Stanford University

2016-2018

Developing pre-clinical models for fibrolamellar FL-HCC: Therapeutic target identification and testing

Principal Investigator: Dr. Julien Sage, Associate Professor, Department of Pediatrics and Genetics

Abstract:

Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare but lethal form of liver cancer for which

few therapeutic options are available. 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, limiting the implementation of clinical trials. One solution to this problem can come from the development of accurate pre-clinical models of FLHCC; such models can be used both to investigate the basic mechanisms of FL-HCC development, which may help identify new therapeutic targets, and to test novel therapeutic strategies. Here we propose to generate a mouse model for FL-HCC. We and others have analyzed the sequence of FL-HCC patients and identified a distinct genetic alteration resulting in the fusion of two proteins (a small piece of “DnaJ” and a larger piece of “PKA” are fused together). This DnaJ-PKA fusion is present in all the FL-HCC tumors sequenced so far and we showed it has pro-tumorigenic effects in cells.

Based on the pattern of development of FL-HCC, mostly in children and young adults, we hypothesize that the expression of the DnaJ-PKA fusion initiates cancer in specific liver stem/progenito cell populations during liver development. We have introduced the DnaJ-PKA DNA fusion into the genome of mice but the fusion protein can only be expressed upon activation of an activating enzyme (named “Cre”). To test our hypothesis, we will introduce the Cre enzyme at specific stages of liver development using genetic tools in mice.

If tumors develop, this will conclusively demonstrate that expression of the DnaJ-PKA fusion is an essential step in FL-HCC development, providing novel insights into the mechanisms of FL-HCC development. In addition, the generation of mice developing FL-HCC tumors resembling human tumors would provide a pre-clinical platform to test new therapeutic strategies.