Conditional robustness analysis for fragility discovery and target identification in biochemical networks and in cancer systems biology.
BACKGROUND
The study of cancer therapy is a key issue in the field of oncology research and the development of target therapies is one of the main problems currently under investigation. This is particularly relevant in different types of tumor where traditional chemotherapy approaches often fail, such as lung cancer.


RESULTS
We started from the general definition of robustness introduced by Kitano and applied it to the analysis of dynamical biochemical networks, proposing a new algorithm based on moment independent analysis of input/output uncertainty. The framework utilizes novel computational methods which enable evaluating the model fragility with respect to quantitative performance measures and parameters such as reaction rate constants and initial conditions. The algorithm generates a small subset of parameters that can be used to act on complex networks and to obtain the desired behaviors. We have applied the proposed framework to the EGFR-IGF1R signal transduction network, a crucial pathway in lung cancer, as an example of Cancer Systems Biology application in drug discovery. Furthermore, we have tested our framework on a pulse generator network as an example of Synthetic Biology application, thus proving the suitability of our methodology to the characterization of the input/output synthetic circuits.


CONCLUSIONS
The achieved results are of immediate practical application in computational biology, and while we demonstrate their use in two specific examples, they can in fact be used to study a wider class of biological systems.
Dept of Experimental Medicine, University of Perugia, Polo Unico Sant'Andrea delle Fratte, Via Gambuli, 1, Perugia, 06156, IT. fortunato.bianconi@unipg.it.
Fortunato
F
Bianconi
Center for Applied Proteomics and Molecular Medicine George Mason University, 10900 University Blvd, Manassas, 20110, USA. ebaldell@gmu.edu.
Elisa
E
Baldelli
Vienna
V
Ludovini
Dept of Medical Oncology, Santa Maria della Misericordia Hospital, Azienda Ospedaliera di Perugia, Piazzale Menghini, 1, Loc. Sant'Andrea delle Fratte, Perugia, 06156, IT. ludoviniv@hotmail.com.
Vienna
V
Luovini
Center for Applied Proteomics and Molecular Medicine George Mason University, 10900 University Blvd, Manassas, 20110, USA. epetrico@gmu.edu.
Emanuel F
EF
Petricoin
Dept of Medical Oncology, Santa Maria della Misericordia Hospital, Azienda Ospedaliera di Perugia, Piazzale Menghini, 1, Loc. Sant'Andrea delle Fratte, Perugia, 06156, IT. luciocrino@unipg.it.
Lucio
L
Crinò
Dept of Engineering, University of Perugia, G. Duranti, 93, Perugia, 06125, IT. luciocrino@unipg.it.
Paolo
P
Valigi
D000465:Algorithms; D019295:Computational Biology / Q000379:methods; D055808:Drug Discovery; D066246:ErbB Receptors / Q000378:metabolism; D025461:Feedback, Physiological; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D053858:Metabolic Networks and Pathways; D008962:Models, Theoretical; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000378:metabolism; D015398:Signal Transduction; D058615:Synthetic Biology / Q000379:methods; D049490:Systems Biology; D035501:Uncertainty
C000597236:IGF1R protein, human; D017451:Receptors, Somatomedin; C512478:EGFR protein, human; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1