Bone Abstracts

Background: Cabozantinib (CBZ) is a receptor tyrosine kinase inhibitor with activity against MET, VEGFR2, FLT3, c-KIT, and RET. Pre-clinical studies in models of prostate cancer bone metastasis demonstrated that CBZ treatment induced both a suppression of tumour growth and an alteration in bone remodelling, suggesting that both tumour and bone microenvironment represented potential CBZ targets. This is the first study exploring the potential direct activity of CBZ in bone using a totally human model of primary osteoclasts (OCLs) and osteoblasts (OBLs).

Methods: Primary OCLs were differentiated from CD14+ monocytes; primary OBLs were obtained from mesenchymal stem cells. OCL differentiation and activity were evaluated by TRAP and Bone Resorption assays; OBL differentiation was analysed by ALP and Alizarin Red assays. Gene expression analyses was performed by Real Time PCR and OPG and RANKL protein secretion measured by ELISA.

Results: Our results showed that non-cytotoxic doses of CBZ had a statistically significant inhibitory effect on OCL differentiation (P=0.0145) and bone resorption activity (P=0.0252). Moreover, we found that CBZ down-modulated the expression of OCL marker genes: TRAP (P=0.006) and CATHEPSIN K (P=0.004). On the other hand CBZ treatment had no a significant impact on OBLs vitality, differentiation and activity. Intriguingly we found that CBZ induced in OBLs an alteration of RANKL/OPG balance increasing OPG mRNA levels (P=0.015) and down-modulating RANKL expression (P<0.001). A significant drop in RANKL secretion (P=0.043) and an increase of OPG production (P=0.004) was confirmed by ELISA.

Conclusion: Overall, this is the first evidence in human of the ‘direct’ effect of CBZ on OCLs and ‘indirect’ osteoblast-mediated through a modulation of RANKL/OPG balance. These multiple effects of CBZ on the cells of bone microenvironment are consistent with its effectiveness in reducing lesions from prostate cancer metastases.