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

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 s...

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Autores principales: Beck, Olaf, Paret, Claudia, Russo, Alexandra, Burhenne, Jürgen, Fresnais, Margaux, Steimel, Kevin, Seidmann, Larissa, Wagner, Daniel-Christoph, Vewinger, Nadine, Lehmann, Nadine, Sprang, Maximilian, Backes, Nora, Roth, Lea, Neu, Marie Astrid, Wingerter, Arthur, Henninger, Nicole, El Malki, Khalifa, Otto, Henrike, Alt, Francesca, Desuki, Alexander, Kindler, Thomas, Faber, Joerg
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225940/
https://www.ncbi.nlm.nih.gov/pubmed/32224911
http://dx.doi.org/10.3390/cancers12040793
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author Beck, Olaf
Paret, Claudia
Russo, Alexandra
Burhenne, Jürgen
Fresnais, Margaux
Steimel, Kevin
Seidmann, Larissa
Wagner, Daniel-Christoph
Vewinger, Nadine
Lehmann, Nadine
Sprang, Maximilian
Backes, Nora
Roth, Lea
Neu, Marie Astrid
Wingerter, Arthur
Henninger, Nicole
El Malki, Khalifa
Otto, Henrike
Alt, Francesca
Desuki, Alexander
Kindler, Thomas
Faber, Joerg
author_facet Beck, Olaf
Paret, Claudia
Russo, Alexandra
Burhenne, Jürgen
Fresnais, Margaux
Steimel, Kevin
Seidmann, Larissa
Wagner, Daniel-Christoph
Vewinger, Nadine
Lehmann, Nadine
Sprang, Maximilian
Backes, Nora
Roth, Lea
Neu, Marie Astrid
Wingerter, Arthur
Henninger, Nicole
El Malki, Khalifa
Otto, Henrike
Alt, Francesca
Desuki, Alexander
Kindler, Thomas
Faber, Joerg
author_sort Beck, Olaf
collection PubMed
description 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.
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spelling pubmed-72259402020-05-18 Safety and Activity of the Combination of Ceritinib and Dasatinib in Osteosarcoma Beck, Olaf Paret, Claudia Russo, Alexandra Burhenne, Jürgen Fresnais, Margaux Steimel, Kevin Seidmann, Larissa Wagner, Daniel-Christoph Vewinger, Nadine Lehmann, Nadine Sprang, Maximilian Backes, Nora Roth, Lea Neu, Marie Astrid Wingerter, Arthur Henninger, Nicole El Malki, Khalifa Otto, Henrike Alt, Francesca Desuki, Alexander Kindler, Thomas Faber, Joerg Cancers (Basel) Article 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. MDPI 2020-03-26 /pmc/articles/PMC7225940/ /pubmed/32224911 http://dx.doi.org/10.3390/cancers12040793 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Beck, Olaf
Paret, Claudia
Russo, Alexandra
Burhenne, Jürgen
Fresnais, Margaux
Steimel, Kevin
Seidmann, Larissa
Wagner, Daniel-Christoph
Vewinger, Nadine
Lehmann, Nadine
Sprang, Maximilian
Backes, Nora
Roth, Lea
Neu, Marie Astrid
Wingerter, Arthur
Henninger, Nicole
El Malki, Khalifa
Otto, Henrike
Alt, Francesca
Desuki, Alexander
Kindler, Thomas
Faber, Joerg
Safety and Activity of the Combination of Ceritinib and Dasatinib in Osteosarcoma
title Safety and Activity of the Combination of Ceritinib and Dasatinib in Osteosarcoma
title_full Safety and Activity of the Combination of Ceritinib and Dasatinib in Osteosarcoma
title_fullStr Safety and Activity of the Combination of Ceritinib and Dasatinib in Osteosarcoma
title_full_unstemmed Safety and Activity of the Combination of Ceritinib and Dasatinib in Osteosarcoma
title_short Safety and Activity of the Combination of Ceritinib and Dasatinib in Osteosarcoma
title_sort safety and activity of the combination of ceritinib and dasatinib in osteosarcoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225940/
https://www.ncbi.nlm.nih.gov/pubmed/32224911
http://dx.doi.org/10.3390/cancers12040793
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