Advances in dynamic modeling of colorectal cancer signaling-network regions, a path toward targeted therapies

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Title: Advances in dynamic modeling of colorectal cancer signaling-network regions, a path toward targeted therapies
Authors: Tortolina, Lorenzo
Duffy, David J.
Maffei, Massimo
Carmody, Aimee M.
Kolch, Walter
Kholodenko, Boris N.
et al.
Permanent link: http://hdl.handle.net/10197/9790
Date: 31-Dec-2014
Online since: 2019-04-03T10:29:43Z
Abstract: The interconnected network of pathways downstream of the TGFβ, WNT and EGF-families of receptor ligands play an important role in colorectal cancer pathogenesis. We studied and implemented dynamic simulations of multiple downstream pathways and described the section of the signaling network considered as a Molecular Interaction Map (MIM). Our simulations used Ordinary Differential Equations (ODEs), which involved 447 reactants and their interactions. Starting from an initial "physiologic condition", the model can be adapted to simulate individual pathologic cancer conditions implementing alterations/mutations in relevant onco-proteins. We verified some salient model predictions using the mutated colorectal cancer lines HCT116 and HT29. We measured the amount of MYC and CCND1 mRNAs and AKT and ERK phosphorylated proteins, in response to individual or combination onco-protein inhibitor treatments. Experimental and simulation results were well correlated. Recent independently published results were also predicted by our model. Even in the presence of an approximate and incomplete signaling network information, a predictive dynamic modeling seems already possible. An important long term road seems to be open and can be pursued further, by incremental steps, toward even larger and better parameterized MIMs. Personalized treatment strategies with rational associations of signaling-proteins inhibitors, could become a realistic goal.
Funding Details: European Commission - Seventh Framework Programme (FP7)
Irish Research Council
Science Foundation Ireland
University College Dublin
Type of material: Journal Article
Publisher: Impact Journals
Journal: Oncotarget
Volume: 6
Issue: 7
Start page: 5041
End page: 5058
Copyright (published version): 2014 the Authors
Keywords: Colorectal cancerTarget therapiesSignaling-networkDynamic modelingOnco-protein inhibitors
DOI: 10.18632/oncotarget.3238
HEALTH-2011-278568
Language: en
Status of Item: Peer reviewed
Appears in Collections:Conway Institute Research Collection
SBI Research Collection
Medicine Research Collection

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