Computational analysis of image-based drug profiling predicts synergistic drug combinations: Applications in triple-negative breast cancer

Miriam B. Brandl, Eddy Pasquier, Fuhai Li, Dominik Beck, Sufang Zhang, Hong Zhao, Maria Kavallaris, Stephen T.C. Wong

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

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 invitro and invivo, and has the potential to lead to the development of new therapeutic options in other hard-to-treat cancers.

Original languageEnglish
Pages (from-to)1548-1560
Number of pages13
JournalMolecular Oncology
Volume8
Issue number8
DOIs
StatePublished - Dec 1 2014

Keywords

  • Compound profiling
  • High-content screening
  • KSP/Eg5 inhibitors
  • Microtubule-targeting agents
  • Synergy
  • Triple-negative breast cancer

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