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.
