Evaluation of Two Novel Therapeutics Against Human and Canine Osteosarcoma

Abstract Background: Osteosarcoma (OS) is the most common primary bone tumor in both humans and canines. This tumor has an aggressive course leading to the development of metastatic lesions in most patients diagnosed with this disease. Two new novel agents, MLN9708 and SH4-54, work as a proteasome inhibitor and a STAT3 inhibitor, respectively. Targets of these drugs have been shown to be overexpressed in OS in both species. Methods: Two human and two canine OS cell lines were exposed in vitro to both drugs alone and in combination. The number of cells undergoing apoptosis, as well as the number of cells capable of invasion through a matrigel basement membrane was evaluated after exposure to the drugs. Additionally, PCR and Western blots of downstream targets were evaluated. Finally, both drugs were tested against each cell line in an in vivo murine xenograft model. Results: All four cell lines were sensitive to MLN9708, one of the human cell lines and both canine cell lines were resistant to SH4-54. MLN9708 was also better at inhibiting invasion in three of the four cell lines. In the murine xenografts MLN9708 inhibited growth and metastasis in 143B (human OS) and the combination inhibited growth in the canine OS cell line (MCKOS). Conclusions: Though SH4-54 demonstrated robust cell killing in 143B in vitro, MLN9708 demonstrated broader activity across species for the treatment of OS. Further investigation into this drug is warranted as a treatment for OS. Combination of this drug with a STAT3 inhibitor may be worthwhile in canine OS.