title: Computational analysis of image-based drug profiling predicts synergistic drug combinations: applications in triple-negative breast cancer.
abstract: An imaged-based profiling and analysis system was developed to predict clinically effective synergistic drug combinations that could accelerate the identification of effective multi-drug therapies for the treatment of triple-negative breast cancer and other challenging malignancies. The identification of effective drug combinations for the treatment of triple-negative breast cancer (TNBC) was achieved by integrating high-content screening, computational analysis, and experimental biology. The approach was based on altered cellular phenotypes induced by 55 FDA-approved drugs and biologically active compounds, acquired using fluorescence microscopy and retained in multivariate compound profiles. Dissimilarities between compound profiles guided the identification of 5 combinations, which were assessed for qualitative interaction on TNBC cell growth. The combination of the microtubule-targeting drug vinblastine with KSP/Eg5 motor protein inhibitors monastrol or ispinesib showed potent synergism in 3 independent TNBC cell lines, which was not substantiated in normal fibroblasts. The synergistic interaction was mediated by an increase in mitotic arrest with cells demonstrating typical ispinesib-induced monopolar mitotic spindles, which translated into enhanced apoptosis induction. The antitumour activity of the combination vinblastine/ispinesib was confirmed in an orthotopic mouse model of TNBC. Compared to single drug treatment, combination treatment significantly reduced tumour growth without causing increased toxicity. Image-based profiling and analysis led to the rapid discovery of a drug combination effective against TNBC in vitro and in vivo, and has the potential to lead to the development of new therapeutic options in other hard-to-treat cancers.
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW, Randwick, NSW, Australia; School of Engineering and Information Technology, University of New South Wales, Canberra, ACT, 2600, Australia; Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Weill Cornell Medical College of Cornell University, Houston, TX, 77030, USA.
authors.forename: Miriam B
authors.initials: MB
authors.lastname: Brandl
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW, Randwick, NSW, Australia; Metronomics Global Health Initiative, Marseille, France.
authors.forename: Eddy
authors.initials: E
authors.lastname: Pasquier
authors.affiliation: Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Weill Cornell Medical College of Cornell University, Houston, TX, 77030, USA.
authors.forename: Fuhai
authors.initials: F
authors.lastname: Li
authors.affiliation: Lowy Cancer Research Centre and the Prince of Wales Clinical School, University of New South Wales, Sydney, Australia.
authors.forename: Dominik
authors.initials: D
authors.lastname: Beck
authors.affiliation: Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Weill Cornell Medical College of Cornell University, Houston, TX, 77030, USA.
authors.forename: Sufang
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Weill Cornell Medical College of Cornell University, Houston, TX, 77030, USA. Electronic address: hzhao@houstonmethodist.org.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW, Randwick, NSW, Australia; ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Australian Centre for NanoMedicine, University of New South Wales, NSW, 2052, Australia. Electronic address: m.kavallaris@ccia.unsw.edu.au.
authors.forename: Maria
authors.initials: M
authors.lastname: Kavallaris
authors.affiliation: Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Weill Cornell Medical College of Cornell University, Houston, TX, 77030, USA.
authors.forename: Stephen T C
authors.initials: ST
authors.lastname: Wong
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005260:Female; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008938:Mitosis / Q000187:drug effects; D011743:Pyrimidines / Q000627:therapeutic use; D011799:Quinazolines / Q000627:therapeutic use; D013871:Thiones / Q000627:therapeutic use; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D014747:Vinblastine / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D001549:Benzamides; C470243:KIF11 protein, human; D011743:Pyrimidines; D011799:Quinazolines; D013871:Thiones; D014747:Vinblastine; C400223:monastrol; C508757:ispinesib; D016547:Kinesins
keywords: Compound profiling; High-content screening; KSP/Eg5 inhibitors; Microtubule-targeting agents; Synergy; Triple-negative breast cancer