Identification and Analysis of Metabolic Inhibitors in ctnnb1-driven Hepatocellular Carcinoma (HCC) in Transgenic Zebrafish (Danio rerio)

Overview

of Utah Liver cancer is the third leading cause of cancer deaths worldwide. In 2020, there were about 830,000 deaths due to liver cancer and over 900,000 new diagnoses. About 90% of all primary liver cancers are characterized as hepatocellular carcinomas (HCC). The incidence of HCC is expected to continue growing due to the ongoing rise in metabolic disorders, obesity, and diabetes. Mutations in the gene CTNNB1, which encodes β-catenin, account for ~20-40% of HCC cases. Dr. Evason previously characterized a line of transgenic zebrafish that expresses hepatocyte-specific activated β-catenin, resulting in constitutively active Wnt signaling and significant liver enlargement, which recapitulates human HCC. Our aim is to identify and analyze compounds which have anti-tumor effects, in order to better understand the mechanisms of HCC. In this project, we screened 240 metabolic/protease-related compounds and performed confirmation testing on those that showed the most significant reduction in liver size. Quantitatively, we found that exposure to FAAH- IN-2 resulted in the greatest reduction when treated 3-6 days post fertilization. Furthermore, since FAAH-IN-2 is a derivative of gefitinib, a clinically approved chemotherapeutic, we confirmed that the effects seen with FAAH-IN-2 were independent of gefitinib, as exposure to gefitinib did not impact transgenic larval liver size. Our work successfully identified a key compound that significantly decreases larval liver size in transgenic zebrafish. Further study of FAAH-IN-2 could uncover new insights into the role of FAAH in lipid metabolism and may lead to effective treatments for human CTNNB1-mutated HCC and HCC as a whole.

Competition history

• JSHS 2023 Category not listed

Resources

• National JSHS abstract book ↗

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