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

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Olaf Beck1,2, Claudia Paret1,2,3, Alexandra Russo1,2,3

  • 1Department of Pediatric Hematology/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.

Cancers
|April 1, 2020
PubMed

Insights

The combination of ceritinib and dasatinib effectively reduced osteosarcoma (OS) cell proliferation and showed promise in a patient. This targeted therapy warrants further investigation for pediatric cancer treatment.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Osteosarcoma (OS) is a significant cause of cancer mortality in children.
  • The insulin-like growth factor (IGF) pathway is implicated in OS development, but IGF-targeted therapies have shown limited success as monotherapy.
  • Novel therapeutic strategies are needed to improve outcomes for pediatric OS patients.

Purpose of the Study:

  • To evaluate the efficacy of IGF inhibitors and ceritinib, alone and in combination with dasatinib, against primary OS cells.
  • To assess the safety and tolerability of the ceritinib/dasatinib combination in a pediatric patient with metastatic OS.
  • To investigate the therapeutic effects and drug distribution of ceritinib/dasatinib in vivo.

Main Methods:

  • In vitro testing of IGF inhibitors and ceritinib/dasatinib on seven primary OS cell lines.
  • In vivo treatment of a pediatric patient with metastatic OS using the ceritinib/dasatinib combination.
  • Histopathological and ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis of tumor tissue.
  • Radiological assessment of metastatic disease progression.

Main Results:

  • Picropodophyllin and the ceritinib/dasatinib combination significantly inhibited OS cell proliferation in vitro.
  • The ceritinib/dasatinib combination demonstrated superior efficacy compared to cabozantinib and olaparib in patient-derived cells.
  • The patient tolerated the ceritinib/dasatinib treatment well, with manageable side effects.
  • Histopathology revealed significant tumor necrosis and macrophage infiltration, correlating with drug concentration.
  • Cessation of therapy led to rapid growth of liver metastases, suggesting the need for continuous treatment.

Conclusions:

  • The combination of ceritinib and dasatinib is a safe and potentially effective therapeutic strategy for osteosarcoma.
  • This combination warrants further clinical investigation for developing novel treatment protocols for pediatric OS.
  • The study highlights the importance of sustained targeted therapy in managing metastatic osteosarcoma.
Keywords:
ceritinibdasatinibosteosarcoma

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