Functions of mutant IDH in cholangiocarcinoma

突变IDH在胆管癌中的功能

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要异氯酸酯脱氢酶1是所有癌症中最常见的代谢基因。在上皮中恶性肿瘤，IDH1突变在胆管癌（一种致命的肝脏癌症）中尤为常见管道。这些热点突变会产生oncometabolite，（R）-2-羟基戊二酸酯，抑制 - 酮谷酸酯依赖性酶，改变了表观遗传学和代谢。而药理学抑制突变体IDH1在胆管癌中显示出疗效，影响不耐用，并且有限深入了解响应和抵抗的基础。最近，通过开发MIDH1驱动的基因工程鼠标模型并利用患者样品和模型，我们证明了MIDH1原因肿瘤细胞通过免疫系统逃避攻击。我们发现突变体IDH1的抑制剂通过恢复这种免疫逃避表型，导致敏化对免疫检查点封锁。专业这种逃避的机制涉及（R）-2HG介导的TET2脱甲基酶的失活，该脱甲基酶防止免疫细胞产生的干扰素γ反应肿瘤细胞。第二个机制涉及限制细胞毒性T细胞的募集和活性，尽管我们尚未完全阐明相关的分子基础。根据我们广泛的新初步数据，我们假设 IDH1介导的细胞分化和先天免疫信号传导的控制是潜在的介体 T细胞串扰。本提案将检验该假设并研究T细胞之间的相互作用 IDH1抑制剂响应和最终阻力中的招聘和IFN-G-TET2程序。这些研究将为胆管癌的改进治疗以及其他癌症类型的范围提供信息携带IDH突变。