Identifying New Therapeutic Targets in Fibrolamellar Hepatocellular Carcinoma
Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare but lethal form of liver cancer. Major barriers hampering the development of better therapies for FL-HCC patients include the rarity of the disease and the fact that many of these patients are children, which makes it difficult to start new clinical trials. One solution to this problem can come from the development of accurate pre-clinical models of FL-HCC; such models can be used to both investigate the basic mechanisms of FL-HCC development, which may help to identify new therapeutic targets and to test novel therapeutic strategies. Sequencing FL-HCC tumors in patients has led to the identification a distinct genetic alteration resulting in the fusion of two proteins (a small piece of the “DNAJB1” protein and a larger piece of the “PKA” protein become fused together). This DNAJB1-PKA fusion has pro-tumorigenic effects in liver cells. Based on these observations, we have recently generated a genetically-engineered murine model of FL-HCC with induction of the DNAJB1-PKA fusion in liver cells in young murine models. We have also obtained a tumor from a patient, and this tumor can be propagated in the lab.
We propose to use these models to test novel therapeutic approaches in FL-HCC, including targeting the main component of the fusion, the PKA protein, or other proteins in its network. To this end, we will develop and use a novel small molecule specifically targeting these proteins. It is our hope that these pre-clinical studies will help implement new clinical trials in FL-HCC patients.