Marina Baretti, MD, CRI Clinical Innovator Johns Hopkins University School of Medicine Area of Research: Liver Cancer Dr. Baretti’s project will introduce a critically needed new treatment strategy for fibrolamellar hepatocellular carcinoma (FLC) patients and have implications for targeting tumor metabolism in other tumor types. FLC is a rare and often lethal form of liver cancer that primarily affects children and young adults. There are no approved or effective systemic therapies for FLC, and clinical outcomes need improvement. The driver of this cancer is a fusion between the DNAJB1 exon 1 gene and PRKACA exon 2, the catalytic subunit of protein kinase A (PKA). Pharmacological inhibition of the chimera has proven infeasible because direct targeting of PKA results in unacceptable on-target toxicity. Dr. Baretti’s group is focused on developing novel and effective immunotherapies for FLC. Their preliminary data using preclinical models of FLC and human biospecimens from FLC patients shows that the DNAJB1-PRKACA fusion results in a metabolic rewiring of the tumor cell characterized by glutamine dependence. Prior work from Dr. Baretti’s group and others demonstrates that glutamine dependence creates a nutrient-depleted tumor immune microenvironment (TiME) enriched in immunosuppressive metabolites (e.g., ammonia, acidosis) that blocks the generation of an effective antitumor immune response. Their preclinical work shows that induction of the DNAJB1-PRKACA fusion is associated with impaired T cell function. Furthermore, the combination of JHU-083, a glutamine antagonist, in combination with checkpoint inhibitor therapy dramatically improved antitumor effects and enhanced survival in a preclinical model of FLC. This data suggests that the combination of an immune checkpoint inhibitor and glutamine antimetabolite therapy can dismantle the immunosuppressive microenvironment of FLC and enable restoration of antitumor immunity. Dr. Baretti’s overarching hypothesis is that the DNAJB1-PRKACA fusion induces glutamine dependence, creating a critical vulnerability to glutamine antimetabolite therapy in FLC. Their project aims to 1) enroll patients with advanced stage FLC into a clinical trial of the glutamine antagonist, DRP-104, given with the PDL1-inhibitor, durvalumab; 2) use paired prior-to and during- treatment tumor biopsies and serial blood specimens from clinical trial patients to further define how these agents work in patients. Dr. Baretti’s collaborative team incorporates leading clinical experts in FLC, translational expertise in cancer immunotherapy and cancer metabolism, and leverages the core laboratory resources of the Bloomberg-Kimmel Immune Institute and the Johns Hopkins Sidney Kimmel Cancer Center. Projects and Grants A study of glutamine antagonist DRP-104 in combination with Durvalumab in patients with advanced stage Fibrolamellar Hepatocellular Carcinoma (FLC) Johns Hopkins School of Medicine | Liver Cancer | 2023
