title: Mucolytic Agents Can Enhance HER2 Receptor Accessibility for [(89)Zr]Trastuzumab, Improving HER2 Imaging in a Mucin-Overexpressing Breast Cancer Xenograft Mouse Model.
abstract: OBJECTIVE
  Binding of trastuzumab to HER2 receptors can be impaired by steric hindrance caused by mucin MUC4. As mucolytic drugs can breakdown disulfide bonds of mucoproteins, we checked if this approach could positively affect zirconium-89-labeled trastuzumab ([(89)Zr]T) binding/uptake.
  
  
  METHODS
  The effect of N-acetylcysteine (NAC) and MUC4 knockdown/stimulation on [(89)Zr]T binding/uptake were evaluated in MCF7(HER2-), BT474 and SKBr3(HER2+/MUC4-), and JIMT1(HER2+/MUC4+) cell lines. The results were then validated in SKBR3 and JIMT1 tumor-bearing nude mice with a microPET-CT and ex vivo analysis.
  
  
  RESULTS
  Significant increases in [(89)Zr]T binding/uptake were observed in JIMT1 cells following MUC4 knockdown (62.4 ± 6.5%) and exposure to NAC (62.8 ± 19.4%). Compared to controls, mice treated with NAC showed a significant increase in [(89)Zr]T uptake in MUC4 tumors on microPET-CT (SUVmean (18.3 ± 4.7%), SUVmax (41.7 ± 8.4%)) and individual organ counting (37.3 ± 18.3%). In contrast, no significant differences were observed in SKBr3.
  
  
  CONCLUSIONS
  NAC can enhance [(89)Zr]T accumulation and improve the HER2 imaging of MUC4-overexpressing tumors. The potential positive impact on trastuzumab-based treatment deserves further investigation.
authors.affiliation: Nuclear Medicine Department, Institut Jules Bordet, Université Libre de Bruxelles, 1 rue Heger-Bordet, 1000, Brussels, Belgium. zena.wimana@bordet.be.|Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium. zena.wimana@bordet.be.
authors.forename: Zéna
authors.initials: Z
authors.lastname: Wimana
authors.affiliation: Nuclear Medicine Department, Institut Jules Bordet, Université Libre de Bruxelles, 1 rue Heger-Bordet, 1000, Brussels, Belgium.
authors.forename: G
authors.initials: G
authors.lastname: Gebhart
authors.affiliation: Nuclear Medicine Department, Institut Jules Bordet, Université Libre de Bruxelles, 1 rue Heger-Bordet, 1000, Brussels, Belgium.
authors.forename: T
authors.initials: T
authors.lastname: Guiot
authors.affiliation: Nuclear Medicine Department, Institut Jules Bordet, Université Libre de Bruxelles, 1 rue Heger-Bordet, 1000, Brussels, Belgium.
authors.forename: B
authors.initials: B
authors.lastname: Vanderlinden
authors.affiliation: Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: R
authors.initials: R
authors.lastname: Morandini
authors.affiliation: Center for Microscopy and Molecular Imaging (CMMI), Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: G
authors.initials: G
authors.lastname: Doumont
authors.affiliation: Center for Microscopy and Molecular Imaging (CMMI), Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: F
authors.initials: F
authors.lastname: Sherer
authors.affiliation: Center for Microscopy and Molecular Imaging (CMMI), Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: G
authors.initials: G
authors.lastname: Van Simaeys
authors.affiliation: Center for Microscopy and Molecular Imaging (CMMI), Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: S
authors.initials: S
authors.lastname: Goldman
authors.affiliation: Nuclear Medicine Department, Institut Jules Bordet, Université Libre de Bruxelles, 1 rue Heger-Bordet, 1000, Brussels, Belgium.|Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: G
authors.initials: G
authors.lastname: Ghanem
authors.affiliation: Nuclear Medicine Department, Institut Jules Bordet, Université Libre de Bruxelles, 1 rue Heger-Bordet, 1000, Brussels, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Flamen
mesh_terms: D000111:Acetylcysteine; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D005100:Expectorants / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D057054:Molecular Imaging / Q000379:methods*; D055264:Mucin-4 / Q000235:genetics / Q000378:metabolism; D009077:Mucins / Q000187:drug effects*; D049268:Positron-Emission Tomography / Q000379:methods; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D000111:Acetylcysteine; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D005100:Expectorants; D055264:Mucin-4; D009077:Mucins; D018719:Erb-b2 Receptor Tyrosine Kinases; C524659:Muc4 protein, mouse; C571668:zirconium-89-trastuzumab
keywords: HER2; ImmunoPET; MUC4; N-Acetylcysteine; [89Zr]Trastuzumab