Safety and activity of the combination of ceritinib and dasatinib in osteosarcoma
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Abstract
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 e ect of three IGF specific inhibitors and tested ceritinib as an o -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 e ective 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 e ective 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.