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

Angiogenesis. 2015 Jul;18(3):233-44. doi: 10.1007/s10456-015-9462-9. Epub 2015 Apr 1.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols*
  • Apoptosis
  • Cell Culture Techniques
  • Cell Line, Tumor
  • Cell Movement
  • Cell Survival
  • Chickens
  • Chorioallantoic Membrane / metabolism
  • Cymenes
  • Drug Screening Assays, Antitumor
  • Endothelial Cells / cytology
  • Feedback
  • Female
  • Humans
  • Imidazoles / administration & dosage
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Neoplasms / blood supply*
  • Neoplasms / drug therapy*
  • Neovascularization, Pathologic / drug therapy*
  • Organometallic Compounds / administration & dosage
  • Ovarian Neoplasms / pathology
  • Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
  • Quinolines / administration & dosage
  • Stochastic Processes


  • Cymenes
  • Imidazoles
  • Organometallic Compounds
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Quinolines
  • dichloro(4-cymene)(1,3,5-triaza-7-phosphatricyclo(
  • dactolisib