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

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.

Exploiting Gangliosides for the Therapy of Ewing’s Sarcoma and H3K27M-Mutant Diffuse Midline Glioma

“…Some ES samples showed high GD2 expression, but not all tumor cells were positive in all patients ( Figure 4 B). Osteosarcoma cells were validated as described in [ 32 ]. Osteosarcoma had low to intermediate expression with a high percentage of cells lacking the antigen ( Figure 5 ).…”

“…OS morphology of all primary cell cultures was confirmed by morphological and immunocytochemical analysis performed by an experienced pathologist. The cells were examined for (1) cell morphology, signs of cell and nuclear atypia, presence of atypical mitoses, and osteoid formation (routine HE and Goldner stained sections); (2) lineage differentiation of the tumor cells (standardized immunocytochemical examination); and (3) exclusion of contaminating cell populations (standardized immunocytochemical examination), as described in detail in [ 32 ]. ES morphology was confirmed with the same procedure with additional staining with a CD99 antibody.…”

Sarcoma treatment in the era of molecular medicine

“…Similar preliminary findings have been reported for EwS and RMS (Cheng et al , 2019). Olaparib combined with ceritinib (ALK inhibitor) in OS showed limited toxicity and should be further evaluated (Beck et al , 2020). A clinical trial assessing olaparib combined with ceralasertib (ATR inhibitor) is currently in progress in the context of OS (ClinicalTrials.gov No.…”

Screening a novel signature and predicting the immune landscape of metastatic osteosarcoma in children via immune-related lncRNAs

“…However, the high-risk group were sensitive to dasatinib. Beck et al showed that a combination of ceritinib and dasatinib could be used to treat advanced OSs patients (46). Bortezomib is commonly used to treat multiple myeloma.…”