) understanding the cellular mechanisms of mutant IDH1 reprogrammed pyrimidine synthesis and its genetic vulnerability; 2) elucidating how pharmacologic modulation of nucleotide synthesis disrupts DNA replication and accumulates DNA damage underlying the hypersensitivity of IDH1 mutant cells; and 3) identifying in vivo determinants of IDH1 mutant ICC sensitivity to drug treatments. Dr. Nabeel Bardeesy's laboratory and Massachusetts General Hospital Cancer Center provide an ideal training environment for the proposed research. I will avail the outstanding mentorships with a spectrum of expertise in metabolism, DNA damage, chemical biology, proteomic analysis, and clinical oncology. Thus, I will acquire necessary trainings in DNA damage response pathways, quantitative proteomics and pre-clinical compound characterizations for mechanistic and translational research during the mentored K99 phase. The Pathway to Independence Award will enable me to expand my scientific and technical repertoire and develop a hypothesis-driven research program, with which I will build an integrative and translational research platform to perform cancer metabolism research independently in my own laboratory.

项目摘要了解癌症的理解和发展治疗剂的兴趣是研究致癌病变重编程的代谢是癌症的标志。功能收获的热点突变异氯酸酯脱氢酶基因（IDH）是肝内最常见的遗传改变之一胆管癌（ICC）。 IDH突变导致产生oncometabolite 2-羟基氟酸酯的生产 Perturbs表观遗传学和其他细胞过程。但是，尚不清楚致癌IDH1突变如何改变可能是ICC中新型脆弱性的代谢。为了发现IDH1突变体ICC中的新见解，我们已经建立并表征了IDH1突变体ICC小鼠模型（GEMM）以及衍生的患者体内疾病生物学模型。利用这些模型，我们证明了突变体IDH1重新编程代谢，包括抑制线粒体功能和从头嘧啶的选择性障碍合成，这是新型代谢脆弱性的基础。连贯地，我们从大规模屏幕上识别 IDH1突变细胞的选择性和有效的化学和遗传脆弱性，这些突变细胞影响核苷酸代谢。因此，一个重要的科学目标以及这一NIH独立途径的目标是进一步了解细胞和生理基础的基础，以重编代谢和未来治疗发展的脆弱性。我提出了一个创新的研究计划，结合了尖端代谢组学，蛋白质组学以及经典的生物化学，遗传学和化学生物学方法 IDH1突变体ICC的新代谢脆弱性中的机械和转化见解使用我的人和Gemm型号。我假设致癌IDH1突变导致重编程的核苷酸合成可以利用该靶向IDH1突变体ICC。我将重点介绍三个具体目标：1）了解突变体IDH1的细胞机制重编程了嘧啶合成及其遗传脆弱性； 2）阐明核苷酸合成的药理学调节如何破坏DNA复制并累积 DNA损害IDH1突变细胞超敏反应的背后损害； 3）识别IDH1的体内决定因素突变ICC对药物治疗的敏感性。 Nabeel Bardeesy博士的实验室和马萨诸塞州综合医院癌症中心为拟议的研究提供了理想的培训环境。我会利用出色的具有新陈代谢，DNA损伤，化学生物学，蛋白质组学分析方面的专业知识的指导，和临床肿瘤学。因此，我将获得DNA损伤响应途径的必要培训，定量蛋白质组学和临床前复合特征，用于机械和转化研究期间指导K99阶段。获得独立奖的途径将使我能够扩展我的科学和技术曲目并制定了一个假设驱动的研究计划，我将通过该计划建立一个综合性和转化研究平台，在我自己的实验室独立进行癌症代谢研究。