Osteosarcoma (OS) is the most common primary malignant bone tumor of both humans and dogs, with the incidence in dogs being nearly 15 times that observed in humans. Despite advances in treatment of other cancers, the clinical outcome of OS remains poor for the past several decades. Therefore, identifying novel and effective treatments for osteosarcoma is an urgent need. Among the small molecular compounds we tested in a drug screening study, we identified a bromodomain inhibitor (JQ1) that targets bromodomains which modify chromatin and block transcription of key factors, and a proteasome inhibitor that induces cell death through various mechanisms (bortezomib) as having good growth inhibition effects on three canine OS cell lines (D17, Abrams, and Gracie) and two human OS cell lines (SAOS2 and U2OS). We then determined the IC50 values of these two drugs, the concentration capable of inhibiting proliferation by 50%. The IC50 values of bortezomib and JQ1 are both within achievable plasma concentrations and tolerable levels. JQ1 inhibited OS cell proliferation and survival by inducing G2 cell cycle arrest, while bortezomib induced G1 cell cycle arrest. In addition, these two drugs decreased cell migration ability in wound healing assay as well as invasion ability in a Matrigel assay. Furthermore, in combination studies using both JQ1 and bortezomib, we identified synergistic effects. With these promising results from in vitro studies, we further examined JQ1 as therapeutic agent in an orthotopic tumor xenograft mouse model. Using OS cells stably transfected with a lucerifase vector, we were able to track the tumor progression during the treatment period. Mice treated with JQ1 did not show any signs of adverse effect to the drug, indicating that JQ1 was safe and well tolerated at a daily dosage of 50 mg/kg (IP). While some of the mice in treatment group showed decreasing tumor growth compared to the control group, tumor growth trends in the two groups were not consistent, suggesting that we have to optimize the model and the treatment protocol as well as to evaluate combination treatments with bortezomib and JQ1 in in vivo models.
Citation Format: Ya-Ting Yang, Vilma Yuzbasiyan-Gurkan. Synergistic effects of Bortezomib and JQ1 for human and canine osteosarcoma treatments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4032. doi:10.1158/1538-7445.AM2017-4032