title: A streamlined search technology for identification of synergistic drug combinations.
abstract: A major key to improvement of cancer therapy is the combination of drugs. Mixing drugs that already exist on the market may offer an attractive alternative. Here we report on a new model-based streamlined feedback system control (s-FSC) method, based on a design of experiment approach, for rapidly finding optimal drug mixtures with minimal experimental effort. We tested combinations in an in vitro assay for the viability of a renal cell adenocarcinoma (RCC) cell line, 786-O. An iterative cycle of in vitro testing and s-FSC analysis was repeated a few times until an optimal low dose combination was reached. Starting with ten drugs that target parallel pathways known to play a role in the development and progression of RCC, we identified the best overall drug combination, being a mixture of four drugs (axitinib, erlotinib, dasatinib and AZD4547) at low doses, inhibiting 90% of cell viability. The removal of AZD4547 from the optimized drug combination resulted in 80% of cell viability inhibition, while still maintaining the synergistic interaction. These optimized drug combinations were significantly more potent than monotherapies of all individual drugs (p < 0.001, CI < 0.3).
authors.affiliation: Institute of Chemical Sciences and Engineering, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland.|Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Andrea
authors.initials: A
authors.lastname: Weiss
authors.affiliation: Institute of Chemical Sciences and Engineering, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Berndsen
authors.affiliation: Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Xianting
authors.initials: X
authors.lastname: Ding
authors.affiliation: Department of Mechanical and Aerospace Engineering, University of California, Los Angeles, USA.
authors.forename: Chih-Ming
authors.initials: CM
authors.lastname: Ho
authors.affiliation: Institute of Chemical Sciences and Engineering, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Dyson
authors.affiliation: Institute of Chemical Sciences and Engineering, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland.
authors.forename: Hubert
authors.initials: H
authors.lastname: van den Bergh
authors.affiliation: Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Arjan W
authors.initials: AW
authors.lastname: Griffioen
authors.affiliation: Institute of Chemical Sciences and Engineering, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland.|Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Patrycja
authors.initials: P
authors.lastname: Nowak-Sliwinska
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077784:Axitinib; D001549:Benzamides / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000069439:Dasatinib / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004847:Epithelial Cells / Q000187:drug effects* / Q000473:pathology; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007191:Indazoles / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*
chemical_list: C572463:AZD4547; D000970:Antineoplastic Agents; D001549:Benzamides; D004338:Drug Combinations; D007093:Imidazoles; D007191:Indazoles; D010879:Piperazines; D011720:Pyrazoles; D000077784:Axitinib; D000069347:Erlotinib Hydrochloride; D000069439:Dasatinib