Exploiting metabolic reprogramming to target IDH1 mutated cholangiocarcinoma

项目摘要 对理解和开发癌症治疗的相当大的兴趣一直是研究致癌基因。 病变重编程代谢，这是癌症的标志。基因组中的功能获得性热点突变 异柠檬酸脱氢酶基因（IDH）是肝内胆管癌中最常见的遗传改变之一。 胆管癌（ICC）。IDH突变导致产生癌代谢物2-羟基谷氨酸， 扰乱表观遗传学和其他细胞过程。然而，目前尚不清楚致癌IDH 1突变如何改变 这可能是ICC中新的脆弱性的基础。为了揭示IDH 1突变ICC的新见解，我们 已经建立并表征了IDH 1突变ICC小鼠模型（GEMM），以及患者来源的 用于体内疾病生物学的模型。利用这些模型，我们证明了突变IDH 1重编程 代谢，包括抑制线粒体功能和选择性阻碍从头嘧啶 合成，这是新的代谢脆弱性的基础。连贯地，我们从大屏幕上识别出 IDH 1突变细胞的选择性和有效的化学和遗传脆弱性， 新陈代谢.因此，一个重要的科学目标，以及NIH独立之路的目标，是进一步 了解细胞和生理基础支撑之间的串扰重编程代谢， 未来治疗发展的脆弱性。我提出了一个创新的研究项目， 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，以获得 使用我的人，IDH 1突变ICC的新代谢脆弱性的机制和翻译见解 GEMM模型我假设致癌IDH 1突变导致重编程核苷酸合成 可以利用其靶向IDH 1突变ICC。我将集中在三个具体目标：1）了解 突变IDH 1重编程嘧啶合成的细胞机制及其遗传脆弱性; 2） 阐明核苷酸合成的药理学调节如何破坏DNA复制和积累 IDH 1突变细胞超敏反应的DNA损伤;和3）鉴定IDH 1的体内决定簇 突变ICC对药物治疗的敏感性。Nabeel Bardesy博士的实验室和马萨诸塞州总医院 癌症中心提供了一个理想的培训环境，为拟议的研究。我会利用 在代谢，DNA损伤，化学生物学，蛋白质组学分析， 和临床肿瘤学。因此，我将获得必要的培训，在DNA损伤反应途径，定量 蛋白质组学和临床前化合物表征的机制和翻译研究期间， K99阶段。独立之路奖将使我能够扩大我的科学和技术 剧目，并制定一个假设驱动的研究计划，我将建立一个综合和 转化研究平台，在我自己的实验室独立进行癌症代谢研究。

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.