Identifying New Therapeutic Targets in Fibrolamellar Hepatocellular Carcinoma

Institution: 

Stanford University

Researcher(s): 

Julien Sage, PhD

Grant Type: 

Innovation Grants

Year Awarded: 

2018

Type of Childhood Cancer: 

General Pediatric Cancer

Background
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 have led to the identification of 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. 

Project Goal
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 preclinical studies will help implement new clinical trials in FL-HCC patients.

Project Update June 2, 2020
 In the past year, we have continued to generate tumors in our mouse models to develop cell lines that can be studied. We have also performed pharmacological studies on a lead anti-FLC molecule to determine the best conditions to use this molecule. It is our hope that these preclinical studies will help implement new clinical trials in FL-HCC patients.