title: Rapid screening of novel agents for combination therapy in sarcomas.
abstract: For patients with sarcoma, metastatic disease remains very difficult to cure, and outcomes remain less than optimal. Treatment options have not largely changed, although some promising gains have been made with single agents in specific subtypes with the use of targeted agents. Here, we developed a system to investigate synergy of combinations of targeted and cytotoxic agents in a panel of sarcoma cell lines. Agents were investigated alone and in combination with varying dose ratios. Dose-response curves were analyzed for synergy using methods derived from Chou and Talalay (1984). A promising combination, dasatinib and triciribine, was explored in a murine model using the A673 cell line, and tumors were evaluated by MRI and histology for therapy effect. We found that histone deacetylase inhibitors were synergistic with etoposide, dasatinib, and Akt inhibitors across cell lines. Sorafenib and topotecan demonstrated a mixed response. Our systematic drug screening method allowed us to screen a large number of combinations of sarcoma agents. This method can be easily modified to accommodate other cell line models, and confirmatory assays, such as animal experiments, can provide excellent preclinical data to inform clinical trials for these rare malignancies.
authors.affiliation: Chemical Biology and Molecular Medicine, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA ; Translational Research Lab, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Cubitt
authors.forename: Jiliana
authors.initials: J
authors.lastname: Menth
authors.forename: Jana
authors.initials: J
authors.lastname: Dawson
authors.forename: Gary V
authors.initials: GV
authors.lastname: Martinez
authors.forename: Parastou
authors.initials: P
authors.lastname: Foroutan
authors.forename: David L
authors.initials: DL
authors.lastname: Morse
authors.forename: Marilyn M
authors.initials: MM
authors.lastname: Bui
authors.forename: G Douglas
authors.initials: GD
authors.lastname: Letson
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Sullivan
authors.forename: Damon R
authors.initials: DR
authors.lastname: Reed