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

Autor:	Beck O; Department of Pediatric Hematology/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.; University Cancer Center (UCT), University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany., Paret C; Department of Pediatric Hematology/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.; University Cancer Center (UCT), University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.; German Cancer Consortium (DKTK), site Frankfurt/Mainz, Germany, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany., Russo A; Department of Pediatric Hematology/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.; University Cancer Center (UCT), University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.; German Cancer Consortium (DKTK), site Frankfurt/Mainz, Germany, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany., Burhenne J; Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, 69120 Heidelberg, Germany.; German Cancer Consortium (DKTK)-German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany., Fresnais M; Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, 69120 Heidelberg, Germany.; German Cancer Consortium (DKTK)-German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany., Steimel K; Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, 69120 Heidelberg, Germany., Seidmann L; Institute of Pathology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany., Wagner DC; Institute of Pathology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany., Vewinger N; Department of Pediatric Hematology/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.; University Cancer Center (UCT), University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany., Lehmann N; Department of Pediatric Hematology/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.; University Cancer Center (UCT), University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany., Sprang M; Department of Pediatric Hematology/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.; University Cancer Center (UCT), University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany., Backes N; Department of Pediatric Hematology/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.; University Cancer Center (UCT), University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany., Roth L; Department of Pediatric Hematology/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.; University Cancer Center (UCT), University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany., Neu MA; Department of Pediatric Hematology/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.; University Cancer Center (UCT), University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany., Wingerter A; Department of Pediatric Hematology/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.; University Cancer Center (UCT), University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany., Henninger N; Department of Pediatric Hematology/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.; University Cancer Center (UCT), University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany., Malki KE; Department of Pediatric Hematology/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.; University Cancer Center (UCT), University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany., Otto H; Department of Pediatric Hematology/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.; University Cancer Center (UCT), University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany., Alt F; Department of Pediatric Hematology/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.; University Cancer Center (UCT), University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany., Desuki A; University Cancer Center (UCT), University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.; Department of Hematology, Medical Oncology, and Pneumology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany., Kindler T; University Cancer Center (UCT), University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.; German Cancer Consortium (DKTK), site Frankfurt/Mainz, Germany, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.; Department of Hematology, Medical Oncology, and Pneumology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany., Faber J; Department of Pediatric Hematology/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.; University Cancer Center (UCT), University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.; German Cancer Consortium (DKTK), site Frankfurt/Mainz, Germany, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Jazyk:	angličtina
Zdroj:	Cancers [Cancers (Basel)] 2020 Mar 26; Vol. 12 (4). Date of Electronic Publication: 2020 Mar 26.
DOI:	10.3390/cancers12040793
Abstrakt:	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.
Databáze:	MEDLINE
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