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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.
Highlights
Osteosarcoma (OS) is the second-leading cause of cancer-related death in pediatric patients and the most common primary bone tumor
Our results indicate the relevance of PPP alone and in combination with dasatinib in treatment of OS
Our results indicate that INSR phosphorylation can be induced by IGF2 in the primary cells of the patient we treated in this study, and that ALK was not mutated, further experiments are necessary to clarify the activation of the insulin-like growth factor (IGF) pathway and the response to ceritinib/dasatinib in OS
Summary
Osteosarcoma (OS) is the second-leading cause of cancer-related death in pediatric patients and the most common primary bone tumor. The current management strategy for newly diagnosed osteosarcoma includes neoadjuvant chemotherapy followed by the surgical removal of the primary tumor along with all clinically evident metastatic disease, plus the addition of adjuvant chemotherapy after surgery [1,2,3]. Despite these multimodal therapeutic treatments, numerous patients develop recurrent or metastatic disease and new molecular strategies are urgently needed [4]. Even if the complex genetic heterogeneity of OS renders targeted agents unlikely to succeed as monotherapy, very few combinations have been tested so far and no Phase-II trials have transposed to successful first-line Phase-III trials in the last three decades [6]
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