Abstract 4220: Heterogeneous distribution of prognostic protein markers in glioblastoma

Abstract

Abstract Background: Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor in adults. The heterogeneity of the disease leads to significant variability in response to standard therapy (surgery plus concurrent radiation and temozolomide). An accurate and reliable predictor of patient prognosis represents an unmet need to improve the care of GBM patients. While protein markers are an effective readout of cellular function, proteomics has rarely been utilized in GBM prognostic marker discovery. Experimental Procedures: GBM patients were prospectively recruited (Ohio Brain Tumor Study) and proteomics discovery using liquid chromatography mass spectrometry analysis (LC MS/MS) was performed in a discovery set of 27 patients including 13 short-term survivors (< 9 months, STS) and 14 long-term survivors (>= 18 months, LTS). Statistically significant proteins were evaluated in two independent datasets, including in18 samples micro-dissected from multiple tumor areas of 6 GBM patients. Results: Proteomics discovery identified 11,941 peptides in 2,495 unique proteins, with 172 proteins exhibiting significant dysregulation when comparing STS and LTS. Proteins involved in glycolysis/TCA cycle were up-regulated in STS compared to LTS by examination of individual targets as well as upon application of a novel protein and peptide pathway enrichment analysis. Validation of these dysregulated proteins and other protein markers from the literature in our first validation set (18 samples micro-dissected from n=6 patients) demonstrated that they were very unevenly distributed throughout individual patients' tumors. Several proteins overcame the heterogeneous nature of the tumors and were both prognostic markers differentially expressed between LTS and STS, as well as potential drug targets owing to their even distribution throughout the tumor. Protein abundance of significant marker proteins were verified in a second independent validation set using Western immunoblots. Conclusion: The current study verified the importance of metabolism in GBM pathology and demonstrated the heterogeneous nature of GBMs at the protein level. Citation Format: Lindsay C. Stetson, Quinn T. Ostrom, Peter Liao, Andrew E. Sloan, Mark R. Chance, Jill S. Barnholtz-Sloan. Heterogeneous distribution of prognostic protein markers in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4220.