Nature Biotechnology22, 701 - 706 (2004)
Published online: 9 May 2004; | doi:10.1038/nbt968
Imaging the pharmacodynamics of HER2 degradation in response to Hsp90 inhibitors
Peter M Smith-Jones1, David B Solit2, Timothy Akhurst1, Farzana Afroze1, Neal Rosen2
& Steven M Larson1
1
Nuclear Medicine Service, Box 77, Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA.
2
Department of Medicine and Program in Cell Biology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA.
Correspondence should be addressed to Peter M Smith-Jones smith-jp@mskcc.org
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 68Ga, 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.
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