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Screening out irrelevant cell-based models of disease

Nature Reviews Drug Discovery volume 15, pages 751–769 (2016)Cite this article

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Abstract

The common and persistent failures to translate promising preclinical drug candidates into clinical success highlight the limited effectiveness of disease models currently used in drug discovery. An apparent reluctance to explore and adopt alternative cell- and tissue-based model systems, coupled with a detachment from clinical practice during assay validation, contributes to ineffective translational research. To help address these issues and stimulate debate, here we propose a set of principles to facilitate the definition and development of disease-relevant assays, and we discuss new opportunities for exploiting the latest advances in cell-based assay technologies in drug discovery, including induced pluripotent stem cells, three-dimensional (3D) co-culture and organ-on-a-chip systems, complemented by advances in single-cell imaging and gene editing technologies. Funding to support precompetitive, multidisciplinary collaborations to develop novel preclinical models and cell-based screening technologies could have a key role in improving their clinical relevance, and ultimately increase clinical success rates.

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Figure 1: Novel assay technologies and their integration.
Figure 2: Evolution of more physiologically relevant cell-culture assay systems.
Figure 3: Contributions of new cell-based assay technologies to the early-stage drug discovery pipeline.
Figure 4: Precompetitive consortia facilitating predictive assay development, experimental and personalized medicine strategies.

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Acknowledgements

The authors thank H. Ebner for assistance in the writing of this manuscript. E.D.N is supported by the program Paris Alliance of Cancer Research Institutes (PACRI), Investissements d'Avenir, launched by the French government with the reference ANR-11-PHUC-002. N.A. and S.L.S. are grateful for support from the 7th Framework Programme of the European Commission (LEISHDRUG project, 223414) and the French Government (L'Agence nationale de la recherche (ANR)) programmes: Investissements d'Avenir programme ('Laboratoire d'Excellence Integrative Biology of Emerging Infectious Diseases'; grant ANR-10-LABX-62-IBEID); France BioImaging (FBI; grant ANR-10-INSB-04-01) and the Fondation Française pour la Recherche Médicale (FRM; Grands Équipements Program). N.O.C. acknowledges a fellowship award from Research Councils UK (RCUK). P.H. acknowledges support from the Hungarian National Brain Research Program (grant MTA-SE-NAP B-BIOMAG). V.P. and P.H. acknowledge support from the TEKES Finland Distinguished Professor Programme (FiDiPro) Fellow Grant (40294/13). M.C.M is supported by the Spanish Ministry of Economy and Competitiveness (MINECO) and the The Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) foundation, and received funding from the Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505), MINECO (grant BIO2014-62200-EXP) and the Innovative Training Networks (ITN) EU Horizon 2020 (EU-H2020) programme (grant 641639 BIOPOL). V.P. and P.Ö. received funding from the European Union's 7th Framework Programme (FP7/2007–2013; grant 258068); EU-FP7 Systems Microscopy Network of Excellence (NoE) project, the Sigrid Juselius Foundation, the Cancer Society of Finland, the Academy of Finland (Centre of Excellence in Translational Cancer Biology), the Magnus Ehrnrooth foundation and the TEKES FiDiPro Fellow Grant (40294/13), and TEKES New Generation Biobanking Grant (40294/11). Research in the Kallioniemi group at the Science for Life Laboratory received funding from K. Wallenberg and A. Wallenberg (grant 2015.0291), and the Karolinska Institutet. G.T. is supported by École Polytechnique Fédérale de Lausanne (EPFL) and the Swiss National Science Foundation/ National Centres of Competence in Research (SNF/NCCR) in Chemical Biology. D.E. acknowledges research support from Cancer Research UK (CRUK) and the Higher Education Funding Council for England (HEFCE).

