Imaging the pharmacodynamics of HER2 degradation in response to Hsp90 inhibitors |
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Authors: | Smith-Jones Peter M Solit David B Akhurst Timothy Afroze Farzana Rosen Neal Larson Steven M |
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Affiliation: | Department of Radiology, Memorial Sloan Kettering Cancer Center, New York 10021, USA. smith-jp@mskcc.org |
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Abstract: | 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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