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Drug target optimization in chronic myeloid leukemia using innovative computational platform

Chuang, R., Hall, B. A., Benque, D., Cook, B., Ishtiaq, S., Piterman, N., Taylor, A., Vardi, M., Koschmieder, S., Gottgens, B. and Fisher, J. (2015). Drug target optimization in chronic myeloid leukemia using innovative computational platform. Scientific Reports, 5, doi: 10.1038/srep08190

Abstract

Chronic Myeloid Leukemia (CML) represents a paradigm for the wider cancer field. Despite the fact that tyrosine kinase inhibitors have established targeted molecular therapy in CML, patients often face the risk of developing drug resistance, caused by mutations and/or activation of alternative cellular pathways. To optimize drug development, one needs to systematically test all possible combinations of drug targets within the genetic network that regulates the disease. The BioModelAnalyzer (BMA) is a user-friendly computational tool that allows us to do exactly that. We used BMA to build a CML network-model composed of 54 nodes linked by 104 interactions that encapsulates experimental data collected from 160 publications. While previous studies were limited by their focus on a single pathway or cellular process, our executable model allowed us to probe dynamic interactions between multiple pathways and cellular outcomes, suggest new combinatorial therapeutic targets, and highlight previously unexplored sensitivities to Interleukin-3.

Publication Type: Article
Publisher Keywords: Algorithms; Apoptosis; Computational Biology; Computer Simulation; Fusion Proteins, bcr-abl; Gene Knockout Techniques; Gene Regulatory Networks; Humans; Imatinib Mesylate; Interleukin-3; Interleukin-6; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Models, Biological; bcl-X Protein; ras Proteins
Departments: School of Mathematics, Computer Science & Engineering > Computer Science > Human Computer Interaction Design
URI: http://openaccess.city.ac.uk/id/eprint/18372
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