Project Abstract
Fibrolamellar hepatocellular carcinoma (FLC) is a rare and often lethal form of liver cancer that primarily affects
children and young adults without cirrhosis. There are no approved systemic therapies for FLC, and it is usually
refractory to treatment approaches developed for other forms of liver cancer. A chimeric transcript between
DNAJB1 and PRKACA was identified as a signature genomic event in FLC and leads to activation of PKAc.
However, pharmacological inhibition of PKAc for FLC with traditional small molecule inhibitors has been
infeasible due to on-target toxicity. Our preliminary data derived from preclinical models of FLC and human FLC
tumors show that the DNAJB1-PRKACA fusion results in a metabolic rewiring of the tumor cell, leading to
glutamine dependence. Induction of the DNAJB1-PRKACA fusion in preclinical cell lines is associated with
sensitivity to glutamine antimetabolite therapy. Glutamine dependency in FLC results in a nutrient-depleted tumor
immune microenvironment (TiME) that is enriched in immunosuppressive metabolites (e.g., ammonia, acidosis),
impairing antitumor immunity. In an in vivo model of FLC, the combination of glutamine antimetabolite therapy
plus an immune checkpoint inhibitor (ICI) reverses T cell dysfunction within the tumor immune microenvironment
(TiME) and induces antitumor immunity resulting in robust tumor control. We are translating these preclinical
findings into a clinical trial of a glutamine antagonist (sirpiglenastat) in combination with a PDL1 inhibitor
(durvalumab). In Aim 1, we will conduct a clinical trial to test the safety and clinical activity of sirpiglenastat in
combination with durvalumab, in children or adults with advanced FLC. In Aim 2, we will determine whether
treatment with sirpiglenastat combined with durvalumab suppresses glutamine-dependent processes and
increase the number of activated FLC-specific T cells within the tumor microenvironment. In Aim 3, we will identify
the molecular mechanism and specific metabolic perturbations through which the DNAJB1-PRKACA fusion
induces glutamine addiction and immune suppression. This work will advance a promising new treatment
approach for advanced FLC, a tumor type that currently confers a median survival of only one year. Uncovering
the activity of specific pathways that make FLC glutamine dependent will establish a more complete
understanding of metabolic biomarkers of glutamine addiction, and will reveal synergistic vulnerabilities, which
may be targetable for even more effective treatment approaches. We anticipate that these avenues of inquiry
will likely be generalizable to other classes of glutamine addicted tumors.
