Exploring novel SRC-regulated pathways in IDH mutant intrahepatic cholangiocarcinoma

项目摘要/摘要 摘要肝内胆管细胞癌是一种高致死性的肝癌，其发病率呈上升趋势。 在全球范围内，预后不到一年。目前对大多数患者的护理标准 目前患有晚期疾病的患者仍在接受联合化疗。然而，最近的基因 研究已经确定，许多ICC肿瘤都含有突变，可以用“靶向治疗”来治疗。 这种靶向治疗通常以药丸的形式给予，通常副作用比 化疗。因此，现在有希望改变ICC的治疗模式，从目前的 所有患者联合化疗的标准为靶向治疗肝细胞癌患者 “靶向”突变。ICC中最常见的这些突变属于一种称为异柠檬酸的基因 脱氢酶(IDH)。尽管目前正在进行临床试验以评估靶向治疗的疗效 在IDH突变体ICC中，早期试验结果表明，将需要顺序或组合策略来诱导 这种疾病的持久缓解。在我们之前的工作中，我们使用了idh突变体icc的实验室模型，如 人癌细胞株和患者来源的异种移植(PDX)显示IDH突变的ICC细胞非常 对一种名为达沙替尼的靶向治疗敏感。达沙替尼通过抑制IDH突变的ICC细胞活性来杀伤IDH突变的ICC细胞 一种叫做SRC的蛋白质。有趣的是，这种对src活性的依赖似乎是IDH的高度特异性。 突变的ICC细胞与无IDH突变的ICC肿瘤细胞或来自 是否检测出其他癌症。这项提议旨在将传统的分子生物学和生物化学方法结合起来。 利用先进的技术，如磷酸蛋白质组学，CRISPR/Cas9介导的基因组编辑，以及 多聚核糖体分析揭示SRC在IDH突变体ICC中发挥的独特功能并阐明 为什么ICC的这一特定基因亚集如此依赖于SRC活性。这项工作将受益于我们独特的 试剂，由大量ICC模型系统组成，包括人类细胞系和PDX以及 弗雷德·哈钦森癌症研究所的丰富和高度协作的科学环境。最终， 我们工作的长期目标是提高我们对这些肿瘤的不同生物学基础的理解。 希望为ICC患者开发更有效、毒性更低的治疗方案。

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.