Functions of mutant IDH in cholangiocarcinoma

突变IDH在胆管癌中的功能

• 批准号: 10800231
• 负责人: NABEEL El-BARDEESY
• 金额: $ 65.35万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10800231
• 关键词: Address; Affect; Allografting; Antigens; Automobile Driving; Bile duct carcinoma; Biological; Biology; CD8-Positive T-Lymphocytes; CRISPR screen; CTLA4 blockade; Cell Differentiation process; Cells; Cholangiocarcinoma; Cytotoxic T-Lymphocytes; DNA; DNA Repair; Data; Double-Stranded RNA; Endogenous Retroviruses; Enzymes; Epigenetic Process; Epithelium; FDA approved; Frequencies; Gene Expression; Genes; Genetic; Genetic Transcription; Genetically Engineered Mouse; Glioma; Growth; HNF4A gene; Hepatocyte; Human; IFNGR1 gene; IRF3 gene; Immune; Immune Evasion; Immune signaling; Immune system; Immunologic Surveillance; Immunologics; Immunosuppression; Interferon Type II; Interferons; Intrahepatic Cholangiocarcinoma; Isocitrate Dehydrogenase; MAP3K7 gene; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Mediator; Metabolic; Metabolism; Modeling; Molecular; Mutate; Mutation; Natural Immunity; Oncogenes; Pathway interactions; Patients; Phenotype; Process; Production; Proteins; Recurrence; Recurrent tumor; Regulatory T-Lymphocyte; Resistance; Reverse Transcription; Role; Sampling; Signal Transduction; Solid Neoplasm; Stimulator of Interferon Genes; T cell infiltration; T-Cell Depletion; T-Lymphocyte; T-cell receptor repertoire; Testing; Treatment Failure; Tumor Immunity; Tumor Promotion; Up-Regulation; Work; alpha ketoglutarate; bile duct; cancer type; demethylation; derepression; ds-DNA; fascinate; immune checkpoint; immune checkpoint blockade; immunoregulation; improved; in vivo; inhibitor; innate immune pathways; insight; mutant; neoplastic cell; novel; pharmacologic; prevent; programs; recruit; response; restoration; sensor; synergism; therapeutic development; transcription factor; transcriptomics; treatment response; tumor; tumor growth; tumor progression

PROJECT SUMMARY Isocitrate dehydrogenase 1 is the most frequently mutated metabolic gene across all cancers. Among epithelial malignancies, IDH1 mutations are particularly common in cholangiocarcinoma, a deadly cancer of the liver bile ducts. These hot-spot mutations generate the oncometabolite, (R)-2-hydroxyglutarate, which inhibits - ketoglutarate-dependent enzymes, altering epigenetics and metabolism. While pharmacological inhibition of mutant IDH1 shows efficacy in cholangiocarcinoma, the effects are not durable, and there has been limited insight into the basis for response and resistance. Recently, by developing mIDH1-driven genetically engineered mouse models and utilizing patient samples and models, we demonstrated that mIDH1 causes tumor cells to evade attack by the immune system. We find that inhibitors of mutant IDH1 slow tumor growth by reverting this immune evasion phenotype, leading to sensitization to immune checkpoint blockade. A major mechanism of this evasion involves the (R)-2HG-mediated inactivation of the TET2 demethylase, which prevents the tumor cells from responding to interferon gamma produced by immune cells. The second mechanism involves limiting the recruitment and activity of cytotoxic T cells, although we have yet to fully elucidate the associated molecular basis. Based on our extensive new preliminary data, we hypothesize that IDH1-mediated control of cellular differentiation and of innate immune signaling are potential mediators of this T cell cross-talk. The present proposal will test this hypothesis and investigate the interplay between T cell recruitment and the IFN-g-TET2 program in IDH1 inhibitor response and eventual resistance. These studies will inform the improved treatment of cholangiocarcinoma and potentially the range of other cancer types harboring IDH mutations.

项目摘要 异柠檬酸脱氢酶1是所有癌症中最常见的突变代谢基因。上皮细胞间 在恶性肿瘤中，IDH 1突变在胆管癌中特别常见，胆管癌是一种致命的肝胆癌 管道这些热点突变产生癌代谢物，（R）-2-羟基戊二酸，它抑制- 酮戊二酸依赖酶，改变表观遗传学和代谢。虽然药理学抑制 突变体IDH 1在胆管癌中显示出功效，但效果不持久， 洞察反应和抵抗的基础。最近，通过开发mIDH 1驱动的基因， 工程小鼠模型，并利用患者样本和模型，我们证明了mIDH 1导致 肿瘤细胞逃避免疫系统的攻击。我们发现突变IDH 1的抑制剂通过抑制肿瘤生长来减缓肿瘤生长。 逆转这种免疫逃避表型，导致对免疫检查点阻断的敏化。一个主要 这种逃避的机制涉及（R）-2HG介导的TET 2脱甲基酶的失活， 阻止肿瘤细胞对免疫细胞产生的干扰素γ产生反应。第二 这一机制涉及限制细胞毒性T细胞的募集和活性，尽管我们还没有完全 阐明相关的分子基础。根据我们广泛的新的初步数据，我们假设， IDH 1介导的细胞分化和先天免疫信号传导的控制是这一过程的潜在介质。 T细胞串扰。目前的建议将测试这一假设，并调查T细胞之间的相互作用， 招募和IFN-g-TET 2程序在IDH 1抑制剂应答和最终耐药性中的作用。这些研究 将为胆管癌的治疗提供信息，并可能为其他癌症类型提供信息。 携带IDH突变。