Exploiting metabolic reprogramming to target IDH1 mutated cholangiocarcinoma

项目摘要 人们对了解和开发癌症的治疗方法很感兴趣，对致癌因素的研究 病变重新编程新陈代谢，这是癌症的标志。功能获得性热点突变 异柠檬酸脱氢酶基因(Idh)是肝内最常见的遗传改变之一。 胆管癌(ICC)。IDH突变导致肿瘤代谢物2-羟基葡萄糖酸盐的产生， 扰乱表观遗传学和其他细胞过程。然而，目前还不清楚致癌的IDH1突变是如何改变的 新陈代谢可能是国际刑事法院新漏洞的基础。为了揭示IDH1突变体ICC的新见解，我们 已经建立并表征了IDH1突变ICC小鼠模型(GEMM)，以及患者来源的 活体疾病生物学模型。利用这些模型，我们证明了突变的IDH1重新编程 代谢包括线粒体功能的抑制和从头开始的嘧啶的选择性障碍 合成，这是新的代谢脆弱性的基础。我们一致地从大屏幕上识别出 影响核苷酸的IDH1突变细胞的选择性和潜在的化学和遗传脆弱性 新陈代谢。因此，NIH独立之路的一个重要科学目标是进一步 了解细胞和生理基础，支持重新编程的代谢和 对未来治疗发展的脆弱性。我提出了一个创新的研究计划，结合了尖端技术 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 利用My Human对IDH1突变体ICC新陈代谢脆弱性的机械论和翻译洞察力 和GEMM模型。我假设致癌基因IDH1突变导致重新编程的核苷酸合成 这可以被用来针对IDH1突变的ICC。我将重点关注三个具体目标：1)了解 突变IDH1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物调节如何扰乱DNA复制和积累 IDH1突变细胞超敏反应的DNA损伤；3)体内IDH1决定因素的鉴定 突变的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。我会利用优秀的 在新陈代谢、DNA损伤、化学生物学、蛋白质组分析、 和临床肿瘤学。因此，我将获得必要的DNA损伤反应途径方面的培训， 蛋白质组学和临床前化合物特性用于机械性和转化性研究 指导K99阶段。独立之路奖将使我能够扩展我的科学和技术 制定和开发一个以假设为导向的研究计划，通过这个计划，我将建立一个综合和 在我自己的实验室独立进行癌症代谢研究的翻译研究平台。

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.