Exploring novel SRC-regulated pathways in IDH mutant intrahepatic cholangiocarcinoma

项目概要/摘要 肝内胆管细胞癌（Intrahepatic cholangiocarcinoma，ICC）是一种高致死性肝癌，其发病率有逐年上升的趋势 全球范围内，并进行预测不到一年。目前对大多数患者的护理标准 晚期疾病患者的联合化疗仍有毒性。然而，最近的遗传 研究已经确定，许多ICC肿瘤具有可以用“靶向疗法”治疗的突变。 这种靶向治疗通常可以以药丸形式给予，并且通常具有比常规治疗更少的副作用。 化疗因此，现在有希望改变ICC的治疗模式，从目前的 所有患者的联合化疗标准，以及ICC患者的靶向治疗 “可靶向”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ICC中，早期试验结果表明，需要顺序或组合策略来诱导 这种疾病的持久缓解。在我们以前的工作中，我们使用IDH突变ICC的实验室模型，如 人癌细胞系和患者来源的异种移植物（PDX），以显示IDH突变的ICC细胞是极其 对靶向治疗达沙替尼敏感。达沙替尼通过抑制IDH突变ICC细胞的活性来杀死IDH突变ICC细胞。 一种叫做SRC的蛋白质有趣的是，这种对SRC活性的依赖似乎对IDH具有高度特异性 当与来自不具有IDH突变的ICC肿瘤的细胞或来自IDH突变的ICC肿瘤的肿瘤细胞相比时， 其他癌症检测该建议旨在将传统的分子生物学和生物化学方法结合起来 利用磷酸化蛋白质组学、CRISPR/Cas9介导的基因组编辑等先进技术， 多聚核糖体分析，以揭示SRC在IDH突变ICC中发挥的独特功能作用，并阐明 为什么ICC的这个特定基因亚群如此依赖于SRC活性。这项工作将受益于我们独特的 试剂，包括一个大型的ICC模型系统，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合作的科学环境。最后， 我们工作的长期目标是提高我们对这些肿瘤的独特生物学的理解， 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.