fibrolamellar carcinoma drug repurposing pediatric rare tumors patient derived xenografts drug screening fusion gene Abbreviations: ATR -Ataxia telangiectasia and Rad3-related protein AURKA -Aurora kinase A AURKB -Aurora kinase B Bcl-xL -B-cell lymphoma-extra large encoded by the BCL2-like 1 gene Bcl2 -B-cell lymphoma 2 ITS -Insulin, (human) Transferrin, Selenium BID -BH3 Interacting Domain Death Agonist BIM -Bcl-2-like protein 11 CA12 -Carbonic anhydrase 12 CDc7 -Cell division cycle 7-related protein kinase CDK -Cyclin depedent protein kinase Cyp19A1 -Also know as aromatase or estrogen synthase DAB -3,3'-Diaminobenzidine DMSO -Dimethyl sulfoxide DNA-PK -DNA protein kinase EGFR -Epidermal growth factor receptor eIF4F -Eukaryotic initiation factor 4F ErbB2 -erythroblastic oncogene B, also known as Her-2 protooncogene Neu and as epidermal growth factor receptor-2 FLC -fibrolamellar hepatocellular carcinoma H&E -hematoxylin and eosin HSA -Highest Single Agent HCC -hepatocellular carcinoma HDAC -Histone deacetylase HSP70 -Heat Shock Protein 70

Hepatoblastoma is the most common childhood liver cancer. Although survival has improved significantly over the past few decades, there remains a group of children with aggressive disease who do not respond to current treatment regimens. There is a critical need for novel models to study aggressive hepatoblastoma as research to find new treatments is hampered by the small number of laboratory models of the disease. Organoids have emerged as robust models for many diseases, including cancer. We have generated and characterized a novel organoid model of aggressive hepatoblastoma directly from freshly resected patient tumors as a proof of concept for this approach. Hepatoblastoma tumor organoids recapitulate the key elements of patient tumors, including tumor architecture, mutational profile, gene expression patterns, and features of Wnt/β-catenin signaling that are hallmarks of hepatoblastoma pathophysiology. Tumor organoids were successfully used alongside non-tumor liver organoids from the same patient to perform a drug screen using twelve candidate compounds. One drug, JQ1, demonstrated increased destruction of liver organoids from hepatoblastoma tumor tissue relative to organoids from the adjacent non-tumor liver. Our findings suggest that hepatoblastoma organoids could be used for a variety of applications and have the potential to improve treatment options for the subset of hepatoblastoma patients who do not respond to existing treatments.

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