Author information

Author notes

  1. Peter Horvath, Nathalie Aulner, Marc Bickle, Anthony M. Davies, Elaine Del Nery, Daniel Ebner, Maria C. Montoya, Päivi Östling, Vilja Pietiäinen, Leo S. Price, Spencer L. Shorte, Gerardo Turcatti, Carina von Schantz and Neil O. Carragher: All authors are part of the European Cell-Based Assays Interest Group.

Authors and Affiliations

  1. Synthetic and Systems Biology Unit, Biological Research Centre of the Hungarian Academy of Sciences, Szeged H-6726, Hungary; and at the Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki 00290, Finland.,

    Peter Horvath

  2. and at the Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki 00290, Finland.,

    Peter Horvath

  3. Imagopole-Citech, Institut Pasteur, Paris, 75015, France

    Nathalie Aulner & Spencer L. Shorte

  4. Technology Development Studio, Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, 01307, Germany

    Marc Bickle

  5. Translational Cell Imaging Queensland (TCIQ), Institute of Health Biomedical Innovation, Queensland University of Technology, Brisbane, 4102, QLD, Australia

    Anthony M. Davies

  6. The Irish National Centre for High Content Screening and Analysis, Trinity Translational Medicine Institute, Trinity College Dublin, Phase 3 Trinity Health Sciences 1.20, St James Hospital, Dublin, D8, Republic of Ireland

    Anthony M. Davies

  7. Department of Translational Research, Institut Curie, PSL Research University, The Biophenics High-Content Screening Laboratory, Cell and Tissue Imaging Facility (PICT-IBiSA), Paris, F-75005, France

    Elaine Del Nery

  8. Target Discovery Institute, University of Oxford, Oxford, OX3 7FZ, UK

    Daniel Ebner

  9. Cellomics Unit, Cell Biology & Physiology Program, Cell & Developmental Biology Area, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, 28029, Spain

    Maria C. Montoya

  10. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, 00290, Finland

    Päivi Östling, Vilja Pietiäinen & Carina von Schantz

  11. Department of Oncology and Pathology, Science for Life Laboratory, Karolinska Institutet, Stockholm, 17165, Sweden

    Päivi Östling

  12. Faculty of Science, Leiden Academic Centre for Drug Research, Toxicology, Universiteit Leiden, The Netherlands; and at OcellO, J.H Oortweg 21, 2333 CH, Leiden, The Netherlands.,

    Leo S. Price

  13. and at OcellO, J.H Oortweg 21, 2333 CH, Leiden, The Netherlands.,

    Leo S. Price

  14. Biomolecular Screening Facility, Swiss Federal Institute of Technology (EPFL), Lausanne, CH-1015, Switzerland

    Gerardo Turcatti

  15. Cancer Research UK Edinburgh Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XR, UK

    Neil O. Carragher

Authors
  1. Peter Horvath
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  2. Nathalie Aulner
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  3. Marc Bickle
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  4. Anthony M. Davies
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  5. Elaine Del Nery
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  6. Daniel Ebner
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  7. Maria C. Montoya
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  8. Päivi Östling
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  9. Vilja Pietiäinen
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  10. Leo S. Price
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  11. Spencer L. Shorte
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  12. Gerardo Turcatti
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  13. Carina von Schantz
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  14. Neil O. Carragher
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Corresponding author

Correspondence to Neil O. Carragher.

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Competing interests

L.P. is a founder and shareholder of OcellO B.V., a contract research organization that offers drug screening services. The content of the article is not influenced in any way by his involvement.

P.H. is the founder and a shareholder of Single-cell technologies Inc., a biodata analysis company. The content of the article is not influenced in any way by his involvement.

A.M.D. is the inventor of the suspension technology referred to in the article as Happy Cell. He is also a board member, director and shareholder of the company that distributes this technology. The content of the article is not influenced in any way by his involvement.

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Horvath, P., Aulner, N., Bickle, M. et al. Screening out irrelevant cell-based models of disease. Nat Rev Drug Discov 15, 751–769 (2016). https://doi.org/10.1038/nrd.2016.175

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