Abstract A219: Efficacy of a spectrum-selective cathepsin inhibitor in a mouse model of bone cancer.

Introduction: Increased cathepsin levels and activity have been shown to play a role in a variety of tumors, including lung and breast malignancies, and are correlated to poor patient prognosis. Proteolytic activity of cathepsins S, L, B and K may play a role in degradation of the basement membrane and extracellular matrix allowing a loss of cell adhesion and facilitating tumor metastasis. Cathepsin K inhibition has been reported to suppress bone resorption in women with breast cancer by inhibiting osteoclast function. Studies with cathepsin S inhibitors have demonstrated a reduction in nociception in animals, suggesting a role for cathepsin S in tumor-associated neuropathy. We report the efficacy of the spectrum-selective cathepsin inhibitor VBY-825 in a mouse model of metastatic breast cancer. Results and Discussion: VBY-825 is a potent ketoamide-based inhibitor of cathepsins S, B, K, V, and L with pM or single digit nM affinity on this spectrum of cysteine proteases. VBY-825 has been shown to have potent anti-tumor activity in a spontaneous mouse model of pancreatic cancer (Elie et al, 2010, Biochimie). VBY-825 potently inhibited angiogenesis in tumor cell lines, endothelial cell co-cultures and tumor matrix invasion when assayed in an in vitro 3D tumor cell growth assay. Pharmacokinetic behavior of VBY-825 supported once daily dosing resulting in plasma levels sufficient for sustained inhibition of the target cathepsins. Efficacy of VBY-825 was assessed in a murine bone cancer model in which murine 66.1 breast cancer cells are injected and confined to the intramedullary space of the femur of non-immunocompromised mice. Beginning on post surgical day 7 animals received either VBY-825, zoledronic acid, or 5% dextrose vehicle once daily for 14 days. Similarly to the bisphosphonate, VBY-825 in this model significantly reduced bone matrix degradation. VBY-825 also reduced behaviors associated with spontaneous pain including flinching and guarding with significantly greater efficacy than zoledronic acid suggesting that VBY-825 may also induce analgesia against bone cancer pain. Conclusions: These studies demonstrate that the cathepsin inhibitor VBY-825 is effective in a model of bone cancer and associated chronic pain, demonstrating both analgesic activity as well as protection from bone matrix loss and remodeling. These studies support the role of multiple cathepsins as therapeutic targets in metastatic and primary bone cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A219.