Apologies if anyone already posted this (I've been busy with other stuff recently) -
Nature Biotechnology 22, 701 - 706 (2004)
Published online: 09 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...
This was of interest in the discussion section -
...The Hsp90 inhibitor 17-AAG is in phase 1 clinical trials. However, it is not clear whether the doses and schedule with which the drug is being administered affect the target in the tumor. We will use this technique in breast cancer patients whose tumors express high levels of HER2 to answer these questions...Empirical determination of the kinetics and magnitude of the decline in HER2 expression as a function of different schedules in preclinical and clinical models will allow formulation of a rational schedule that allows maximal inhibition of the target... |
