This project is focused on continuing our commitment to identify novel candidate therapies for fibrolamellar carcinoma (FLC), a rare but deadly type of liver cancer that disproportionately affects children and adolescents. Unlike typical adult-onset liver cancer, otherwise known as hepatocellular carcinoma (HCC), which is generally preceded by liver damage and can be detected early in the course of the disease, there are no obvious warning signs in FLC. Therefore, young FLC patients often already have advanced metastatic disease by the time of diagnosis, which renders surgical resection impractical, and also markedly reduces the survival rate. Numerous clinical studies have demonstrated that FLC is highly resistant to the drugs currently in use for HCC and other related cancers. Due to the low estimated incidence of the disease (<5 for every 1 million births), FLC is often overlooked by biomedical funding agencies. Children afflicted with the disease often pass away during adolescence, so there is a dire need for effective therapies. Based on previous epigenomic, metabolomic, and microRNA profiling, as well as initial drug studies, we have developed two new exciting hypotheses about therapeutic vulnerabilities in FLC. First, we hypothesize that inhibition of two candidate FLC oncogenes, CA12 or SLC16A14, independently and/or in conjunction with FDA-approved drugs, will dramatically reduce FLC cell viability, proliferation, and invasive capacity. Second, we hypothesize that the increase in LDHB promotes glycolysis and FLC tumor cell survival, which can be reversed by miR-375 mimics. In this project, we propose to test these hypotheses in several different disease models of FLC. The findings from the proposed studies will likely lay the foundation for completely novel, effective strategies for molecular therapy. We have developed strong collaborations with many labs in the FLC research network, and these studies will continue to strengthen those partnerships as we work together toward the common goal of curing FLC.