Abstract
Cabozantinib, a c-MET and vascular endothelial growth factor receptor 2 inhibitor, demonstrated to prolong progression free survival and improve skeletal disease-related endpoints in castration-resistant prostate cancer and in metastatic renal carcinoma. Our purpose is to investigate the direct effect of cabozantinib on bone microenvironment using a total human model of primary osteoclasts and osteoblasts.Osteoclasts were differentiated from monocytes isolated from healthy donors; osteoblasts were derived from human mesenchymal stem cells obtained from bone fragments of orthopedic surgery patients. Osteoclast activity was evaluated by tartrate resistant acid phosphatase (TRAP) staining and bone resorption assays and osteoblast differentiation was detected by alkaline phosphatase and alizarin red staining.Our results show that non-cytotoxic doses of cabozantinib significantly inhibit osteoclast differentiation (p=0.0145) and bone resorption activity (p=0.0252). Moreover, cabozantinib down-modulates the expression of osteoclast marker genes, TRAP (p=0.006), CATHEPSIN K (p=0.004) and Receptor Activator of Nuclear Factor k B (RANK) (p=0.001). Cabozantinib treatment has no effect on osteoblast viability or differentiation, but increases osteoprotegerin mRNA (p=0.015) and protein levels (p=0.004) and down-modulates Receptor Activator of Nuclear Factor k B Ligand (RANKL) at both mRNA (p<0.001) and protein levels (p=0.043). Direct cell-to-cell contact between cabozantinib pre-treated osteoblasts and untreated osteoclasts confirmed the indirect anti-resorptive effect of cabozantinib.We demonstrate that cabozantinib inhibits osteoclast functions “directly” and “indirectly” reducing the RANKL/osteoprotegerin ratio in osteoblasts.
Highlights
Cabozantinib is an orally bioavailable receptor tyrosine kinase inhibitor with a strong activity against c-MET and vascular endothelial growth factor receptor 2 (VEGFR2) that promote tumour progression and angiogenesis
Osteoclast activity was evaluated by tartrate resistant acid phosphatase (TRAP) staining and bone resorption assays and osteoblast differentiation was detected by alkaline phosphatase and alizarin red staining
We did not find a significant increase of osteoblast mineralization following cabozantinib treatment, molecular analysis revealed a significant upregulation of some osteoblastogenesis markers such as Runt-related transcription factor 2 (RUNX2) (p = 0.003) and OSTERIX (p = 0.015), a down-modulation of OSTEOCALCIN (OCN), while Alkaline Phosphatase (ALP) mRNA levels did not change in treated osteoclasts
Summary
Cabozantinib is an orally bioavailable receptor tyrosine kinase inhibitor with a strong activity against c-MET and vascular endothelial growth factor receptor 2 (VEGFR2) that promote tumour progression and angiogenesis. SRE, in men who showed previous events, were observed in 15 of 91 patients (16%) in the cabozantinib arm and in 31 of 90 patients (34%) in the everolimus arm [17, 18] Overall, these clinical and preclinical data support the hypothesis that bone microenvironment may represent a potential mediator of observed treatment responses, but it is not yet clear if cabozantinib acts on bone metastases directly or indirectly regulating osteoclasts and osteoblasts, or both. Cell lines are helpful at the early phases of evaluating the therapeutic drugs, but they do not fully reproduce the physiology of primary cells and species-related differences could represent a drawback for the translation of the outcomes from bench to bedside [21, 22] This is the first study investigating cabozantinib effect on bone microenvironment using a total human primary model
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