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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.

项目总结