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Angiogenesis
Published in: Angiogenesis 3/2015

Open Access 01-07-2015 | Original Paper

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

Authors: 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

Published in: Angiogenesis | Issue 3/2015

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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.
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Metadata
Title
Rapid optimization of drug combinations for the optimal angiostatic treatment of cancer
Authors
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
Publication date
01-07-2015
Publisher
Springer Netherlands
Published in
Angiogenesis / Issue 3/2015
Print ISSN: 0969-6970
Electronic ISSN: 1573-7209
DOI
https://doi.org/10.1007/s10456-015-9462-9

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