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. 2020 Mar 26;12(4):793.
doi: 10.3390/cancers12040793.

Safety and Activity of the Combination of Ceritinib and Dasatinib in Osteosarcoma

Olaf Beck  1   2 , Claudia Paret  1   2   3 , Alexandra Russo  1   2   3 , Jürgen Burhenne  4   5 , Margaux Fresnais  4   5 , Kevin Steimel  4 , Larissa Seidmann  6 , Daniel-Christoph Wagner  6 , Nadine Vewinger  1   2 , Nadine Lehmann  1   2 , Maximilian Sprang  1   2 , Nora Backes  1   2 , Lea Roth  1   2 , Marie Astrid Neu  1   2 , Arthur Wingerter  1   2 , Nicole Henninger  1   2 , Khalifa El Malki  1   2 , Henrike Otto  1   2 , Francesca Alt  1   2 , Alexander Desuki  2   7 , Thomas Kindler  2   3   7 , Joerg Faber  1   2   3
Affiliations

Safety and Activity of the Combination of Ceritinib and Dasatinib in Osteosarcoma

Olaf Beck et al. Cancers (Basel). .

Abstract

Osteosarcoma (OS) is the second most common cause of cancer-related death in pediatric patients. The insulin-like growth factor (IGF) pathway plays a relevant role in the biology of OS but no IGF targeted therapies have been successful as monotherapy so far. Here, we tested the effect of three IGF specific inhibitors and tested ceritinib as an off-target inhibitor, alone or in combination with dasatinib, on the proliferation of seven primary OS cells. Picropodophyllin, particularly in combination with dasatinib and the combination ceritinib/dasatinib were effective in abrogating the proliferation. The ceritinib/dasatinib combination was applied to the primary cells of a 16-year-old girl with a long history of lung metastases, and was more effective than cabozantinib and olaparib. Therefore, the combination was used to treat the patient. The treatment was well tolerated, with toxicity limited to skin rush and diarrhea. A histopathological evaluation of the tumor after three months of therapy indicated regions of high necrosis and extensive infiltration of macrophages. The extension of the necrosis was proportional to the concentration of dasatinib and ceritinib in the area, as analysed by an ultra performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS). After the cessation of the therapy, radiological analysis indicated a massive growth of the patient's liver metastases. In conclusion, these data indicate that the combination of ceritinib/dasatinib is safe and may be used to develop new therapy protocols.

Keywords: ceritinib; dasatinib; osteosarcoma.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Drug screening identifies ceritinib and dasatinib as potent inhibitors of OS proliferation in vitro. (a) Primary tumor cells of six patients (corresponding to seven samples) and the HOS cells were incubated with the indicated inhibitors. After nine days, the cell proliferation was measured. The ratio between the absorbance at day nine and the absorbance at day zero is indicated. At least two independent experiments were used to calculate the ratio and each experiment was done in triplicates. Low proliferation is outlined in red, middle in orange, and strong in blue. (b) The primary tumor cells of sample 386 were incubated with the indicated inhibitors. After nine days, the cell proliferation was measured and the ratio between the absorbance at day nine and the absorbance at day zero was calculated. The proliferation experiments were carried out in biological duplicates. Data are represented as the mean ± Standard deviation (SD). (c) 386 cells were stimulated after starvation with IGF2. The expression of IGF1R, INSR, AKT serine/threonine kinase 1 (AKT), extracellular-signal regulated kinases (ERK), kinase Src (Src) and their phosphorylated (P) form was analyzed by Western blot with specific antibodies. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as loading control. A representative experiment of three independent experiments is shown. Densitometric analysis of two independent experiments is shown. The control (unstimulated) condition was normalized to one.
Figure 2
Figure 2
Concentration of ceritinib and dasatinib in plasma. The concentration of ceritinib and dasatinib (in ng/mL) was measured before the application (blue) and four hours after the application (orange).
Figure 3
Figure 3
Necrosis and macrophage infiltration after treatment with certinib/dasatinib. Frozen sections from four different pleural sites stained with hematoxylin and eosin (HE, upper row) and CD68 immunohistochemistry (lower row). Conventional histology unveiled extensive necrosis, inflammatory cell infiltration and scattered small tumor cell groups (arrowheads) in samples 1 (A) and 2 (B). In contrast, vital tumor cell content was increased in sample 3 (C) and particularly in sample 4 (D). Scale bar: 500 µm.
Figure 4
Figure 4
Liver metastases during and after the ceritinib/dasatinib therapy. The size (in cm) of two metastases (M) was monitored by ultrasound examination. The ceritinib/dasatinib combination was assumed until the date indicated by therapy end.
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