Center for therapeutic targeting of the Fusion Oncoprotein of Fibrolamellar Hepatocellular Carcinoma

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。这个项目将确定融合癌蛋白 导致发病机制，并将开发靶向融合癌蛋白的治疗剂。前两个项目 将探讨发病机制：在项目1中，引起变化的融合癌蛋白有什么不同 在项目2中，它在人类类器官或小鼠组织中的表达如何导致特定的病理学 在肝脏中。接下来的两个项目将探索治疗方法：在项目3中，靶向融合mRNA 在项目4中，靶向融合癌蛋白 通过小分子来阻止活性，或者小分子将其发送到蛋白酶体，或者小分子 用于变构抑制。 第98页 项目总结/摘要

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. This project will determine how the fusion oncoprotein leads to pathogenesis and will develop therapeutics targeted to the fusion oncoprotein. The first two projects will explore the pathogenesis: In project 1, what is different about the fusion oncoprotein that causes changes in the cell; In Project 2, how its expression in human organoids or in mouse tissue leads to a specific pathology in the liver. The next two projects will explore the therapeutics: In project 3 targeting to the fusion mRNA transcript with shRNA and anti-sense oligonucleotides and in Project 4, targeting the fusion oncoprotein through small molecules to block activity, or small molecules to send it to the proteasome, or small molecules for allosteric inhibition. Page 98 Project Summary/Abstract