Abstract A51: Advances in the etiology and therapeutics of a lethal childhood cancer, fibrolamellar hepatocellular carcinoma

Introduction: Fibrolamellar hepatocellular carcinoma (FLC) is a liver cancer affecting adolescents and young adults without underlying liver disease. Patients with FLC are often diagnosed with advanced-stage disease and have a poor 5-year survival. Recently we have made advances in both understanding the etiology of FLC as well as developing therapeutics. We have found that the bulk of the genome lacks recurrent single-nucleotide or structural variants (inversions, amplifications) with the exception of a deletion in one copy of chromosome 19. This results in a fusion of the first exon of the heat shock protein, DNAJB1, with the 2nd through 10th exons of PRKACA, the catalytic subunit of protein kinase A. Expression of this fusion in the livers of mice, either by CRISPR or transposon, is sufficient to phenocopy the disease. The kinase activity of the fusion protein is essential for transformation, but equivalent expression of the native kinase is not sufficient. Results: Etiology: We have tested the ability of the native kinase and fusion oncokinase to phosphorylate potential substrates in human liver. We have found a discrete set of substrates that are phosphorylated in human liver for which we are now testing, which are critical for the pathogenesis of this cancer. Therapeutics: We have purified the fusion oncokinase without a tag and used a high-throughput screen to find inhibitors. We have found inhibitors in the nanomolar range for which we are using structural analysis to inform our medicinal chemistry. Additionally, we have developed several “never-in-plastic” patient-derived xenograft (PDX) models that retain expression of the driver, histology, transcriptome, and proteome of the original human tumor. We have also screened for compounds that induce tumor cell death and tumor regression in FLC PDXs. Conclusion: Subtle changes in the kinase substrate profile of the fusion kinase provide new leads for therapeutics for FLC. The ability to find inhibitors of the kinase in the nanomolar range, as well as the ability to screen for inhibitors of the PDX, offers the first hope for treatment against this lethal tumor. Citation Format: Gadi Lalazar, Melissa Jarmel, Ruisi Wang, Michael Tomasini, David Requena, Denise Ng, Sanford M. Simon. Advances in the etiology and therapeutics of a lethal childhood cancer, fibrolamellar hepatocellular carcinoma [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A51.