Abstract
BACKGROUND: Ependymoma (EPN) is a childhood brain cancer that is often resistant to cytotoxic therapies. Molecular profiling has led to a better understanding of unique EPN subtypes and revealed a critical role of EPHB2 in driving disease. With this in mind, new treatments for EPN are desperately needed and should be developed in a molecular subtype-specific fashion. METHODS: We developed a syngeneic mouse model of EPHB2-driven genetically engineered EPN tumor cells. We performed transcriptomic profiling and analysis of EPHB2-driven murine EPN tumors and human EPN datasets to reveal multiple protein kinases as potential druggable targets. After identifying the tyrosine kinase inhibitor, Dasatinib, as a potentially effective FDA-approved agent, we measured changes in the murine microenvironment during EPN growth and after Dasatinib treatment. RESULTS: We determined that Dasatinib inhibited the growth of EPN both in vitro and in vivo, through blocking EPHB2 and ABL1 signaling. Furthermore, we identified an increased frequency of immunosuppressive M2-like tumor- associated macrophages (TAMs), which proportionally increased with tumor size during tumor progression. However, treatment with Dasatinib reprogrammed the EPN immune microenvironment by polarizing TAMs toward an anti-tumor M1-like phenotype and increasing CD8 T cell activation. In addition, Dasatinib treatment induced complete regression of established EPN tumors in 78% of the animals and protected survivors against tumor recurrence. Depletion of CD8 T cells compromised the durability of response and reduced overall survival. CONCLUSION: In conclusion, these data indicate that Dasatinib may be an effective therapy for EPHB2-driven molecular subgroup of EPN by activating the anti-tumor immune response and support further investigation of Dasatinib in clinical trials.