Rapid optimization of drug combinations for the optimal angiostatic treatment of cancer

Andrea Weiss, Xianting Ding, Judy R. van Beijnum, Ieong Wong, Tse J. Wong, Robert H. Berndsen, Olivier Dormond, Marchien Dallinga, Li Shen, Reinier O. Schlingemann, Roberto Pili, Chih Ming Ho, Paul J. Dyson, Hubert van den Bergh, Arjan W. Griffioen, Patrycja Nowak-Sliwinska

Research output: Contribution to journalArticle

63 Scopus citations

Abstract

Drug combinations can improve angiostatic cancer treatment efficacy and enable the reduction of side effects and drug resistance. Combining drugs is non-trivial due to the high number of possibilities. We applied a feedback system control (FSC) technique with a population-based stochastic search algorithm to navigate through the large parametric space of nine angiostatic drugs at four concentrations to identify optimal low-dose drug combinations. This implied an iterative approach of in vitro testing of endothelial cell viability and algorithm-based analysis. The optimal synergistic drug combination, containing erlotinib, BEZ-235 and RAPTA-C, was reached in a small number of iterations. Final drug combinations showed enhanced endothelial cell specificity and synergistically inhibited proliferation (p < 0.001), but not migration of endothelial cells, and forced enhanced numbers of endothelial cells to undergo apoptosis (p < 0.01). Successful translation of this drug combination was achieved in two preclinical in vivo tumor models. Tumor growth was inhibited synergistically and significantly (p < 0.05 and p < 0.01, respectively) using reduced drug doses as compared to optimal single-drug concentrations. At the applied conditions, single-drug monotherapies had no or negligible activity in these models. We suggest that FSC can be used for rapid identification of effective, reduced dose, multi-drug combinations for the treatment of cancer and other diseases.

Original languageEnglish (US)
Pages (from-to)233-244
Number of pages12
JournalAngiogenesis
Volume18
Issue number3
DOIs
StatePublished - Jul 20 2015

Keywords

  • Anti-angiogenesis
  • Combination therapy
  • Drug–drug interactions
  • Feedback system control
  • Search algorithm

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cancer Research

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  • Cite this

    Weiss, A., Ding, X., van Beijnum, J. R., Wong, I., Wong, T. J., Berndsen, R. H., Dormond, O., Dallinga, M., Shen, L., Schlingemann, R. O., Pili, R., Ho, C. M., Dyson, P. J., van den Bergh, H., Griffioen, A. W., & Nowak-Sliwinska, P. (2015). Rapid optimization of drug combinations for the optimal angiostatic treatment of cancer. Angiogenesis, 18(3), 233-244. https://doi.org/10.1007/s10456-015-9462-9