Abstract
Glioblastoma (GBM) is the most common type of primary malignant tumor in adults and contributes disproportionately to cancer morbidity and mortality. The ability to augment current knowledge based on the genome and transcriptome with information regarding protein abundance and post-translational modifications with small molecule and lipid abundance has provided novel biological insights into GBM tumorigenesis. In this presentation we will discuss results from proteogenomic and metabolomic investigations of prospectively recruited, newly diagnosed, treatment-naive glioblastomas (GBMs; N=99). Multiple key findings emerged that were not known from traditional genomic analyses as implemented in most currently available datasets. Analysis of protein phosphorylation identified key signaling intermediates in the RTK/RAS pathway common to multiple RTK genomic alterations, potentially offering common therapeutic targets for different oncogenic drivers in GBM. Phosphoproteomics also identified potential druggable targets based on kinase-substrate pathway analysis, as well as novel phosphoprotein targets associated with the regulation of telomere length by ATRX in IDH mutants. Identification of distinct Immune High and Immune Low phenotypes in GBM from whole genome interrogation of the proteome were driven by tumor-associated macrophage markers, and associated with distinct epigenetic modifications and histone acetylation patterns. Identification of key metabolic changes in IDH mutants facilitating the accumulation of oncometabolite 2-HG were also associated with lipidomic changes. Taken all together this work identifies additional therapeutic channels for GBM and novel information useful for more accurate stratification patients for effective treatment.