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.