Multivalent Cathepsin Inhibitor, VBY-825, Attenuates Breast-Induced Bone Cancer Remodelling and Pain

Abstract

Metastatic bone cancer originates from breast malignancies causing severe pain and bone destruction in patients. Amongst the novel therapies under clinical development for the treatment of bone metastases are cathepsin inhibitors. Cysteine cathepsins (B, C, F, H, K, L, O, L2/V, W, X/Z) are highly expressed in many human cancers and have been associated with poor patient prognosis. In the RIP1-Tag2 transgenic model of pancreatic cancer, mice treated with VBY-825, reversible inhibitor of cathepsins S, B, V, L, K showed a significant reduction in tumor incidence and growth. In this study, we evaluate the efficacy of the cathepsin inhibitor, VBY-825 as treatment for cancer-induced bone pain. Breast cancer cells, 66.1, were injected within the intramedullary space of the femurs of female mice. After seven days of inoculation, the animals were treated with VBY-825 or vehicle (5% dextrose) subcutaneously for seven days. Spontaneous pain behaviors were significantly attenuated in cancer-induced mice treated with VBY-825, compared to vehicle treated animals. Additionally, cancer-induced animals treated with VBY-825 demonstrated both an improvement in bone integrity and reduction of tumor burden. These results indicate that a cathepsin inhibitor targeting multiple cathepsins, such as VBY-825, could be a novel therapeutic for bone metastases.