Timeframe: 2016 – 2019
Goal: Develop a pre-clinical mouse model for fibrolamellar carcinoma
Principal Investigator: Dr. Julien Sage, PhD
Study overview: There are few effective therapies for FLC patients and development of improved therapeutics are hampered by the rarity of the disease and the challenge of including pediatric patients in many clinical trials. One solution to this problem is the development of accurate models of FLC. This study proposed to generate the first mouse model for FLC. Such models could be used to investigate the basic mechanisms of FLC development, identify new therapeutic targets, and to test novel therapeutic strategies.
The study had two specific aims:
- Determining the consequences of DNAJB1-PKA expression during liver development. The team had already generated a transgenic mouse in which the DNAJB1-PRKACA gene fusion is inserted into the mouse genome in an inducible manner. By switching on the expression of DnaJ-PKA at specific stages of liver development, they planned to examine exactly how and when this fusion contributes to FLC formation.
- Generating the first pre-clinical mouse model of FLC. To induce the development of FLC tumors in Rosa26LSL-DNAJB1-PRKACA-GFP mice, they planned to cross these transgenic mice with mice in which the Cre recombinase can be activated in liver stem/progenitor cells during liver development. They planned to follow tumor development in aging cohorts of mice, and to determine the accuracy of the model in comparison to human tumors using histopathological methods and by RNA sequencing.
For additional details see the article published by Stanford on FCF’s grant and collaboration.
Key findings: Since the initiation of the effort, two different studies published at the end of 2017 showed that activation of the fusion early in life is not necessary and that FLC can be modeled in mice after activation of the fusion in hepatocytes in young mice. Based on those studies, and to avoid duplicating published work, the team modified its research plan to focus on the tumor development effort and the development of better models of FLC. Their idea was to generate a number of aging mice with induction of the fusion and to develop cell lines or allografts with those mice.
At the conclusion of the study, the team had generated and begun to analyze a mouse model of FLC that is different from previous models. Approximately 20-25% of the genetically engineered mice developed tumors, but the growth of these tumors was slower than what was observed in humans. While that slow growth rate and the low penetrance are major impediments to performing pre-clinical treatment studies using the models, the hope is that the model can still be used to generate cell lines and allografts. To achieve that new goal, the mice need to be aged at least 2 years to wait for very large tumors to grow, which was not not anticipated by the initial proposal.