BIOL-05. IDENTIFICATION AND VALIDATION OF PA2G4 AS A POTENTIAL THERAPEUTIC TARGET IN PEDIATRIC DIFFUSE GLIOMAS

Abstract

Abstract Brain tumors are the second most common pediatric malignancy after leukemia. High grade gliomas have a significantly high morbidity and mortality in children, with a 5-year survival rate under 20%. This study aims to identify important biological mechanisms and proteins as prognostic biomarkers and novel therapeutic targets. We hypothesize that higher grade pediatric diffuse gliomas can be effectively targeted by knocking down expression of the proliferation associated protein 2G4 (PA2G4) that binds to MYCN and prevents its ubiquitination. LC-MS/MS proteomic profiling was performed on 28 formalin-fixed paraffin embedded primary diffuse glioma samples from Nationwide Children’s Hospital (Columbus, OH). Cox proportional hazard models were used to correlate individual proteins with progression-free survival (PFS) and overall survival (OS). Differences in fold change were calculated for each protein between low grade (LGG, grade 2) and high-grade glioma (HGG, grades 3-4) patients. Ingenuity Pathway Analysis was performed considering only proteins with p-values <0.05. In vitro studies were performed to evaluate the roles of PA2G4 in the SF188 glioma cell line. In comparing high- and low-grade tumors, 471 proteins were found to be significantly differentially expressed. Eighty-six and 121 proteins were significantly associated with OS and PFS, respectively. PA2G4 was expressed 2.0-fold higher in HGG vs LGG (p=0.015). Additionally, high expression of PA2G4 protein was associated with significantly worse PFS (p=0.041) and OS (p=0.035) and selected for further studies. Preliminary in vitro results showed that knocking-down PA2G4 decreased AKT phosphorylation/activation and levels of MYCN protein. Given that activated MYCN plays critical oncogenic roles in patients with poor survival PA2G4 may serve as a novel therapeutic target in higher grade pediatric diffuse gliomas. Studies are underway to unfold how PA2G4 affects treatment resistance and tumor recurrence in pediatric patients.