PDTM-19. MYC AND FAK/SRC COMBINATION TREATMENT OF FOXR2-HIGH BRAIN TUMORS

Abstract

Abstract Brain tumors are the leading cause of cancer-related deaths in children. To identify novel therapeutic targets in two types of pediatric brain tumors, medulloblastoma (MB) and central nervous system primitive neuroectodermal tumors (CNS-PNETs), we performed a Sleeping Beauty transposon mutagenesis screen in mice. In doing this, we identified FOXR2 (Forkhead box R2) as a candidate oncogene in MB. FOXR2 is expressed at high levels in a subset of human MB and increased FOXR2 expression drives MB formation in mice. FOXR2 has been implicated as an oncogene in several cancers of neural original, including CNS-PNET, adult and pediatric high-grade glioma, and malignant peripheral nerve sheath tumors. We have also found that FOXR2 is upregulated in non-MYCN amplified high-risk neuroblastoma. Therefore, we propose that FOXR2 represents a strong candidate for targeted therapy across multiple brain tumor entities. We have uncovered a dual role of FOXR2 in stabilization of CMYC protein and activation of the FAK/SRC signaling pathway. We are working to further define the mechanism of FOXR2-mediated MYC stabilization and FAK/SRC activation. We plan to treat FOXR2-high tumors with combinations of drugs effective against tumors with high MYC, FAK, or SRC in clinical development. Inhibitors or combinations of that score well in vitro will be used to treat mice with orthotopically injected FOXR2-high tumor cells (MB, neuroblastoma, and glioma). In addition, we are working to construct mouse models of FOXR2-driven neural tumors for use in drug testing. We hypothesize that FOXR2-high tumors will be sensitive to MYC and FAK/SRC inhibitor combination therapy, establishing FOXR2 as a molecular marker for treatment success of MYC and FAK/SRC inhibitors in patients.