title: A mathematical model of combination therapy using the EGFR signaling network.
abstract: An increasing awareness of the significance of abnormal signal transduction in tumors and the concomitant development of target-based drugs to selectively modulate aberrantly-activated signaling pathways has given rise to a variety of promising new strategies in cancer treatment. This paper uses mathematical modeling to investigate a novel type of combination therapy in which multiple nodes in a signaling cascade are targeted simultaneously with selective inhibitors, pursuing the hypothesis that such an approach may induce the desired signal attenuation with lower doses of the necessary agents than when one node is targeted in isolation. A mathematical model is presented which builds upon previous theoretical work on EGFR signaling, simulating the effect of administering multiple kinase inhibitors in various combinations. The model demonstrates that attenuation of biochemical signals is significantly enhanced when multiple upstream processes are inhibited, in comparison with the inhibition of a single upstream process. Moreover, this enhanced attenuation is most pronounced in signals downstream of serially-connected target points. In addition, the inhibition of serially-connected processes appears to have a supra-additive (synergistic) effect on the attenuation of downstream signals, owing to the highly non-linear relationships between network parameters and signals.
authors.affiliation: FDA-NCI Clinical Proteomics Program, Laboratory of Pathology, Center for Cancer Research, NCI/NIH, 8800 Rockville Pike, Building 29A, HFM 710, Bethesda, MD 20892, USA. araujor@mail.nih.gov
authors.forename: R P
authors.initials: RP
authors.lastname: Araujo
authors.forename: E F
authors.initials: EF
authors.lastname: Petricoin
authors.forename: L A
authors.initials: LA
authors.lastname: Liotta
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D003198:Computer Simulation; D016503:Drug Delivery Systems / Q000379:methods; D015195:Drug Design; D004360:Drug Therapy, Computer-Assisted / Q000379:methods*; D066246:ErbB Receptors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D009363:Neoplasm Proteins; D066246:ErbB Receptors