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.
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York 10021, USA. smith-jp@mskcc.org
authors.forename: Peter M
authors.initials: PM
authors.lastname: Smith-Jones
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
authors.forename: Timothy
authors.initials: T
authors.lastname: Akhurst
authors.forename: Farzana
authors.initials: F
authors.lastname: Afroze
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
authors.forename: Steven M
authors.initials: SM
authors.lastname: Larson
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D016227:Benzoquinones; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003301:Copper Radioisotopes; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry; D006801:Humans; D015151:Immunoblotting; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000494:pharmacology; D007205:Indium Radioisotopes; D007553:Isotope Labeling; D047029:Lactams, Macrocyclic; D051379:Mice; D008819:Mice, Nude; D015336:Molecular Probe Techniques; D009369:Neoplasms / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism*; D017828:Rifabutin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014018:Tissue Distribution; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D016227:Benzoquinones; D003301:Copper Radioisotopes; D018841:HSP90 Heat-Shock Proteins; D006573:Heterocyclic Compounds, 1-Ring; D007140:Immunoglobulin Fab Fragments; D007205:Indium Radioisotopes; D047029:Lactams, Macrocyclic; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D017828:Rifabutin; D000068878:Trastuzumab; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; C112765:tanespimycin