Neuro Oncol. 2018; 20(5):621-631.
SYK Inhibition Blocks Proliferation and Migration of Glioma Cells, and Modifies the Tumor Microenvironment.
Gerald Moncayo, Michal Grzmil, Tatiana Smirnova, Pawel Zmarz, Roland M Huber, Debby Hynx, Hubertus Kohler, Yuhua Wang, Hans-Rudolf Hotz, Nancy E Hynes, Georg Keller, Stephan Frank, Adrian Merlo, Brian A Hemmings.
Glioblastoma (GBM) is one of the most aggressive human brain tumors with a median survival of 15-18 months. There is a desperate need to find novel therapeutic targets. Various receptor protein kinases have been identified as potential targets; however, response rates in clinical studies have been somewhat disappointing. Targeting the Spleen Tyrosine Kinase (SYK), which acts downstream of a range of oncogenic receptors, may therefore show more promising results.
Kinase expression of brain tumor samples including GBM and low-grade tumors were compared to normal brain and normal human astrocytes (NHA) by microarray analysis. Furthermore, SYK, LYN, SLP76 and PLCG2 protein expression was analyzed by immunohistochemistry, western blot, and immunofluorescence of additional GBM patient samples, murine glioma samples and cell lines. SYK was then blocked chemically and genetically in vitro and in vivo in two different mouse models. Multiphoton intravital imaging and multicolor flow cytometry were performed in a syngeneic immunocompetent C57BL/6J mouse GL261 glioma model to study the effect of these inhibitors on the tumor microenvironment.
SYK, LYN, SLP76 and PLCG2 were found expressed in human and murine glioma samples and cell lines. SYK inhibition blocked proliferation, migration, and colony formation. Flow cytometric and multiphoton imaging imply that targeting SYK in vivo attenuated GBM tumor growth and invasiveness, and reduced B and CD11b+ cell mobility and infiltration.
Our data suggest that gliomas express a SYK signaling network important in glioma progression and inhibition of which results in reduced invasion with slower tumor progression.
Conflict of Interest
PCT/EP2010/065367 Spleen tyrosine kinase and brain cancers WO 2011045352 A3. The present invention relates to a method for treating cancer, for instance brain tumors, in a subject by inhibiting spleen tyrosine kinase.
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