title: Visualising dual downregulation of insulin-like growth factor receptor-1 and vascular endothelial growth factor-A by heat shock protein 90 inhibition effect in triple negative breast cancer.
abstract: OBJECTIVE
  Triple negative breast cancer (TNBC) is biologically characterised by heterogeneous presence of molecular pathways underlying it. Insulin-like growth factor receptor-1 (IGF-1R) expression and vascular endothelial growth factor-A (VEGF-A) have been identified as key factors in these pathways in TNBC. In this study, we aimed at in vivo PET imaging the effect of heat shock protein (Hsp) 90 inhibition by means of NVP-AUY922 on these pathways, with zirconium-89 ((89)Zr) labelled antibodies targeting IGF-1R and VEGF-A.
  
  
  METHODS
  In vitro NVP-AUY922 effects on cellular IGF-1R expression and VEGF-A secretion were determined in MCF-7 and MDA-MB-231 cell lines. Moreover human TNBC bearing MDA-MB-231 mice received 50mg/kg NVP-AUY922 or vehicle q3d intraperitoneally for 21days. PET scans with (89)Zr-MAB391 and (89)Zr-bevacizumab for visualisation of IGF-1R and VEGF-A were performed before and during treatment. Ex vivo biodistribution and correlative tissue analyses were performed.
  
  
  RESULTS
  NVP-AUY922 treatment reduced IGF-1R expression and VEGF-A excretion in both cell lines. Hsp90 inhibition lowered tumour uptake on (89)Zr-MAB391-PET by 37.3% (P<0.01) and on (89)Zr-bevacizumab-PET by 44.4% (P<0.01). This was confirmed by ex vivo biodistribution with a reduction of 41.3% injected dose (ID)/g for (89)Zr-MAB391 and 37.8% ID/g for (89)Zr-bevacizumab, while no differences were observed for other tissues. This coincided with reduced IGF-1R expression and mean vessel density in the NVP-AUY922 treated tumours.
  
  
  CONCLUSIONS
  (89)Zr-MAB391 and (89)Zr-bevacizumab PET reflect effect of Hsp90 inhibitors and can therefore potentially be used to monitor therapeutic effects of Hsp90 inhibitor therapy in TNBC.
authors.affiliation: Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Department of Hospital and Clinical Pharmacy, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Anton G T
authors.initials: AG
authors.lastname: Terwisscha van Scheltinga
authors.affiliation: Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Paul
authors.initials: P
authors.lastname: Berghuis
authors.affiliation: Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Hilde H
authors.initials: HH
authors.lastname: Nienhuis
authors.affiliation: Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Hetty
authors.initials: H
authors.lastname: Timmer-Bosscha
authors.affiliation: Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Linda
authors.initials: L
authors.lastname: Pot
authors.affiliation: Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Sietske B M
authors.initials: SB
authors.lastname: Gaykema
authors.affiliation: Department of Hospital and Clinical Pharmacy, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Marjolijn N
authors.initials: MN
authors.lastname: Lub-de Hooge
authors.affiliation: Department of Hospital and Clinical Pharmacy, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Jos G W
authors.initials: JG
authors.lastname: Kosterink
authors.affiliation: Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Elisabeth G E
authors.initials: EG
authors.lastname: de Vries
authors.affiliation: Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. Electronic address: c.p.schroder@umcg.nl.
authors.forename: Carolien P
authors.initials: CP
authors.lastname: Schröder
mesh_terms: D000818:Animals; D015536:Down-Regulation; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D012118:Resorcinols / Q000494:pharmacology*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D012118:Resorcinols; D042461:Vascular Endothelial Growth Factor A; D017526:Receptor, IGF Type 1
keywords: Biomarker; Hsp90 inhibition; IGF-1R; PET; Triple negative breast cancer; VEGF-A; Zirconium-89