A mathematical model of combination therapy using the EGFR signaling network
A mathematical model of combination therapy using the EGFR signaling network
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DOI：
10.1016/j.biosystems.2004.10.002
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发表时间：
2005-04-01
期刊：
影响因子：
1.6
通讯作者：
Liotta, LA
中科院分区：
文献类型：
--
作者：
Araujo, RP;Petricoin, EF;Liotta, LA
随着人们对异常信号转导在肿瘤中的重要性的认识不断提高，以及靶向药物选择性调节异常激活的信号转导途径的发展，已经产生了各种有前途的癌症治疗新策略。本文使用数学建模来研究一种新型的组合疗法，其中信号级联中的多个节点同时被选择性抑制剂靶向，追求这样的假设，即这种方法可能会诱导所需的信号衰减与较低剂量的必要的代理比当一个节点被单独靶向。一个数学模型，建立在以前的理论工作EGFR信号，模拟管理多种激酶抑制剂在各种组合的效果。该模型表明，当多个上游过程被抑制时，与抑制单个上游过程相比，生化信号的衰减显著增强。此外，这种增强的衰减在串联连接的目标点的下游信号中最为明显。此外，由于网络参数和信号之间的高度非线性关系，串联过程的抑制似乎对下游信号的衰减具有超加性（协同）效应。(c)2004爱思唯尔爱尔兰有限公司保留所有权利。
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. (c) 2004 Elsevier Ireland Ltd. All rights reserved.