title: Prediction in the face of uncertainty: a Monte Carlo-based approach for systems biology of cancer treatment.
abstract: Cancer is known to be a complex disease and its therapy is difficult. Much information is available on molecules and pathways involved in cancer onset and progression and this data provides a valuable resource for the development of predictive computer models that can help to identify new potential drug targets or to improve therapies. Modeling cancer treatment has to take into account many cellular pathways usually leading to the construction of large mathematical models. The development of such models is complicated by the fact that relevant parameters are either completely unknown, or can at best be measured under highly artificial conditions. Here we propose an approach for constructing predictive models of such complex biological networks in the absence of accurate knowledge on parameter values, and apply this strategy to predict the effects of perturbations induced by anti-cancer drug target inhibitions on an epidermal growth factor (EGF) signaling network. The strategy is based on a Monte Carlo approach, in which the kinetic parameters are repeatedly sampled from specific probability distributions and used for multiple parallel simulations. Simulation results from different forms of the model (e.g., a model that expresses a certain mutation or mutation pattern or the treatment by a certain drug or drug combination) can be compared with the unperturbed control model and used for the prediction of the perturbation effects. This framework opens the way to experiment with complex biological networks in the computer, likely to save costs in drug development and to improve patient therapy.
authors.affiliation: Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin, Germany. wierling@molgen.mpg.de
authors.forename: Christoph
authors.initials: C
authors.lastname: Wierling
authors.forename: Alexander
authors.initials: A
authors.lastname: Kühn
authors.forename: Hendrik
authors.initials: H
authors.lastname: Hache
authors.forename: Andriani
authors.initials: A
authors.lastname: Daskalaki
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Maschke-Dutz
authors.forename: Svetlana
authors.initials: S
authors.lastname: Peycheva
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Ralf
authors.initials: R
authors.lastname: Herwig
authors.forename: Hans
authors.initials: H
authors.lastname: Lehrach
mesh_terms: D003198:Computer Simulation; D004815:Epidermal Growth Factor / Q000378:metabolism; D006801:Humans; D009010:Monte Carlo Method; D009369:Neoplasms / Q000628:therapy*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D015398:Signal Transduction; D049490:Systems Biology / Q000379:methods*
chemical_list: D047428:Protein Kinase Inhibitors; D004815:Epidermal Growth Factor