Imaging the pharmacodynamics of HER2 degradation in response to Hsp90 inhibitors
Imaging the pharmacodynamics of HER2 degradation in response to Hsp90 inhibitors
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DOI：
10.1038/nbt968
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发表时间：
2004-06-01
影响因子：
46.9
通讯作者：
Larson, SM
中科院分区：
文献类型：
--
作者：
Smith-Jones, PM;Solit, DB;Larson, SM
由于无法评估药物对患者靶标的影响，关键信号通路治疗抑制剂的开发受到阻碍。 17-烯丙氨基格尔德霉素 (17-AAG) 是第一个在临床试验中进行测试的 Hsp90 抑制剂。它会导致 HER2 和其他 Hsp90 靶点的降解，并在临床前模型中具有抗肿瘤活性。我们开发了一种对 17-AAG 对 Hsp90 的抑制进行成像的方法。我们用正电子发射体 Ga-68 标记了抗 HER2 抗体赫赛汀的 F(ab) 2 片段，从而可以对 HER2 表达进行连续正电子发射断层扫描成像。我们使用这种方法来量化动物肿瘤中 17-AAG 诱导的 HER2 丢失和恢复随时间的变化。这种方法可以对靶向药物的药效学进行无创成像，并将有助于基于靶点抑制的联合治疗的合理设计。
The development of therapeutic inhibitors of key signaling pathways has been hampered by the inability to assess the effect of a drug on its target in the patient. 17-allylaminogeldanamycin (17-AAG) is the first Hsp90 inhibitor to be tested in a clinical trial. It causes the degradation of HER2 and other Hsp90 targets, and has antitumor activity in preclinical models. We have developed a method for imaging the inhibition of Hsp90 by 17-AAG. We labeled an F( ab) 2 fragment of the anti-HER2 antibody Herceptin with Ga-68, a positron emitter, which allows the sequential positron-emission tomographic imaging of HER2 expression. We have used this method to quantify as a function of time the loss and recovery of HER2 induced by 17-AAG in animal tumors. This approach allows noninvasive imaging of the pharmacodynamics of a targeted drug and will facilitate the rational design of combination therapy based on target inhibition.