Targeting the oncoprotein that drives FLC

项目总结/摘要 纤维板层型肝细胞癌（FLC）是儿童、青少年和老年人常见的致死性原发性肿瘤。 年轻人原发性肿瘤由DNA中的单一改变引发和驱动：约400 kb的缺失 导致热休克辅助分子伴侣DNAJB 1和蛋白质催化亚基之间的融合基因 激酶A，PRKACA。如果肿瘤局限于肝脏，那么手术是公认的治疗方法。但如果 肿瘤已经转移，没有公认的治疗方法。项目4将开发针对 融合癌蛋白它将使用治疗方法来阻断癌蛋白的激酶活性，并使用治疗方法来 将癌蛋白靶向蛋白酶体进行破坏。该疗法将在分离的蛋白质上进行测试， 来自患者来源的异种移植物的解离细胞，在FLC的人肝类器官和患有患者的小鼠中 衍生的异种移植物和基因工程小鼠模型。

Project Summary / Abstract Fibrolamellar hepatocellular carcinoma (FLC) is a usually lethal primary tumor in children, adolescents and young adults. The primary tumor is initiated and driven by a single alteration in the DNA: A deletion of ~400kb that results in a fusion gene between the heat shock co-chaperone DNAJB1 and the catalytic subunit of protein kinase A, PRKACA. If the tumor is limited to the liver, then surgery is the accepted therapy. However, if the tumor has metastasized, there is no accepted therapy. Project 4 will develop therapeutics targeted to the fusion oncoprotein. It will use therapeutics to block the kinase activity of the oncoprotein and therapeutics to target the oncoprotein to the proteasome for destruction. The therapeutics will be tested on isolated protein, in dissociated cells from patient-derived xenografts, in human liver organoids of FLC and in mice with patient derived xenografts and in genetically engineered mouse models.