title: In vitro discovery of promising anti-cancer drug combinations using iterative maximisation of a therapeutic index.
abstract: In vitro-based search for promising anti-cancer drug combinations may provide important leads to improved cancer therapies. Currently there are no integrated computational-experimental methods specifically designed to search for combinations, maximizing a predefined therapeutic index (TI) defined in terms of appropriate model systems. Here, such a pipeline is presented allowing the search for optimal combinations among an arbitrary number of drugs while also taking experimental variability into account. The TI optimized is the cytotoxicity difference (in vitro) between a target model and an adverse side effect model. Focusing on colorectal carcinoma (CRC), the pipeline provided several combinations that are effective in six different CRC models with limited cytotoxicity in normal cell models. Herein we describe the identification of the combination (Trichostatin A, Afungin, 17-AAG) and present results from subsequent characterisations, including efficacy in primary cultures of tumour cells from CRC patients. We hypothesize that its effect derives from potentiation of the proteotoxic action of 17-AAG by Trichostatin A and Afungin. The discovered drug combinations against CRC are significant findings themselves and also indicate that the proposed strategy has great potential for suggesting drug combination treatments suitable for other cancer types as well as for other complex diseases.
authors.affiliation: Uppsala University, Dept of Medical Sciences, Cancer Pharmacology and Computational Medicine, Akademiska Sjukhuset, SE-751 85 Uppsala, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Kashif
authors.affiliation: Uppsala University, Dept of Medical Sciences, Cancer Pharmacology and Computational Medicine, Akademiska Sjukhuset, SE-751 85 Uppsala, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Andersson
authors.affiliation: Uppsala University, Dept of Medical Sciences, Cancer Pharmacology and Computational Medicine, Akademiska Sjukhuset, SE-751 85 Uppsala, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Hassan
authors.affiliation: Uppsala University, Dept of Medical Sciences, Cancer Pharmacology and Computational Medicine, Akademiska Sjukhuset, SE-751 85 Uppsala, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Karlsson
authors.affiliation: Uppsala University, Dept of Medical Sciences, Cancer Pharmacology and Computational Medicine, Akademiska Sjukhuset, SE-751 85 Uppsala, Sweden.
authors.forename: W
authors.initials: W
authors.lastname: Senkowski
authors.affiliation: Uppsala University, Dept of Medical Sciences, Cancer Pharmacology and Computational Medicine, Akademiska Sjukhuset, SE-751 85 Uppsala, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Fryknäs
authors.affiliation: Uppsala University, Dept of Immunology, Genetics and Pathology (Experimental and Clinical Oncology), Akademiska Sjukhuset, SE-751 85 Uppsala, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Nygren
authors.affiliation: Uppsala University, Dept of Medical Sciences, Cancer Pharmacology and Computational Medicine, Akademiska Sjukhuset, SE-751 85 Uppsala, Sweden.
authors.forename: R
authors.initials: R
authors.lastname: Larsson
authors.affiliation: Uppsala University, Dept of Medical Sciences, Cancer Pharmacology and Computational Medicine, Akademiska Sjukhuset, SE-751 85 Uppsala, Sweden.
authors.forename: M G
authors.initials: MG
authors.lastname: Gustafsson
mesh_terms: D000465:Algorithms; D000970:Antineoplastic Agents / Q000494:pharmacology*; D057205:Automation, Laboratory; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D004359:Drug Therapy, Combination; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D018874:Spheroids, Cellular; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents