Analysis of compound synergy in high-throughput cellular screens by population-based lifetime modeling

Despite the successful introduction of potent anti-cancer therapeutics, most of these drugs lead to only modest tumor-shrinkage or transient responses, followed by re-growth of tumors. Combining different compounds has resulted in enhanced tumor control and prolonged survival. However, methods query...

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Published in:PloS one 2010-01, Vol.5 (1), p.e8919
Main Authors: Peifer, Martin, Weiss, Jonathan, Sos, Martin L, Koker, Mirjam, Heynck, Stefanie, Netzer, Christian, Fischer, Stefanie, Rode, Haridas, Rauh, Daniel, Rahnenführer, Jörg, Thomas, Roman K
Format: Article
Language:English
Subjects:
Algorithms
Analysis
Antineoplastic Agents - pharmacology
Biotechnology
Cancer
Cancer therapies
Cancer treatment
Cell death
Cell Line, Tumor
Chemotherapy
Clinical trials
Computational Biology
Drug dosages
Drug Synergism
Drugs
Enzymes
Epidermal growth factor
Estimates
Feasibility studies
Genetics and Genomics/Pharmacogenomics
Genomics
Humans
Laboratories
Leukemia
Ligands
Lung cancer
Medical research
Medical screening
Modelling
Models, Theoretical
Mutation
Neoplasms - drug therapy
Neoplasms - pathology
Oncology/Lung Cancer
Pharmacology/Drug Development
Pharmacology/Personalized Medicine
Physicists
Population (statistical)
Recipes
Shrinkage
Signaling
Stochastic Processes
Stochasticity
Topology
Transient response
Tumor cell lines
Tumors
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container_issue 1
container_start_page e8919
container_title PloS one
container_volume 5
creator Peifer, Martin
Weiss, Jonathan
Sos, Martin L
Koker, Mirjam
Heynck, Stefanie
Netzer, Christian
Fischer, Stefanie
Rode, Haridas
Rauh, Daniel
Rahnenführer, Jörg
Thomas, Roman K
description Despite the successful introduction of potent anti-cancer therapeutics, most of these drugs lead to only modest tumor-shrinkage or transient responses, followed by re-growth of tumors. Combining different compounds has resulted in enhanced tumor control and prolonged survival. However, methods querying the efficacy of such combinations have been hampered by limited scalability, analytical resolution, statistical feasibility, or a combination thereof. We have developed a theoretical framework modeling cellular viability as a stochastic lifetime process to determine synergistic compound combinations from high-throughput cellular screens. We apply our method to data derived from chemical perturbations of 65 cancer cell lines with two inhibitors. Our analysis revealed synergy for the combination of both compounds in subsets of cell lines. By contrast, in cell lines in which inhibition of one of both targets was sufficient to induce cell death, no synergy was detected, compatible with the topology of the oncogenically activated signaling network. In summary, we provide a tool for the measurement of synergy strength for combination perturbation experiments that might help define pathway topologies and direct clinical trials.
doi_str_mv 10.1371/journal.pone.0008919
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subjects Algorithms
Analysis
Antineoplastic Agents - pharmacology
Biotechnology
Cancer
Cancer therapies
Cancer treatment
Cell death
Cell Line, Tumor
Chemotherapy
Clinical trials
Computational Biology
Drug dosages
Drug Synergism
Drugs
Enzymes
Epidermal growth factor
Estimates
Feasibility studies
Genetics and Genomics/Pharmacogenomics
Genomics
Humans
Laboratories
Leukemia
Ligands
Lung cancer
Medical research
Medical screening
Modelling
Models, Theoretical
Mutation
Neoplasms - drug therapy
Neoplasms - pathology
Oncology/Lung Cancer
Pharmacology/Drug Development
Pharmacology/Personalized Medicine
Physicists
Population (statistical)
Recipes
Shrinkage
Signaling
Stochastic Processes
Stochasticity
Topology
Transient response
Tumor cell lines
Tumors
title Analysis of compound synergy in high-throughput cellular screens by population-based lifetime modeling
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