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

50 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Drug Combinations
Endothelial cells
Endothelial Cells
Pharmaceutical Preparations
Neoplasms
Tumors
Feedback
Control systems
Oncology
Drug-Related Side Effects and Adverse Reactions
Drug Resistance
Cell Survival
Identification (control systems)
Apoptosis
Testing
Growth
Population

Keywords

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

ASJC Scopus subject areas

  • Cancer Research
  • Physiology
  • Clinical Biochemistry

Cite this

Weiss, A., Ding, X., van Beijnum, J. R., Wong, I., Wong, T. J., Berndsen, R. H., ... 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

Rapid optimization of drug combinations for the optimal angiostatic treatment of cancer. / Weiss, Andrea; Ding, Xianting; van Beijnum, Judy R.; Wong, Ieong; Wong, Tse J.; Berndsen, Robert H.; Dormond, Olivier; Dallinga, Marchien; Shen, Li; Schlingemann, Reinier O.; Pili, Roberto; Ho, Chih Ming; Dyson, Paul J.; van den Bergh, Hubert; Griffioen, Arjan W.; Nowak-Sliwinska, Patrycja.

In: Angiogenesis, Vol. 18, No. 3, 20.07.2015, p. 233-244.

Research output: Contribution to journalArticle

Weiss, A, Ding, X, van Beijnum, JR, Wong, I, Wong, TJ, Berndsen, RH, Dormond, O, Dallinga, M, Shen, L, Schlingemann, RO, Pili, R, Ho, CM, Dyson, PJ, van den Bergh, H, Griffioen, AW & Nowak-Sliwinska, P 2015, 'Rapid optimization of drug combinations for the optimal angiostatic treatment of cancer', Angiogenesis, vol. 18, no. 3, pp. 233-244. https://doi.org/10.1007/s10456-015-9462-9
Weiss A, Ding X, van Beijnum JR, Wong I, Wong TJ, Berndsen RH et al. Rapid optimization of drug combinations for the optimal angiostatic treatment of cancer. Angiogenesis. 2015 Jul 20;18(3):233-244. https://doi.org/10.1007/s10456-015-9462-9
Weiss, Andrea ; Ding, Xianting ; van Beijnum, Judy R. ; Wong, Ieong ; Wong, Tse J. ; Berndsen, Robert H. ; Dormond, Olivier ; Dallinga, Marchien ; Shen, Li ; Schlingemann, Reinier O. ; Pili, Roberto ; Ho, Chih Ming ; Dyson, Paul J. ; van den Bergh, Hubert ; Griffioen, Arjan W. ; Nowak-Sliwinska, Patrycja. / Rapid optimization of drug combinations for the optimal angiostatic treatment of cancer. In: Angiogenesis. 2015 ; Vol. 18, No. 3. pp. 233-244.
@article{83c61b49bfae4787b1ba625f3d612fad,
title = "Rapid optimization of drug combinations for the optimal angiostatic treatment of cancer",
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.",
keywords = "Anti-angiogenesis, Combination therapy, Drug–drug interactions, Feedback system control, Search algorithm",
author = "Andrea Weiss and Xianting Ding and {van Beijnum}, {Judy R.} and Ieong Wong and Wong, {Tse J.} and Berndsen, {Robert H.} and Olivier Dormond and Marchien Dallinga and Li Shen and Schlingemann, {Reinier O.} and Roberto Pili and Ho, {Chih Ming} and Dyson, {Paul J.} and {van den Bergh}, Hubert and Griffioen, {Arjan W.} and Patrycja Nowak-Sliwinska",
year = "2015",
month = "7",
day = "20",
doi = "10.1007/s10456-015-9462-9",
language = "English (US)",
volume = "18",
pages = "233--244",
journal = "Angiogenesis",
issn = "0969-6970",
publisher = "Springer Netherlands",
number = "3",

}

TY - JOUR

T1 - Rapid optimization of drug combinations for the optimal angiostatic treatment of cancer

AU - Weiss, Andrea

AU - Ding, Xianting

AU - van Beijnum, Judy R.

AU - Wong, Ieong

AU - Wong, Tse J.

AU - Berndsen, Robert H.

AU - Dormond, Olivier

AU - Dallinga, Marchien

AU - Shen, Li

AU - Schlingemann, Reinier O.

AU - Pili, Roberto

AU - Ho, Chih Ming

AU - Dyson, Paul J.

AU - van den Bergh, Hubert

AU - Griffioen, Arjan W.

AU - Nowak-Sliwinska, Patrycja

PY - 2015/7/20

Y1 - 2015/7/20

N2 - 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.

AB - 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.

KW - Anti-angiogenesis

KW - Combination therapy

KW - Drug–drug interactions

KW - Feedback system control

KW - Search algorithm

UR - http://www.scopus.com/inward/record.url?scp=84931563239&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84931563239&partnerID=8YFLogxK

U2 - 10.1007/s10456-015-9462-9

DO - 10.1007/s10456-015-9462-9

M3 - Article

C2 - 25824484

AN - SCOPUS:84931563239

VL - 18

SP - 233

EP - 244

JO - Angiogenesis

JF - Angiogenesis

SN - 0969-6970

IS - 3

ER -