Abstract
Bone sarcomas are a group of heterogeneous malignant mesenchymal tumors. Complete surgical resection is still the cornerstone of treatment, but, in the advanced/unresectable setting, their management remains challenging and not significantly improved by target- and immuno-therapies. We focused on the tyrosine kinase Eph type-A receptor-2 (EphA2), a key oncoprotein implicated in self-renewal, angiogenesis, and metastasis, in several solid tumors and thus representing a novel potential therapeutic target. Aiming at better characterizing its expression throughout the main bone sarcoma histotypes, we investigated EPHA2 expression in the Cancer Cell Lines Encyclopedia and in public datasets with clinical annotations. looking for correlations with molecular, histopathological and patients’ features and clinical outcomes in a total of 232 osteosarcomas, 197 Ewing’s sarcomas, and 102 chondrosarcomas. We observed EPHA2 expression in bone sarcoma cell lines. We demonstrated higher EPHA2 expression in tumor tissues when compared to normal counterparts. A significant correlation was found between EPHA2 expression and Huvos grade (osteosarcoma) and with worse overall survival (dedifferentiated chondrosarcoma). Next, we characterized EPHA2 expression and activation in bone sarcoma primary tissues and in patient-derived xenografts generated in our laboratory to verify their reliability as in vivo models of osteosarcoma, Ewing’s sarcoma and chondrosarcoma. Furthermore, for the first time, we demonstrated EPHA2 expression in chondrosarcoma, suggesting its potential key role in this histotype. Indeed, we observed a significant dose-dependent antitumor effect of the EphA2-inhibitor ALW-II-41-27 in patient-derived in vitro models. In conclusion, EphA2 targeting represents a promising novel therapeutic strategy against bone sarcomas.
Highlights
Bone sarcomas are a rare and heterogeneous group of malignant mesenchymal primary tumors originating from the osseous tissue, representing less than 1% of all malignancies.In particular, osteosarcoma and Ewing’s sarcoma occur mainly in adolescents and young adults, while chondrosarcoma has a peak incidence in the seventh decade [1]
We showed that erythropoietin-producing hepatocellular (Eph) type-A receptor-2 (EphA2) targeting with the small molecule inhibitor ALW-II-41-27 resulted in marked reduction in cell growth and cell viability in four in vitro models, Cells 2021, 10, 2893 which we derived from primary osteosarcoma, Ewing’s sarcoma and chondrosarcoma tumor tissues
We showed that EphA2 down-regulation is implicated in the synergistic antitumor activity of pazopanib and trametinib in preclinical models of osteosarcoma
Summary
Bone sarcomas are a rare and heterogeneous group of malignant mesenchymal primary tumors originating from the osseous tissue, representing less than 1% of all malignancies.In particular, osteosarcoma and Ewing’s sarcoma occur mainly in adolescents and young adults, while chondrosarcoma has a peak incidence in the seventh decade [1]. Multikinase inhibitors with a specific antiangiogenic activity in osteosarcoma [3,4,5], a novel inhibitor of transcriptional-promoting activity of ETS family transcription factors in sarcomas [6], and inhibitors of IDH1/2 activity in chondrosarcomas [7,8], have displayed some clinical benefits, but without exceeding a progression-free survival in the range of six months. These results underpin the need to continue exploring innovative avenues in the quest for key targets through which novel therapies could hijack tumor progression and metastasis. Molecules involved in cell migration and tumor metastasis are of particular interest
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