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、青少年和年轻人常见的致死性原发性肿瘤。原发性肿瘤是由DNA中的单一改变引发和驱动的：约400 kb的缺失导致热休克辅助分子伴侣DNAJB 1和蛋白激酶A的催化亚基PRKACA之间的融合基因。如果肿瘤局限于肝脏，那么手术是公认的治疗方法。然而，如果肿瘤已经转移，则没有可接受的治疗。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。致病机制是通过检测引起细胞变化的融合癌蛋白的不同之处来探索的。治疗药物将通过小分子靶向融合癌蛋白以阻断活性，或小分子将其发送到蛋白酶体，或小分子进行变构抑制。

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. Pathogenesis is being probed by examining what is different about the fusion oncoprotein that causes changes in the cell. Therapeutics will target the fusion oncoprotein through small molecules to block activity, or small molecules to send it to the proteasome, or small molecules for allosteric inhibition.