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Glioblastoma multiforme (GBM) is one of the most aggressive human cancers. Glioma cells expressed immunoreceptor tyrosine-based activation motif (ITAM) bearing molecules, such as Fc receptors, T cell receptor components and C-type lectins and expression was up regulated in two distinct tumor-derived prognostic signatures identified in GBM and low-grade gliomas. Targeting SYK, downstream of ITAM molecules, attenuated GBM tumor growth and invasiveness, and reduced B and CD11b+ cell mobility and infiltration resulting in improved survival. In addition, GBM tumor cells were found to display phagocytic characteristics in vitro and in vivo by flow cytometry and two photon imaging. Our data demonstrate that gliomas are hematopoietic-like tumors that express an immune signaling network important in glioma progression, and identify targets for therapeutic intervention. Citation Format: Gerald Moncayo. Glioma cells display a prognostically significant hematopoietic phenotype. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4041.

Glioblastoma multiforme (GBM) is the most common aggressive brain cancer with a median survival of approximately 1 year. In a search for novel molecular targets that could be therapeutically developed, our kinome-focused microarray analysis identified the MAP (mitogen-activated protein) kinase-interacting kinase 1 (MNK1) as an attractive theranostic candidate. MNK1 overexpression was confirmed in both primary GBMs and glioma cell lines. Inhibition of MNK1 activity in GBM cells by the small molecule CGP57380 suppressed eIF4E phosphorylation, proliferation, and colony formation whereas concomitant treatment with CGP57380 and the mTOR inhibitor rapamycin accentuated growth inhibition and cell-cycle arrest. siRNA-mediated knockdown of MNK1 expression reduced proliferation of cells incubated with rapamycin. Conversely, overexpression of full-length MNK1 reduced rapamycin-induced growth inhibition. Analysis of polysomal profiles revealed inhibition of translation in CGP57380 and rapamycin-treated cells. Microarray analysis of total and polysomal RNA from MNK1-depleted GBM cells identified mRNAs involved in regulation of TGF-β pathway. Translation of SMAD2 mRNA as well as TGF-β–induced cell motility and vimentin expression was regulated by MNK1 signaling. Tissue microarray analysis revealed a positive correlation between the immunohistochemical staining of MNK1 and SMAD2. Taken together, our findings offer insights into how MNK1 pathways control translation of cancer-related mRNAs including SMAD2, a key component of the TGF-β signaling pathway. Furthermore, they suggest MNK1-controlled translational pathways in targeted strategies to more effectively treat GBM. Cancer Res; 71(6); 2392–402. ©2011 AACR.

Glioblastoma multiforme (GBM) is the most common and deadly form of brain cancer. Despite intensive research the median survival of GBM remains at 1 year, with less than 10 % of patients surviving over 5 years. Our analysis of fresh GBM, secondary GBM, high grade astrocytoma, oligodendroglioma, normal brain and normal human astrocytes showed increased expression of 19 novel protein kinases in GBM and targets previously associated with gliomagenesis (e.g. EGFR or PDGF). Two of these kinases which are mainly expressed in hematopoietic cells were the cytoplasmic kinases SYK and LYN. We confirmed the overexpression in GBM tumours and cell lines through western blot and immunohistochemistry analysis. More importantly, SYK expression was derived from the GBM tumours and not from infiltrating leukocytes as shown through colocalization with GFAP, and not with CD45. SYK was found strongly activated at the membrane after EGF and treatment with three specific small molecule inhibitors and siRNA targeting SYK strongly blocked proliferation and migration of GBM cells. This was confirmed through wtSYK and kinase dead SYK overexpression. In addition, SYK phosphorylation was found to be cell cycle regulated after synchronization. Due to our preliminary results we will test the therapeutic potential of SYK inhibitors and epistatic kinase interactions on our xenograft model measuring the efficacy of therapeutics crossing the blood brain barrier with the ultimate goal of discovering alternative treatments for GBM. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1240. doi:1538-7445.AM2012-1240