Abstract 1803: A new spectrum-selective cathepsin inhibitor, VBY-825, inhibits bone destruction in a syngeneic 5TGM1 multiple myeloma mouse model
Authors: Suominen Mari I. , Tuomela Johanna , Alhoniemi Esa , Fagerlund Katja M. , Rissanen Jukka P. , Halleen Jussi M. , Holsinger Leslie J. 
Published: May 2015

Abstract
Multiple myeloma (MM) is the second most common blood cancer after non Hodgkin lymphoma. It is a monoclonal B-cell neoplasia with clinical hallmarks of multiple osteolytic lesions causing bone pain, fractures and hypercalcemia. Chemo- or radiotherapy may induce remissions, but MM is generally thought to be incurable. Our aim was to observe the effects of a cathepsin inhibitor VBY-825 on bone lesions and tumor burden in the syngeneic 5TGM1 mouse MM model using immunocompetent C57BL/KaLwRij mice. VBY-825 is a potent inhibitor of cathepsins K, L, B, V, and S. 5TGM1 cells were inoculated via tail vein in 7 weeks old female C57BL/KaLwRij mice, which were divided to 4 groups: Control group received vehicle of VBY-825 (5% dextrose 10 ml/kg daily), Control group received bortezomib vehicle (3 ml/kg twice a week), Reference group received bortezomib (0.5 mg/kg twice a week) and Study group received VBY-825 (100 mg/kg daily). Administration of all compounds began one day before tumor cell inoculation and continued until day 34. Disease progression was followed by measuring the serum levels of paraprotein (IgG2b) and TRACP 5b, radiography, and body weight. The animals were sacrificed 5 weeks after inoculation, examined macroscopically, and their bones were collected for histomorphometric analysis.
The reference compound bortezomib had no effects on body weight but it delayed the disease progression based on IgG2b measurements. It also decreased the number and total area of osteolytic lesions, but not mean osteolytic lesion area (MOLA). VBY-825 had no effect on body weight or IgG2b level, frequency of soft tissue tumors or intraosseous tumor area. VBY-825 decreased total and MOLA, consistent with inhibited resorption. There was also a trend of increased relative trabecular bone area. Serum TRACP 5b activity in the VBY-825 treated group did not differ from the respective vehicle group, whereas the number of osteoclasts at tumor-bone interface was increased in VBY-825 treated animals. These findings suggest that VBY-825 decreased osteoclast function and resorption activity without decreasing the number of osteoclasts
In conclusion, VBY-825 had no effects on tumor growth but it inhibited bone destruction in this mouse model of MM, which is consistent with its potency on cathepsin S and K, which are known to be important in osteoclast-mediated bone resorption. VBY-825 is a promising candidate for the treatment of tumor-associated bone disease.
Citation Format: Mari I. Suominen, Johanna Tuomela, Esa Alhoniemi, Katja M. Fagerlund, Jukka P. Rissanen, Jussi M. Halleen, Leslie J. Holsinger. A new spectrum-selective cathepsin inhibitor, VBY-825, inhibits bone destruction in a syngeneic 5TGM1 multiple myeloma mouse model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1803. doi:10.1158/1538-7445.AM2014-1803