Osteosarcoma (OS) is the most common primary malignant bone tumor of both humans and dogs. Despite advances in treatment of other cancers, the clinical outcome of OS remains poor for the past decades. Therefore, there is a great need to identify novel and effective treatments for osteosarcoma. Several classes of novel small molecules with anti-tumor activities have become available in the last few years. Among these are tyrosine kinase inhibitors (TKIs) which are able to inhibit kinase activity of many receptor tyrosine kinases. Another class of molecules target bromodomains which modify chromatin and block transcription of key factors, another class of molecules target inhibition of the proteasome which induces cell death through various mechanisms. Previous findings from our lab identified two TKIs (sunitinib, sorafenib), a bromodomain inhibitor (JQ1), and a proteasome inhibitor (bortezomib) as having good growth inhibition effects in low concentrations on three canine OS cell lines (D17, Abrams, and Gracie) and two human OS cell lines (SAOS2 and U2OS) in a series of drug screening assay. Among these candidates, we hypothesized that bortezomib and JQ1 would be effective against canine and human OS cell lines. We then determined the exact IC50 values of these two drugs, the concentration capable of inhibiting proliferation by 50%. The IC50 values of bortezomib varied in cells from 0.01 to 0.22 μM and JQ1 from 0.5 μM to 12.5 μM, which all within achievable plasma concentration and tolerable levels. In addition, these two drugs shown to decrease cell migration ability in wound healing assay as well as invasion ability in matrigel assay. With the promising results from in vitro studies, we further exam JQ1 as therapeutic strategy in an orthotopic tumor xenograft mouse model. However, the evaluation of JQ1 efficiency need to be evaluated before human and canine OS clinical trials.

Citation Format: Yating Yang, Vilma Yuzbasiyan-Gurkan. Bortezomib and JQ1 hold promise for human and canine osteosarcoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1749. doi:10.1158/1538-7445.AM2015-1749

©2015 American Association for Cancer Research.
2015