Hixon Mary L, Paccagnella Luisa, Millham Robert, Perez-Olle Raul, Gualberto Antonio
Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School of Brown University, Providence, RI, USA.
Rev Recent Clin Trials. 2010 Sep;5(3):189-208. doi: 10.2174/157488710792007329.
Progress has been made towards the development of agents targeting tyrosine kinase receptors and other molecules involved in signalling pathways important for cell proliferation, motility, and apoptosis. Inhibitor molecules designed to be highly specific with the aim of decreasing toxicity have proven to be generally well tolerated. However, the efficacy of targeted agents may be impacted by cross-talk between pathways and downregulation of negative feed-back loops. That is the case of the IGF-IR/PI3K/Akt/mTOR pathway. This issue raises the question of how these targeted agents could be combined to prevent or delay resistance without significantly increasing toxicity. Several mTOR inhibitors have been approved for cancer therapy, and late-stage clinical trials of IGF-IR inhibitors are underway. The outcome of ongoing clinical studies of IGF-IR, PI3K, Akt and mTOR inhibitors as well as further testing of the combination of these agents will be key for the development of therapeutic options in a wide range of oncology indications.
在开发针对酪氨酸激酶受体以及参与对细胞增殖、运动和凋亡至关重要的信号通路的其他分子的药物方面已经取得了进展。旨在高度特异性以降低毒性而设计的抑制剂分子已被证明通常耐受性良好。然而，靶向药物的疗效可能会受到信号通路之间的串扰和负反馈回路下调的影响。胰岛素样生长因子1受体/磷脂酰肌醇-3-激酶/蛋白激酶B/哺乳动物雷帕霉素靶蛋白（IGF-IR/PI3K/Akt/mTOR）信号通路就是这种情况。这个问题引发了一个疑问，即如何将这些靶向药物联合使用以预防或延迟耐药性，同时又不会显著增加毒性。几种mTOR抑制剂已被批准用于癌症治疗，IGF-IR抑制剂的晚期临床试验正在进行中。正在进行的IGF-IR、PI3K、Akt和mTOR抑制剂临床研究的结果以及这些药物联合使用的进一步测试，对于开发广泛肿瘤学适应症的治疗选择至关重要。
