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

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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