title: Identification of Synergistic, Clinically Achievable, Combination Therapies for Osteosarcoma.
abstract: Systemic 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.
authors.affiliation: Sunshine Lab, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612 Florida USA.|Translational Research Lab, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612 Florida USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Yu
authors.affiliation: Sunshine Lab, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612 Florida USA.|Translational Research Lab, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612 Florida USA.
authors.forename: Elliot
authors.initials: E
authors.lastname: Kahen
authors.affiliation: Translational Research Lab, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612 Florida USA.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Cubitt
authors.affiliation: Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612 Florida USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: McGuire
authors.affiliation: Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612 Florida USA.
authors.forename: Jenny
authors.initials: J
authors.lastname: Kreahling
authors.affiliation: Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612 Florida USA.|Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612 Florida USA.
authors.forename: Jae
authors.initials: J
authors.lastname: Lee
authors.affiliation: Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612 Florida USA.|Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612 Florida USA.
authors.forename: Soner
authors.initials: S
authors.lastname: Altiok
authors.affiliation: Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612 Florida USA.|Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612 Florida USA.
authors.forename: Conor C
authors.initials: CC
authors.lastname: Lynch
authors.affiliation: Translational Research Lab, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612 Florida USA.|Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612 Florida USA.|Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612 Florida USA.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Sullivan
authors.affiliation: Sunshine Lab, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612 Florida USA.|Sarcoma Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612 Florida USA.|Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612 Florida USA.|Adolescent and Young Adult Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612 Florida USA.
authors.forename: Damon R
authors.initials: DR
authors.lastname: Reed
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D034261:Epothilones / Q000627:therapeutic use / Q000633:toxicity; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008875:Middle Aged; D012516:Osteosarcoma / Q000188:drug therapy* / Q000473:pathology; D061988:Proteasome Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011720:Pyrazoles / Q000627:therapeutic use / Q000633:toxicity; D011743:Pyrimidines / Q000627:therapeutic use / Q000633:toxicity; D011744:Pyrimidinones; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D034261:Epothilones; D056572:Histone Deacetylase Inhibitors; D061988:Proteasome Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D011744:Pyrimidinones; C430592:ixabepilone; C549567:adavosertib