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.
authors.affiliation: Institute of Chemical Sciences and Engineering, Swiss Federal Institute of Technology (EPFL), 1015, Lausanne, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Weiss
authors.forename: Xianting
authors.initials: X
authors.lastname: Ding
authors.forename: Judy R
authors.initials: JR
authors.lastname: van Beijnum
authors.forename: Ieong
authors.initials: I
authors.lastname: Wong
authors.forename: Tse J
authors.initials: TJ
authors.lastname: Wong
authors.forename: Robert H
authors.initials: RH
authors.lastname: Berndsen
authors.forename: Olivier
authors.initials: O
authors.lastname: Dormond
authors.forename: Marchien
authors.initials: M
authors.lastname: Dallinga
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.forename: Reinier O
authors.initials: RO
authors.lastname: Schlingemann
authors.forename: Roberto
authors.initials: R
authors.lastname: Pili
authors.forename: Chih-Ming
authors.initials: CM
authors.lastname: Ho
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Dyson
authors.forename: Hubert
authors.initials: H
authors.lastname: van den Bergh
authors.forename: Arjan W
authors.initials: AW
authors.lastname: Griffioen
authors.forename: Patrycja
authors.initials: P
authors.lastname: Nowak-Sliwinska
mesh_terms: D000465:Algorithms; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D002645:Chickens; D049033:Chorioallantoic Membrane / Q000378:metabolism; D000081007:Cymenes; D004354:Drug Screening Assays, Antitumor; D042783:Endothelial Cells / Q000166:cytology; D005246:Feedback; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D009942:Organometallic Compounds / Q000008:administration & dosage; D010051:Ovarian Neoplasms / Q000473:pathology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011804:Quinolines / Q000008:administration & dosage; D013269:Stochastic Processes
chemical_list: D000081007:Cymenes; D007093:Imidazoles; D009942:Organometallic Compounds; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011804:Quinolines; C530402:dichloro(4-cymene)(1,3,5-triaza-7-phosphatricyclo(3.3.1.1)decane)ruthenium(II); C531198:dactolisib
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