gms | German Medical Science

66. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)
Friendship Meeting mit der Italienischen Gesellschaft für Neurochirurgie (SINch)

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

7. - 10. Juni 2015, Karlsruhe

Therapeutic efficacy of the multi-receptor tyrosine kinase inhibitor axitinib in an intracranial xenograft mouse model of human glioblastoma

Meeting Abstract

  • Jan Walter - Klinik für Neurochirurgie, Universitätsklinikum der Friedrich-Schiller-Universität, Jena
  • Theresa Kahlert - Klinik für Neurochirurgie, Universitätsklinikum der Friedrich-Schiller-Universität, Jena
  • Diana Freitag - Klinik für Neurochirurgie, Universitätsklinikum der Friedrich-Schiller-Universität, Jena
  • Arend Koch - Institut für Neuropathologie, Charité - Universitätsmedizin Berlin, Berlin
  • Rolf Kalff - Klinik für Neurochirurgie, Universitätsklinikum der Friedrich-Schiller-Universität, Jena
  • Christian Ewald - Klinik für Neurochirurgie, Universitätsklinikum der Friedrich-Schiller-Universität, Jena

Deutsche Gesellschaft für Neurochirurgie. 66. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC). Karlsruhe, 07.-10.06.2015. Düsseldorf: German Medical Science GMS Publishing House; 2015. DocDI.03.06

doi: 10.3205/15dgnc110, urn:nbn:de:0183-15dgnc1108

Veröffentlicht: 2. Juni 2015

© 2015 Walter et al.
Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung). Lizenz-Angaben siehe http://creativecommons.org/licenses/by/4.0/.


Gliederung

Text

Objective: Multi-receptor tyrosine kinase (RTK) inhibition in general and anti-angiogenic therapy in particular is a promising strategy in the treatment of glioblastomas. The small molecule RTK-inhibitor axitinib that selectively targets VEGFR1-3 and in part PDGFRb as wells as c-KIT (CD117) has proven single-agent clinical activity in lung cancer (NSCLC), thyroid and renal cell cancer. In line with a very recent report of axitinib-mediated antiangiogenic effects in a preclinical GBM model we show its efficacy in an intracranial xenograft mouse model of human GBM.

Method: For intracranial glioblastoma establishment 8-10 weeks old female immunodeficient SCID mice were injected stereotactically with 1x105 LN229 tumor cells (22 mice) and thereafter randomly divided into 3 groups. Tumor establishment was controlled after 2 weeks with 3T-MRI (t0, FLAIR, T1 ± Gd). In treatment group 1 (11 mice) axitinib (25mg/kg) and in group 2 (5 mice) vehicle solution was then applied daily for 4 weeks. Both groups were analyzed for tumor and edema volume in comparison to untreated mice (n=6) in control group 3 again with subsequent MRI (t1). Overall survival, health status and body weight were recorded every day, and animals were monitored for neurological symptoms. Animals were sacrificed when they showed significant deterioration or neurological deficits. After death rodent brains were removed and analyzed histopathologically.

Results: Axitinib proved its anti-tumor and anti-angiogenic effect in all treated animals with intracranial LN229 gliomas. At t1 axitinib treated mice (group 1) showed a deceleration of further tumor growth. In comparison to the vehicle and control groups tumor and FLAIR-signal volume even decreased in treated animals. Moreover, untreated mice showed an increase tumor progression associated symptoms, like hydrocephalus, seizures, hemiparesis and behavioral changes. Morphological and histopathological analysis revealed reduced vessel density and fewer vascular abnormalities in axitinib-treated tumors. Additionally, overall survival was prolonged in axitinib-treated mice.

Conclusions: This in-vivo study demonstrates that the multi-RTK inhibitor axitinib exhibits anti-tumor and anti-angiogenic activity, resulting in a modestly prolonged survival of mice bearing orthotopic intracranial GBMs. These results support further investigation of axitinib as a targeted anti-angiogenic and anti-proliferative agent in GBM treatment.