title: Systems medicine in colorectal cancer: from a mathematical model toward a new type of clinical trial.
abstract: Current colorectal cancer (CRC) treatment guidelines are primarily based on clinical features, such as cancer stage and grade. However, outcomes may be improved using molecular treatment guidelines. Potentially useful biomarkers include driver mutations and somatically inherited alterations, signaling proteins (their expression levels and (post) translational modifications), mRNAs, micro-RNAs and long noncoding RNAs. Moving to an integrated system is potentially very relevant. To implement such an integrated system: we focus on an important region of the signaling network, immediately above the G1-S restriction point, and discuss the reconstruction of a Molecular Interaction Map and interrogating it with a dynamic mathematical model. Extensive model pretraining achieved satisfactory, validated, performance. The model helps to propose future target combination priorities, and restricts drastically the number of drugs to be finally tested at a cellular, in vivo, and clinical-trial level. Our model allows for the inclusion of the unique molecular profiles of each individual patient's tumor. While existing clinical guidelines are well established, dynamic modeling may be used for future targeted combination therapies, which may progressively become part of clinical practice within the near future. WIREs Syst Biol Med 2016, 8:314-336. doi: 10.1002/wsbm.1342 For further resources related to this article, please visit the WIREs website.
authors.affiliation: Department of Internal Medicine and Medical Specializations (DIMI), University of Genoa, Genoa, Italy.|IRCCS Azienda Ospedaliera Universitaria San Martino-IST, Genoa, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Castagnino
authors.affiliation: Department of Internal Medicine and Medical Specializations (DIMI), University of Genoa, Genoa, Italy.|IRCCS Azienda Ospedaliera Universitaria San Martino-IST, Genoa, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Maffei
authors.affiliation: Department of Internal Medicine and Medical Specializations (DIMI), University of Genoa, Genoa, Italy.|IRCCS Azienda Ospedaliera Universitaria San Martino-IST, Genoa, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Tortolina
authors.affiliation: Department of Internal Medicine and Medical Specializations (DIMI), University of Genoa, Genoa, Italy.|IRCCS Azienda Ospedaliera Universitaria San Martino-IST, Genoa, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Zoppoli
authors.affiliation: Department of Internal Medicine and Medical Specializations (DIMI), University of Genoa, Genoa, Italy.|IRCCS Azienda Ospedaliera Universitaria San Martino-IST, Genoa, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Piras
authors.affiliation: Department of Internal Medicine and Medical Specializations (DIMI), University of Genoa, Genoa, Italy.|IRCCS Azienda Ospedaliera Universitaria San Martino-IST, Genoa, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Nencioni
authors.affiliation: Department of Internal Medicine and Medical Specializations (DIMI), University of Genoa, Genoa, Italy.
authors.forename: Eva
authors.initials: E
authors.lastname: Moran
authors.affiliation: Department of Internal Medicine and Medical Specializations (DIMI), University of Genoa, Genoa, Italy.|IRCCS Azienda Ospedaliera Universitaria San Martino-IST, Genoa, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ballestrero
authors.affiliation: Department of Internal Medicine and Medical Specializations (DIMI), University of Genoa, Genoa, Italy.|IRCCS Azienda Ospedaliera Universitaria San Martino-IST, Genoa, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Patrone
authors.affiliation: Department of Internal Medicine and Medical Specializations (DIMI), University of Genoa, Genoa, Italy.|IRCCS Azienda Ospedaliera Universitaria San Martino-IST, Genoa, Italy.
authors.forename: Silvio
authors.initials: S
authors.lastname: Parodi
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism; D008962:Models, Theoretical; D020641:Polymorphism, Single Nucleotide; D017410:Practice Guidelines as Topic; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D035683:MicroRNAs; D012333:RNA, Messenger