Article
Improved outcome after targeted therapy with everolimus or axitinib in a spinal metastasis mouse model
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Authors
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Tobias Kratzsch
- Klinik für Neurochirurgie, Charité - Universitätsmedizin Berlin, Berlin, Germany
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Thomas Broggini
- Klinik für Neurochirurgie, Charité - Universitätsmedizin Berlin, Berlin, Germany
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Andras Piffko
- Klinik für Neurochirurgie, Charité - Universitätsmedizin Berlin, Berlin, Germany
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Marcus Czabanka
- Klinik für Neurochirurgie, Charité - Universitätsmedizin Berlin, Berlin, Germany
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Peter Vajkoczy
- Klinik für Neurochirurgie, Charité - Universitätsmedizin Berlin, Berlin, Germany
| Published: | June 8, 2016 |
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Outline
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Objective: An optimal pharmacological treatment of spinal metastases is still not established. Therefore, we performed two targeted therapy approaches on hematogenous spinal metastasis formation. We used everolimus as an inhibitor of the mammalian target of rapamycin (mTOR) complex, as well as axitinib, a tyrosine kinase inhibitor that blocks vascular endothelial growth factors (VEGF) 1-3.
Method: We used our previously established spinal metastasis mouse model by injecting 1x105 luciferin-transfected B16 melanoma cells into the left common carotid artery. Mice were then treated with everolimus (10.0 mg/kg i.p. daily for consecutive 16 days), axitinib (25.0 mg/kg i.p. daily for consecutive 19 days) as well as solvent (control), starting therapy on postoperative day three. Mice were examined daily, after occurrence of paresis or paraplegia, a spinal magnetic resonance imaging (MRI) was performed and mice were immediately sacrificed.
Results: The everolimus as well as axitinib therapy was well tolerated, during therapy we observed considerably less cachectic and retarted mice in the treatment groups. Overall survival (composed of death due to unknown reason or death after killing because of paresis) was 22.7 ± 3.8 days in the control group (n=9), significantly prolonged to 29.5 ± 7.8 days in the everolimus group (n=6), and 28.3 ± 5.4 days in the axitinib group (n=6). In the control group, 88.9% of mice (8 out of 9) showed pareses on the lower limbs compared to only 50% in the everolimus group (3 out of 6) and 50% in the axitinib group (3 out of 6). After pareses onset, spinal MRI (if practicable) showed correlating intraspinal metastasis formation. The time to neurological deficit due to MRI verified spinal tumors was 22.2 ± 5.1 days in the control group (5 out of 9), 26.0 ± 2.0 days in the everolimus group (3 out of 6), and 26.7 ± 6.0 days in the axitinib group (3 out of 6).
Conclusions: There was a prolonged time to neurological deficit in both treatment groups, indicating a feasible effect of everolimus as well as axitinib against spinal metastasis.
