Non-invasive PET imaging of EGFR degradation induced by a heat shock protein 90 inhibitor.
OBJECTIVE
The aim of this study is to non-invasively monitor the epidermal growth factor receptor (EGFR) response to a Hsp90 inhibitor-17-AAG treatment in a PC-3 prostate cancer model.


METHODS
Nude mice bearing PC-3 tumor were injected intraperitoneally with 17-AAG and then imaged with micro positron emission tomography (microPET) using (64)Cu-DOTA-cetuximab. Biodistribution studies, immunofluorescence staining, and Western blot were performed to validate the microPET results.


RESULTS
PC-3 cells are sensitive to 17-AAG treatment in a dose-dependent manner. Quantitative microPET showed that (64)Cu-DOTA-cetuximab has prominent tumor activity accumulation in untreated tumors (14.6 +/- 2.6%ID/g) but significantly lower uptake in 17-AAG-treated tumors (8.9 +/- 1.6% ID/g) at 24 h post-injection. Both immunofluorescence staining and Western blot confirmed the significantly lower EGFR expression level in the tumor tissue upon 17-AAG treatment.


CONCLUSIONS
The early response to anti-Hsp90 therapy was successfully monitored by quantitative PET using (64)Cu-DOTA-cetuximab, which indicates that this approach may be valuable in monitoring the therapeutic response to Hsp90 inhibitor 17-AAG in EGFR-positive cancer patients.
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D016227:Benzoquinones / Q000493:pharmacokinetics / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000068818:Cetuximab; D066246:ErbB Receptors / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006573:Heterocyclic Compounds, 1-Ring / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D047029:Lactams, Macrocyclic / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D049268:Positron-Emission Tomography / Q000379:methods*; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D014018:Tissue Distribution / Q000187:drug effects
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D006573:Heterocyclic Compounds, 1-Ring; D047029:Lactams, Macrocyclic; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; C112765:tanespimycin; D066246:ErbB Receptors; D000068818:Cetuximab