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

Thijs H. Oude Munnink, Maarten A. de Korte, Wouter B. Nagengast, Hetty Timmer-Bosscha, Carolina P. Schroder, Johan R. de Jong, Guus A. M. S. van Dongen, Michael Rugaard Jensen, Cornelia Quadt, Marjolijn N. Lub-de Hooge, Elisabeth G. E. de Vries*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

78 Citations (Scopus)

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 Zr-89-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 Zr-89-trastuzumab. For in vivo evaluation, mice received 50 mg/kg NVP-AUY922 intraperitoneally every other day. Zr-89-trastuzumab was injected intravenously 6 d 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 Zr-89-trastuzumab uptake at 144 h post tracer injection after NVP-AUY922 treatment. PET results were confirmed by ex-vivo Zr-89-trastuzumab biodistribution and HER2 immunohistochemical staining.

NVP-AUY922 effectively downregulates HER2, which can be monitored and quantified in vivo non-invasively with Zr-89-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. (C) 2009 Elsevier Ltd. All rights reserved.

Original languageEnglish
Pages (from-to)678-684
Number of pages7
JournalEuropean Journal of Cancer
Volume46
Issue number3
DOIs
Publication statusPublished - Feb-2010

Keywords

  • HER2
  • Heat shock protein 90
  • NVP-AUY922
  • Zirconium-89
  • Positron emission tomography
  • Breast cancer
  • Biomarker
  • HEAT-SHOCK PROTEINS
  • BREAST-CANCER
  • HEAT-SHOCK-PROTEIN-90 INHIBITOR
  • DEGRADATION
  • THERAPY
  • TRASTUZUMAB
  • EXPRESSION
  • GROWTH
  • 17-AAG
  • ERBB2

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