Monitoring therapeutic response of human ovarian cancer to 17-DMAG by noninvasive PET imaging with (64)Cu-DOTA-trastuzumab.
OBJECTIVE
17-Dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat-shock protein 90 (Hsp90) inhibitor, has been intensively investigated for cancer therapy and is undergoing clinical trials. Human epidermal growth factor receptor 2 (HER-2) is one of the client proteins of Hsp90 and its expression is decreased upon 17-DMAG treatment. In this study, we aimed to noninvasively monitor the HER-2 response to 17-DMAG treatment in xenografted mice.


METHODS
The sensitivity of human ovarian cancer SKOV-3 cells to 17-DMAG in vitro was measured by MTT assay. HER-2 expression in SKOV-3 cells was determined by flow cytometry. Nude mice bearing SKOV-3 tumors were treated with 17-DMAG and the therapeutic efficacy was evaluated by tumor size measurement. Both treated and control mice were imaged with microPET using (64)Cu-DOTA-trastuzumab and (18)F-FDG. Biodistribution studies and immunofluorescence staining were performed to validate the microPET results.


RESULTS
SKOV-3 cells are sensitive to 17-DMAG treatment, in a dose-dependent manner, with an IC(50) value of 24.72 nM after 72 h incubation. The tumor growth curve supported the inhibition effect of 17-DMAG on SKOV-3 tumors. Quantitative microPET imaging showed that (64)Cu-DOTA-trastuzumab had prominent tumor accumulation in untreated SKOV-3 tumors, which was significantly reduced in 17-DMAG-treated tumors. There was no uptake difference detected by FDG PET. Immunofluorescence staining confirmed the significant reduction in tumor HER-2 level upon 17-DMAG treatment.


CONCLUSIONS
The early response to anti-Hsp90 therapy was successfully monitored by quantitative PET using (64)Cu-DOTA-trastuzumab. This approach may be valuable in monitoring the therapeutic response in HER-2-positive cancer patients under 17-DMAG treatment.
The Molecular Imaging Program at Stanford (MIPS), Department of Radiology and Bio-X Program, Stanford University School of Medicine, 1201 Welch Rd, P095, Stanford, CA 94305-5484, USA.
Gang
G
Niu
Zibo
Z
Li
Qizhen
Q
Cao
Xiaoyuan
X
Chen
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized; D016227:Benzoquinones / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003301:Copper Radioisotopes; D005260:Female; D019788:Fluorodeoxyglucose F18; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009942:Organometallic Compounds / Q000493:pharmacokinetics; D010051:Ovarian Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy; D049268:Positron-Emission Tomography; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis; D014018:Tissue Distribution; D000068878:Trastuzumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D016227:Benzoquinones; D003301:Copper Radioisotopes; D019788:Fluorodeoxyglucose F18; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D009942:Organometallic Compounds; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C546788:64Cu-DOTA-trastuzumab; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin