Identification of Synergistic, Clinically Achievable, Combination Therapies for Osteosarcoma

• DOI: 10.1038/srep16991
• Publication Date: 2015-11-25T09:38:07Z
• Authors: Diana Yu; Elliot Kahen; Christopher L. Cu...; Jeremy McGuire; Jenny Kreahling; Jae Lee; Soner Altiok; Conor C. Lynch; Daniel M. Sullivan; Damon R. Reed
• Keywords: 0301 basic medicine; Osteosarcoma; Cell Survival; Transplantation, Heterologous; Mice, Nude; Apoptosis; Bone Neoplasms; Drug Synergism; Pyrimidinones; Middle Aged; Article; 3. Good health; Histone Deacetylase Inhibitors; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Pyrimidines; Epothilones; Animals; Humans; Pyrazoles; Drug Therapy, Combination; Female; Proteasome Inhibitors

AbstractSystemic therapy has improved osteosarcoma event-free and overall survival, but 30–50% of patients originally diagnosed will have progressive or recurrent disease, which is difficult to cure. Osteosarcoma has a complex karyotype, with loss of p53 in the vast majority of cases and an absence of recurrent, targetable pathways. In this study, we explored 54 agents that are clinically approved for other oncologic indications, agents in active clinical development and others with promising preclinical data in osteosarcoma at clinically achievable concentrations in 5 osteosarcoma cell lines. We found significant single-agent activity of multiple agents and tested 10 drugs in all permutations of two-drug combinations to define synergistic combinations by Chou and Talalay analysis. We then evaluated order of addition to choose the combinations that may be best to translate to the clinic. We conclude that the repurposing of chemotherapeutics in osteosarcoma by using an in vitro system may define novel drug combinations with significant in vivo activity. In particular, combinations of proteasome inhibitors with histone deacetylase inhibitors and ixabepilone and MK1775 demonstrated excellent activity in our assays.