Early drug development of inhibitors of the insulin-like growth factor-I receptor pathway: lessons from the first clinical trials.
Early drug development of inhibitors of the insulin-like growth factor-I receptor pathway: lessons from the first clinical trials.
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DOI：
10.1158/1535-7163.mct-08-0265
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发表时间：
2008-09
影响因子：
5.7
通讯作者：
Kurzrock R
中科院分区：
文献类型：
--
作者：
Rodon J;DeSantos V;Ferry RJ Jr;Kurzrock R
胰岛素样生长因子-I受体（IGF-IR）于1986年首次被克隆。从那时起，密集的工作已经定义了经典的磷酸化继电器通过IGF-IR激活，调节细胞增殖，凋亡，运动和命运。对激素在癌症中的作用和生长激素-IGF-IGF结合蛋白轴的理解，特别是产生了第二波发展：设计特异性抑制剂，中断与该轴相关的信号传导。操纵这些通路的能力不仅具有重要的治疗意义，而且还增加了对轴在癌发生和转移中的作用的更深入了解的机会。如今，有超过25种具有相同目标的分子处于不同的发展阶段。在这里，我们回顾了临床和临床前的经验与两个最调查的战略，酪氨酸激酶抑制剂和单克隆抗体，和每个策略的优点和缺点，以及其他替代品和可能的药物组合。我们还回顾了在第一次临床试验中探索的生物标志物，迄今为止已经探索的策略，以及将探索其在癌症治疗中的作用的临床试验。
The insulin-like growth factor-I receptor (IGF-IR) was first cloned in 1986. Since then, intense work has defined classic phosphorelays activated via the IGF-IR, which regulate cell proliferation, apoptosis, motility, and fate. The understanding of the roles of hormones in cancer and the growth hormone–IGF–IGF-binding protein axis specifically has yield to a second wave of development: the design of specific inhibitors that interrupt the signaling associated with this axis. The ability to manipulate these pathways holds not only significant therapeutic implications but also increase the chance of deeper insight about the role of the axis in carcinogenesis and metastasis. Nowadays, >25 molecules with the same goal are at different stages of development. Here, we review the clinical and preclinical experience with the two most-investigated strategies, tyrosine kinase inhibitors and monoclonal antibodies, and the advantages and disadvantages of each strategy, as well as other alternatives and possible drug combinations. We also review the bio-markers explored in the first clinical trials, the strategies that have been explored thus far, and the clinical trials that are going to explore their role in cancer treatment.