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Monitoring therapeutic response of human ovarian cancer to 17-DMAG by noninvasive PET imaging with 64Cu-DOTA-trastuzumab

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

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 64Cu-DOTA-trastuzumab and 18F-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 IC50 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 64Cu-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.

Conclusion

The early response to anti-Hsp90 therapy was successfully monitored by quantitative PET using 64Cu-DOTA-trastuzumab. This approach may be valuable in monitoring the therapeutic response in HER-2-positive cancer patients under 17-DMAG treatment.

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Acknowledgement

This work was supported by the National Cancer Institute (NCI) P50 CA114747 and a DOD Prostate Postdoctoral Fellowship from Department of Defense (to G. Niu).

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Authors and Affiliations

  1. 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 Niu, Zibo Li, Qizhen Cao & Xiaoyuan Chen

  2. USC Molecular Imaging Center, Department of Radiology, Keck School of Medicine, Los Angeles, CA, USA

    Zibo Li

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  1. Gang Niu
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Correspondence to Xiaoyuan Chen.

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Niu, G., Li, Z., Cao, Q. et al. Monitoring therapeutic response of human ovarian cancer to 17-DMAG by noninvasive PET imaging with 64Cu-DOTA-trastuzumab. Eur J Nucl Med Mol Imaging 36, 1510–1519 (2009). https://doi.org/10.1007/s00259-009-1158-1

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