DDDR-11. IDENTIFYING NEW VULNERABILITIES TO TARGET PEDIATRIC LOW-GRADE GLIOMA

Abstract

Abstract Pediatric low-grade gliomas (pLGGs) are the most common solid tumors in children and are associated with devastating lifelong morbidities and mortality. Recent genomic profiling efforts have revealed that these tumors are largely driven by single-driver events that activate MAPK signaling. These insights have led to early clinical trials evaluating the role of MAPK inhibitors for these children with promising initial results. However, pLGGs are not cured by MAPK inhibitors, and tumors often rapidly rebound upon cessation of treatment. Therefore, continuous dosing of these inhibitors is required throughout a child’s development–often with significant and potentially permanent toxicities. In addition, 30-40% of tumors do not respond to MAPK inhibition, indicating primary resistance. We hypothesized that pediatrlc low-grade gliomas may also harbor additional dependencies beyond the MAPK pathway that may represent potential therapeutic targets. To address this, we generated isogenic neural stem cell models that expressed pLGG relevant oncogenes (BRAF family members, FGFR family members and MYB transcription factors, and subjected them to genome-scale CRISPR-cas9 screens. Compared to vector controls, pLGG models exhibited genetic dependencies on pathways that included regulators of cell-cycle and differentiation, in addition to genes involved in regulating the mTOR and MAPK pathways. Cell lines expressing MYB family transcription factors also harbored dependencies on genes involved in the DREAM complex. Together, these genes and pathways represent potential targets for combination treatments with MAPK pathway inhibitors for the treatment of pediatric low-grade gliomas.