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

项目摘要/摘要 摘要纤维板层状肝细胞癌(FLC)是一种常见于儿童、青少年和青少年的原发性肿瘤。 年轻人。原发肿瘤是由DNA的一个单一改变启动和驱动的：~400kb的缺失 这导致了热休克辅助伴侣DNAJB1和蛋白质催化亚单位之间的融合基因 蛋白激酶A，PRKACA。如果肿瘤仅限于肝脏，那么手术是公认的治疗方法。但是，如果 肿瘤已经转移，目前还没有公认的治疗方法。该项目将确定融合癌蛋白如何 导致发病机制，并将开发针对融合癌蛋白的治疗方法。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 在细胞中；在项目2中，它在人类器官或小鼠组织中的表达如何导致一种特定的病理 在肝脏里。接下来的两个项目将探索治疗：在项目3中，以融合mrna为靶点。 带有shRNA和反义寡核苷酸的转录本，在项目4中，靶向融合癌蛋白 通过小分子来阻断活性，或小分子将其发送到蛋白酶体，或小分子 用于变构抑制。 第98页 项目摘要/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