Targeting Hexosamine Synthesis in Pediatric Brain Tumors

PROJECT SUMMARY Pediatric brain tumors display differential mutational profiles and tumor biology than adult tumors, suggesting that pediatric brain tumor patients are not simply small adults. Diffuse midline gliomas (DMG) often harbor a specific lysine-to-methionine mutation in Histone 3 (H3K27a), which portend a 5-year survival rate of only 2%. As a result, DMG-H3K27a tumors lose the histone regulatory marker, H3K27me3, leading to dysregulation of the epigenetic landscape. DMG-H3K27a gliomas have unique metabolic needs, required to sustain their epigenome and growth. We recently identified that DMG-H3K27a gliomas are dependent on the glycolytic enzyme, Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3 (PFKFB3). PFKFB3 is a bifunctional protein that catalyzes the synthesis or degradation of fructose-2,6-bisphosphate (F2,6BP) and is master regulators of glycolysis. While the discovery and targeting of PFKFB3 and F2,6BP results in reduced growth, resistant ultimately develops. Leveraging unbiased approaches we identified that resistance to PFKFB3 and glycolysis is mediated by the Hexosamine biosynthetic pathway. We hypothesize that targeting this pathway as a single agent or in combination with glycolysis inhibitors or novel codon optimized bacterial metabolic enzymes, reverses resistance and selectively targets DMG cells compared to normal neural precursor cells and glial cells. These efforts seek out to support that DMG-H3K27a tumors have additional selective and clinically targetable dependencies. In the proposed studies we will investigate how these metabolic pathways support growth, promote resistance to apoptosis and radiation. These studies are focused on laying the foundation for preclinical therapeutic strategies.