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