Timeframe: 2021 – 2022
Goal: Model development
Principal Investigator: Mark Yarchoan, MD
Study overview: Efforts to identify novel therapies for FLC have been confounded by a lack of preclinical models that accurately reflect the genetics and biology of the disease. This study aimed to establish and validate the first orthotopic, syngeneic, preclinical mouse model of FLC that reproduces the key biological behavior and tumor microenvironment (TME) of human FLC.
Because the tumors in such models grow in the context of an intact immune system, they are therefore appropriate models to study agents that act on the host immune system to enhance tumor immunity such as checkpoint inhibitors and immunotherapy agents. Once successfully established,the resulting preclinical model of FLC will be openly shared with the larger research community. This model could offer unprecedented opportunities to investigate mechanisms underlying FLC pathogenesis, and become a critical tool for investigating novel therapeutic strategies in FLC.
Key findings: The study team has successfully established a new pre-clinical model of FLC. They created a FLC-like murine cell line by inducing hepatoblast cells (TIB-75) to express the DNAJB1-PRKACA fusion and implanted the tumor line orthotopically into the livers of syngeneic BALB/c mice. In mice, these FLC-like tumors have growth kinetics, high levels of infiltrating lymphocytes, and histological features, such as fibrosis, that are consistent with the clinical phenotypes of FLC observed in humans.
The study team is committed to further describing and validating this new model. Additional planned analyses include characterizing the metabolomics of the FLC-like and parenteral cell lines. They intend to publish their findings, and are open to widely distributing the model within the FLC community. The hope is that this model can serve as the basis for in-depth investigation of the DNAJB1-PRKACA chimeric transcript-dependent pathway in the FLC tumor microenvironment, as well as efforts to drug the fusion and/or its downstream factors. Already, the model has proved instrumental in performing pre-clinical assessments of the impact of glutamine antagonist treatment in combination with checkpoint inhibition – work critical to the development of the upcoming DRP-104 clinical trial at Johns Hopkins.