Comparative Phospho-Enriched Proteomic Analysis between the World Health Organization Grades of Meningiomas: Mechanisms of Oncogensis and Evidence for an Aggressive Grade I

Introduction: There are very few treatment options for meninigomas, which fail surgical resection and radiation therapy. While a multimodality use of radiation and chemotherapeutics has slightly improved the outcomes of patients suffering from aggressive meningiomas, the overall patient survival and disease recurrence times have not significantly changed. There is a need for novel therapeutic options. Current trends in chemotherapeutics have strayed away from classical DNA chelating compounds to the development of drugs, which target metabolites and proteins. Examples of protein-targeting compounds, which have under gone clinical trials, are: Geftnib, Erlotinib, Lapatinib, Vandetanib, Bevacizumab, Everolimus, Hydroxy Urea, Sandostatin LR, Sunitinib, Vatalnib, and Imatinib. Many of these compounds have become implemented for clinical use through the identification of up-regulated proteins in meningiomas. Mass spectroscopy (MS) proteomic analysis offers a convenient, and high throughput, method for the identification of biomarkers. Recent developments in proteomic techniques have allowed researchers to isolate specific groups of proteins to obtain higher resolution data.

Objective: To utilize MS to compare the changes in the phospho-proteome between meningioma WHO grades. We sought to identify significant changes in the phospho-proteome, which could give lead to potential drug targets and gain insight into the pathways of oncogenesis of progressively aggressive meningiomas.

Methods: The phospho-proteome of WHO grades 1, 2 and 3, and an unusually aggressive grade 1 phenotype were compared. The proteomes were isolated from each tumor and the phospho-proteome isolated via a titanium oxide column. ITRAQ labeling was performed via the manufacture's protocol (add manufacture). The proteomes were analyzed using a Maldi Tof-Tof MS machine. Protein Pilot was used for the analysis of MS data, while IBM SPSS was used to equate statistical significance. String software was used to reconstruct the proteome for each experiment group.

Results: Over 600 peptides were identified. In total, 55 proteins had a change in expression or phosphorylation equal to or greater than (+/ − ) LOG(10)2 between experimental groups. 11 of the proteins identified had mutations, ten of which have not been reported as mutated in meningiomas. 12 proteins revealed changes in phosphorylated sites on the same peptide across grades.

Conclusions: In total, we have identified 55 potential proteins for drug targets, 11 potential oncogenic mutations, and 12 possible protein targets specific to kinase inhibitors. This data also isolated significant differences in the phospho-proteome between aggressive grade Is and benign grade Is, which supports the existence of a unique subgroup of meningiomas. The unique proteomic signatures discovered add to the evidence of a progressive phenotype as meningiomas become more aggressive.