Imaging the pharmacodynamics of HER2 degradation in response to Hsp90 inhibitors Journal Article
| Authors: | Smith-Jones, P. M.; Solit, D. B.; Akhurst, T.; Afroze, F.; Rosen, N.; Larson, S. M. |
| Article Title: | 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. |
| Keywords: | signal transduction; controlled study; protein expression; unclassified drug; human cell; clinical trial; nonhuman; antineoplastic agents; drug targeting; positron emission tomography; neoplasms; mouse; animals; mice; imatinib; controlled clinical trial; enzyme inhibition; pharmacodynamics; signaling; protein degradation; epidermal growth factor receptor 2; animal experiment; animal model; protein; antineoplastic activity; xenograft model antitumor assays; cell line, tumor; diagnostic imaging; cetuximab; animalia; blotting, western; antibodies, monoclonal; indium radioisotopes; drug mechanism; isotope labeling; tissue distribution; mice, nude; medical imaging; tumors; protein-serine-threonine kinases; 1-phosphatidylinositol 3-kinase; positron-emission tomography; immunoblotting; heat shock protein 90 inhibitor; heat shock protein 90; hsp90 heat-shock proteins; receptor, erbb-2; tumor model; trastuzumab; molecular probe techniques; retinoic acid; non invasive measurement; 1,4,7,10 tetraazacyclododecane 1,4,7,10 tetraacetic acid; protein inhibitor; benzoquinones; lactams, macrocyclic; rifabutin; geldanamycin; oncogene neu; copper radioisotopes; degradation; therapeutic; antibody labeling; gallium; imaging techniques; heterocyclic compounds, 1-ring; drug dosage; immunoglobulin fab fragments; animal tumors; immunoglobulin f(ab')2 fragment; humans; human; female; priority journal; article; 17 allylaminogeldanamycin; gallium 58 |
| Journal Title: | Nature Biotechnology |
| Volume: | 22 |
| Issue: | 6 |
| ISSN: | 1087-0156 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2004-06-01 |
| Start Page: | 701 |
| End Page: | 706 |
| Language: | English |
| DOI: | 10.1038/nbt968 |
| PROVIDER: | scopus |
| PUBMED: | 15133471 |
| DOI/URL: | |
| Notes: | Nat. Biotechnol. -- Cited By (since 1996):224 -- Export Date: 16 June 2014 -- CODEN: NABIF -- Source: Scopus |
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