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89Zr-trastuzumab PET visualizes HER2 downregulation by the HSP90 inhibitor NVP-AUY922 in a human tumour xenograft

Munnink, T. O. and de Korte, M. and Nagengast, W. and Timmer-Bosscha, H. and Schroeder, C. and de Jong, J. and van Dongen, G. and Jensen, Michael Rugaard and Quadt, Cornelia and Lub-de Hooge, M. and de Vries, E. (2009) 89Zr-trastuzumab PET visualizes HER2 downregulation by the HSP90 inhibitor NVP-AUY922 in a human tumour xenograft. European Journal of Cancer, 46 (3). pp. 678-684. ISSN 0959-8049

Abstract

NVP-AUY922, a potent Heat Shock Protein (HSP) 90 inhibitor, downregulates the expression of many oncogenic proteins, including the Human Epidermal growth factor Receptor 2 (HER2). Because HER2 downregulation is a potential biomarker for early response to HSP90 targeted therapies, we used the 89Zr labelled HER2 antibody trastuzumab to quantify the alterations in HER2 expression after NVP-AUY922 treatment with HER2 positron emission tomography (PET) imaging.
The HER2 overexpressing human SKOV-3 ovarian tumour cell line was used for in vitro experiments and as xenograft model in nude athymic mice. In vitro HER2 membrane expression was assessed by flow cytometry and a radio-immuno assay with 89Zr-trastuzumab. For in vivo evaluation, mice received 50 mg/kg NVP-AUY922 intraperitoneally every other day. 89Zr-trastuzumab was injected intravenously 6 days before NVP-AUY922 treatment and after 3 NVP-AUY922 doses. MicroPET imaging was performed at 24, 72 and 144 h post tracer injection followed by ex-vivo biodistribution and immunohistochemical staining.
After 24 h NVP-AUY922 treatment HER2 membrane expression showed profound reduction with flow cytometry (80%) and radio immuno assay (75%). PET tumour quantification, showed a mean reduction of 41% (P = 0.0001) in 89Zr-trastuzumab uptake at 144 h post tracer injection after NVP-AUY922 treatment. PET results were confirmed by ex-vivo 89Zr-trastuzumab biodistribution and HER2 immunohistochemical staining.
NVP-AUY922 effectively downregulates HER2, which can be monitored and quantified in vivo non-invasively with 89Zr-trastuzumab PET. This technique is currently under clinical evaluation and might serve as an early biomarker for HSP90 inhibition in HER2 positive metastatic breast cancer patients.

Item Type: Article
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Additional Information: Author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
Keywords: HER2; Heat shock protein 90; NVP-AUY922; Zirconium-89; Positron emission tomography; Breast cancer; Biomarker
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Date Deposited: 13 Oct 2015 13:17
Last Modified: 13 Oct 2015 13:17
URI: https://oak.novartis.com/id/eprint/1209

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