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European Journal of Nuclear Medicine and Molecular Imaging

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Open Access 01-05-2016 | Original Article

Molecular imaging of EGFR and CD44v6 for prediction and response monitoring of HSP90 inhibition in an in vivo squamous cell carcinoma model

Authors: Diana Spiegelberg, Anja C. Mortensen, Ram K. Selvaraju, Olof Eriksson, Bo Stenerlöw, Marika Nestor

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 5/2016

Abstract

Purpose

Heat shock protein 90 (HSP90) is essential for the activation and stabilization of numerous oncogenic client proteins. AT13387 is a novel HSP90 inhibitor promoting degradation of oncogenic proteins upon binding, and may also act as a radiosensitizer. For optimal treatment there is, however, the need for identification of biomarkers for patient stratification and therapeutic response monitoring, and to find suitable targets for combination treatments. The aim of this study was to assess the response of surface antigens commonly expressed in squamous cell carcinoma to AT13387 treatment, and to find suitable biomarkers for molecular imaging and radioimmunotherapy in combination with HSP90 inhibition.

Methods

Cancer cell proliferation and radioimmunoassays were used to evaluate the effect of AT13387 on target antigen expression in vitro. Inhibitor effects were then assessed in vivo in mice-xenografts. Animals were treated with AT13387 (5 × 50 mg/kg), and were imaged with PET using either ¹⁸F-FDG or ¹²⁴I-labelled tracers for EGFR and CD44v6, and this was followed by ex-vivo biodistribution analysis and immunohistochemical staining.

Results

AT13387 exposure resulted in high cytotoxicity and possible radiosensitization with IC₅₀ values below 4 nM. Both in vitro and in vivo AT13387 effectively downregulated HSP90 client proteins. PET imaging with ¹²⁴I-cetuximab showed a significant decrease of EGFR in AT13387-treated animals compared with untreated animals. In contrast, the squamous cell carcinoma-associated biomarker CD44v6, visualized with ¹²⁴I-AbD19384 as well as ¹⁸F-FDG uptake, were not significantly altered by AT13387 treatment.

Conclusion

We conclude that AT13387 downregulates HSP90 client proteins, and that molecular imaging of these proteins may be a suitable approach for assessing treatment response. Furthermore, radioimmunotherapy targeting CD44v6 in combination with AT13387 may potentiate the radioimmunotherapy outcome due to radiosensitizing effects of the drug, and could potentially lead to a lower dose to normal tissues.

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Title: Molecular imaging of EGFR and CD44v6 for prediction and response monitoring of HSP90 inhibition in an in vivo squamous cell carcinoma model
Authors: Diana Spiegelberg
Anja C. Mortensen
Ram K. Selvaraju
Olof Eriksson
Bo Stenerlöw
Marika Nestor
Publication date: 01-05-2016
Publisher: Springer Berlin Heidelberg
Published in: European Journal of Nuclear Medicine and Molecular Imaging / Issue 5/2016
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-015-3260-x

At a glance: The STEP trials

Springer Medicine

Molecular imaging of EGFR and CD44v6 for prediction and response monitoring of HSP90 inhibition in an in vivo squamous cell carcinoma model

Abstract

Purpose

Methods

Results

Conclusion

At a glance: The STEP trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

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