gms | German Medical Science

67th Annual Meeting of the German Society of Neurosurgery (DGNC)
Joint Meeting with the Korean Neurosurgical Society (KNS)

German Society of Neurosurgery (DGNC)

12 - 15 June 2016, Frankfurt am Main

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

Meeting Abstract

  • Julia Onken - Neurochirurgische Klinik, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Germany
  • Sören Korsing - Neurochirurgische Klinik, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Germany
  • Josefine Radke - Institut für Neuropathologie, Campus Mitte, Charité - Universitätsmedizin Berlin, Germany
  • Irina Krementeskaia - Institut für Experimentelle Neurochirurgie, Charité - Universitätsmedizin Berlin, Germany
  • Melina Niemineä - Institut für Experimentelle Neurochirurgie, Charité - Universitätsmedizin Berlin, Germany
  • Frank Heppner - Institut für Neuropathologie, Campus Mitte, Charité - Universitätsmedizin Berlin, Germany
  • Axel Ullrich - Max-Planck-Institut für Biochemie, Martinsried, Germany
  • Robert Torka - Max-Planck-Institut für Biochemie, Martinsried, Germany
  • Peter Vajkoczy - Neurochirurgische Klinik, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Germany

Deutsche Gesellschaft für Neurochirurgie. 67. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), 1. Joint Meeting mit der Koreanischen Gesellschaft für Neurochirurgie (KNS). Frankfurt am Main, 12.-15.06.2016. Düsseldorf: German Medical Science GMS Publishing House; 2016. DocDI.18.03

doi: 10.3205/16dgnc207, urn:nbn:de:0183-16dgnc2071

Published: June 8, 2016

© 2016 Onken et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at http://creativecommons.org/licenses/by/4.0/.


Outline

Text

Objective: 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 (in assay conc. BMS-777607= 12.5 µM). In vivo, BMS-777607 was applied with a concentration of 30- 100 mg/kg body weight twice a day i.p. for 6-12 days. Tumor growth was assessed with MRI. Impact on proliferation, apoptosis and angiogenesis was investigated by immunohistochemistry (ICH) and functional assays in vitro and in vivo. Human GBM tissue was analyzed in terms of RTK-AXL phosphorylation by immunoprecipitation and immunohistochemistry.

Method:

Results: BMS-777607 induced apoptosis, reduced cell viability as well as migration and invasion 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 %. In vitro and in vivo the effect was dependent on increased apoptosis, decreased proliferation and migration. The tube formation assay confirmed the anti-angiogenic effect of BMS-777607, which became also apparent in tumor xenografts. ICH of human GBM tissue localized phosphorylated RTK-AXL in hypercellular tumor regions, the migratory front of tumor cells in pseudo-palisades, and in vascular proliferates within the tumor. We further proved RTK-AXL phosphorylation in primary and recurrent disease state.

Conclusions: 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.