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  Inhibiting receptor tyrosine kinase AXL with small molecule inhibitor BMS-777607 reduces glioblastoma growth, migration, and invasion in vitro and in vivo

Onken, J., Torka, R., Korsing, S., Radke, J., Krementeskaia, I., Nieminen, M., et al. (2016). Inhibiting receptor tyrosine kinase AXL with small molecule inhibitor BMS-777607 reduces glioblastoma growth, migration, and invasion in vitro and in vivo. OncoTarget, 7(9), 9876-9889. doi:10.18632/oncotarget.7130.

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 Urheber:
Onken, Julia1, Autor
Torka, Robert2, Autor           
Korsing, Soeren1, Autor
Radke, Josefine1, Autor
Krementeskaia, Irina1, Autor
Nieminen, Melina1, Autor
Bai, Xi1, Autor
Ullrich, Axel2, Autor           
Heppner, Frank1, Autor
Vajkoczy, Peter1, Autor
Affiliations:
1external, ou_persistent22              
2Ullrich, Axel / Molecular Biology, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565172              

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Schlagwörter: ADJUVANT TEMOZOLOMIDE; POOR-PROGNOSIS; TUMOR INVASION; CANCER CELLS; LUNG-CANCER; MER; RESISTANCE; CHEMOSENSITIVITY; CONCOMITANT; METASTASISOncology; Cell Biology; glioblastoma multiforme (GBM); small molecule inhibitor BMS-777607; receptor tyrosine kinase AXL (RTK-AXL); invasion; xenograft model;
 Zusammenfassung: Purpose: Receptor tyrosine kinase AXL (RTK-AXL) is regarded as suitable target in glioma therapy. Here we evaluate the anti-tumoral effect of small molecule inhibitor BMS-777607 targeting RTK-AXL in a preclinical glioma model and provide evidence that RTK-AXL is expressed and phosphorylated in primary and recurrent glioblastoma multiforme (GBM). Experimental design: We studied the impact of BMS-777607 targeting RTK-AXL in GBM models in vitro and in vivo utilizing glioma cells SF126 and U118MG. Impact on proliferation, apoptosis and angiogenesis was investigated by immunohistochemistry (IHC) and functional assays in vitro and in vivo. Tumor growth was assessed with MRI. Human GBM tissue was analyzed in terms of RTK-AXL phosphorylation by immunoprecipitation and immunohistochemistry. Results: BMS-777607 displayed various anti-cancer effects dependent on increased apoptosis, decreased proliferation and migration in vitro and ex vivo in SF126 and U118 GBM cells. In vivo we observed a 56% tumor volume reduction in SF126 xenografts and remission in U118MG xenografts of more than 91%. The tube formation assay confirmed the anti-angiogenic effect of BMS-777607, which became also apparent in tumor xenografts. IHC of human GBM tissue localized phosphorylated RTK-AXL in hypercellular tumor regions, the migratory front of tumor cells in pseudopalisades, and in vascular proliferates within the tumor. We further proved RTK-AXL phosphorylation in primary and recurrent disease state. Conclusion: Collectively, these data strongly suggest that targeting RTK-AXL with BMS-777607 could represent a novel and potent regimen for the treatment of primary and recurrent GBM.

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Sprache(n): eng - English
 Datum: 2016
 Publikationsstatus: Erschienen
 Seiten: 14
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: Expertenbegutachtung
 Identifikatoren: ISI: 000375672900021
DOI: 10.18632/oncotarget.7130
 Art des Abschluß: -

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Titel: OncoTarget
Genre der Quelle: Zeitschrift
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Ort, Verlag, Ausgabe: 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA : IMPACT JOURNALS LLC
Seiten: - Band / Heft: 7 (9) Artikelnummer: - Start- / Endseite: 9876 - 9889 Identifikator: ISSN: 1949-2553