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Imaging the pharmacodynamics of HER2 degradation in response to Hsp90 inhibitors

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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Figure 1: Evaluation of DOTA-Herceptin in tumor-bearing nude mice.
Figure 2
Figure 3: MicroPET images (coronal slice and transverse slice through tumor and kidneys) of two different nude mice with single BT-474 tumors.
Figure 4
Figure 5: Monitoring the effect of 17-AAG on tumor HER2 expression.
Figure 6

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Acknowledgements

Department of Energy 95ER62039 (S.M.L. & P.M.S.J.), National Cancer Institute PO1 CA94060 (S.M.L., N.R. & D.B.S.), National Cancer Institute P50 CA86438 (S.M.L., N.R., D.B.S. & P.M.S.J.), D.E.J. Burke Fund for Prostate Cancer Research (F.A.) and the Taub Foundation (N.R. & D.B.S.). D.B.S. is supported in part by an American Society of Clinical Oncology/Career Development Award. The production of 64Cu at Washington University is supported by a grant from the National Cancer Institute (CA86307).

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Correspondence to Peter M Smith-Jones.

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Smith-Jones, P., Solit, D., Akhurst, T. et al. Imaging the pharmacodynamics of HER2 degradation in response to Hsp90 inhibitors. Nat Biotechnol 22, 701–706 (2004). https://doi.org/10.1038/nbt968

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