Exploring novel SRC-regulated pathways in IDH mutant intrahepatic cholangiocarcinoma

探索 IDH 突变型肝内胆管癌中新的 SRC 调节途径

基本信息

批准号：
10319527
负责人：
Sita Kugel
金额：
$ 39.45万
依托单位：
FRED HUTCHINSON CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10319527
关键词：
Ablation Affect Area Automobile Driving Basic Science Binding Biochemical Biological Models Biology CRISPR/Cas technology Cancer cell line Cell Differentiation process Cell Line Cell Size Cell Survival Cells Cholangiocarcinoma Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Combination Drug Therapy Complex Dasatinib Data Dependence Diagnosis Dioxygenases Disease Disease remission Environment Enzymes Epigenetic Process FRAP1 gene Family Genes Genetic Genetic Transcription Genetic study Goals Growth HNF4A gene Hepatocyte Histones Human Human Cell Line Hypersensitivity In Vitro Incidence Induction of Apoptosis Intrahepatic Cholangiocarcinoma Isocitrate Dehydrogenase Laboratories Liver Stem Cell Lysine Maintenance Malignant Neoplasms Malignant neoplasm of liver Mediating Messenger RNA Modeling Molecular Molecular Biology Molecular Profiling Mus Mutation Newly Diagnosed Oncogenic Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phenotype Phosphorylation Play Polyribosomes Prevention Primary Malignant Neoplasm of Liver Production Prognosis Protein phosphatase Proteins Reagent Research Institute Ribosomal Protein S6 Kinase Ribosomes Role Structure System Technology Testing Therapeutic Translational Research Translations Work alpha ketoglutarate anticancer research chemotherapy combinatorial cost effective measures early phase clinical trial efficacy evaluation experimental study falls genome editing high-throughput drug screening histone demethylase improved in vivo inhibitor kinase inhibitor loss of function mutant neoplastic cell novel novel therapeutic intervention patient derived xenograft model phosphoproteomics pill programs repository response screening side effect src-Family Kinases standard of care stem cells targeted treatment therapeutically effective transcription factor transcriptomics tumor tumorigenesis

项目摘要

PROJECT SUMMARY/ABSTRACT Intrahepatic cholangiocarcinoma (ICC) is a highly lethal form of liver cancer which has been rising in incidence worldwide and carries a prognosis of under one year. The current standard of care for the majority of patients who present with advanced stage disease remains toxic combination chemotherapy. However, recent genetic studies have determined that many ICC tumors harbor mutations which can be treated with ‘targeted therapies.’ Such targeted therapies may often be given as a pill form and generally have fewer side effects than chemotherapy. As a result, there is now hope for a shift in the therapeutic paradigm for ICC, from the current standard of combination chemotherapy for all patients to targeted therapies for ICC patients who have ‘targetable’ mutations. The most common of these mutations in ICC fall within a gene called isocitrate dehydrogenase (IDH). Although clinical trials are currently underway to evaluate the efficacy of targeted therapy in IDH mutant ICC, early trial results suggest that sequential or combinatorial strategies will be needed to induce durable remissions in this disease. In our previous work, we used laboratory models of IDH mutant ICC such as human cancer cell lines and patient-derived xenografts (PDXs) to show that IDH mutant ICC cells are extremely sensitive to a targeted therapy called dasatinib. Dasatinib acts to kill IDH mutant ICC cells by inhibiting the activity of a protein called SRC. Interestingly, this dependence on SRC activity appears to be highly specific to IDH mutant ICC cells when compared to cells from ICC tumors that do not have IDH mutations or tumor cells from any other cancer tested. This proposal aims to couple traditional molecular biology and biochemical approaches with advanced technologies such as phosphoproteomics, CRISPR/Cas9-mediated genome editing, and polyribosome profiling to uncover the unique functional role that SRC plays in IDH mutant ICC and to elucidate why this specific genetic subset of ICC is so dependent on SRC activity. This work will be benefited by our unique reagents, consisting of a large panel of ICC model systems, including human cell lines and PDXs as well as the rich and highly collaborative scientific environment at the Fred Hutchinson Cancer Research Institute. Ultimately, the long-term goal of our work is to improve our understanding of the distinct biology underlying these tumors in hopes of developing more effective, and less toxic, therapeutic options for ICC patients.

项目概要/摘要肝内胆管癌（ICC）是一种高度致命的肝癌，其发病率一直在上升全世界范围内，大多数患者的预后不到一年。然而，晚期疾病的联合化疗仍然存在毒性。研究已确定许多 ICC 肿瘤含有可以通过“靶向疗法”治疗的突变。此类靶向疗法通常以药丸形式给药，并且通常比药物疗法具有更少的副作用。因此，现在有希望改变 ICC 的治疗模式。所有患者的联合化疗标准 ICC 患者的靶向治疗标准 ICC 中最常见的突变属于异柠檬酸基因。尽管目前正在进行临床试验来评估靶向治疗的功效。在 IDH 突变 ICC 中，早期试验结果表明需要序贯或组合策略来诱导在我们之前的工作中，我们使用了 IDH 突变 ICC 的实验室模型，例如人类癌细胞系和患者来源的异种移植物 (PDX) 表明 IDH 突变 ICC 细胞极其对达沙替尼（dasatinib）的靶向治疗敏感，达沙替尼（Dasatinib）通过抑制活性来杀死 IDH 突变的 ICC 细胞。一种称为 SRC 的蛋白质表明，这种对 SRC 活性的依赖性似乎对 IDH 具有高度特异性。突变 ICC 细胞与来自不具有 IDH 突变的 ICC 肿瘤细胞或来自该提案旨在将传统的分子生物学和生化方法结合起来。拥有磷酸蛋白质组学、CRISPR/Cas9介导的基因组编辑等先进技术，多核糖体分析揭示 SRC 在 IDH 突变体 ICC 中发挥的独特功能作用并阐明为什么 ICC 的这一特定遗传子集如此依赖于 SRC 活性，这项工作将受益于我们独特的研究。试剂，由一大组 ICC 模型系统组成，包括人类细胞系和 PDX 以及弗雷德·哈钦森癌症研究所拥有丰富且高度协作的科学环境。我们工作的长期目标是提高我们对这些肿瘤背后的独特生物学的理解希望为 ICC 患者开发更有效、毒性更小的治疗选择。