title: Upregulation of mucin glycoprotein MUC1 in the progression to esophageal adenocarcinoma and therapeutic potential with a targeted photoactive antibody-drug conjugate.
abstract: BACKGROUND
  Mucin glycoprotein 1 (MUC1) is a glycosylated transmembrane protein on epithelial cells. We investigate MUC1 as a therapeutic target in Barrett's epithelium (BE) and esophageal adenocarcinoma (EA) and provide proof of concept for a light based therapy targeting MUC1.
  
  
  RESULTS
  MUC1 was present in 21% and 30% of significantly enriched pathways comparing BE and EA to squamous epithelium respectively. MUC1 gene expression was x2.3 and x2.2 higher in BE (p=<0.001) and EA (p=0.03). MUC1 immunohistochemical expression increased during progression to EA and followed tumor invasion. HuHMFG1 based photosensitive antibody drug conjugates (ADC) showed cell internalization, MUC1 selective and light-dependent cytotoxicity (p=0.0006) and superior toxicity over photosensitizer alone (p=0.0022).
  
  
  METHODS
  Gene set enrichment analysis (GSEA) evaluated pathways during BE and EA development and quantified MUC1 gene expression. Immunohistochemistry and flow cytometry evaluated the anti-MUC1 antibody HuHMFG1 in esophageal cells of varying pathological grade. Confocal microscopy examined HuHMFG1 internalization and HuHMFG1 ADCs were created to deliver a MUC1 targeted phototoxic payload.
  
  
  CONCLUSIONS
  MUC1 is a promising target in EA. Molecular and light based targeting of MUC1 with a photosensitive ADC is effective in vitro and after development may enable treatment of locoregional tumors endoscopically.
authors.affiliation: Department for Tissue & Energy, University College London, London, UK.|Upper Gastrointestinal Service, University College London Hospitals NHS Foundation Trust, London, UK.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Adil Butt
authors.affiliation: Department for Tissue & Energy, University College London, London, UK.
authors.forename: Hayley
authors.initials: H
authors.lastname: Pye
authors.affiliation: Upper Gastrointestinal Service, University College London Hospitals NHS Foundation Trust, London, UK.
authors.forename: Rehan J
authors.initials: RJ
authors.lastname: Haidry
authors.affiliation: Department of Pathology, University College London, London, UK.
authors.forename: Dahmane
authors.initials: D
authors.lastname: Oukrif
authors.affiliation: Department for Tissue & Energy, University College London, London, UK.
authors.forename: Saif-U-Rehman
authors.initials: SU
authors.lastname: Khan
authors.affiliation: Department for Tissue & Energy, University College London, London, UK.
authors.forename: Ignazio
authors.initials: I
authors.lastname: Puccio
authors.affiliation: Department for Tissue & Energy, University College London, London, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Gandy
authors.affiliation: Department for Tissue & Energy, University College London, London, UK.
authors.forename: Halla W
authors.initials: HW
authors.lastname: Reinert
authors.affiliation: Department for Tissue & Energy, University College London, London, UK.
authors.forename: Ellie
authors.initials: E
authors.lastname: Bloom
authors.affiliation: Department of Oncology, UCL Cancer Institute, London, UK.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Rashid
authors.affiliation: Antikor BioPharma, Stevenage Bioscience Catalyst, Hertfordshire, UK.|Department of Chemistry, Imperial College London, London, UK.
authors.forename: Gokhan
authors.initials: G
authors.lastname: Yahioglu
authors.affiliation: Department for Tissue & Energy, University College London, London, UK.|Antikor BioPharma, Stevenage Bioscience Catalyst, Hertfordshire, UK.|Department of Chemistry, Imperial College London, London, UK.
authors.forename: Mahendra P
authors.initials: MP
authors.lastname: Deonarain
authors.affiliation: Department for Tissue & Energy, University College London, London, UK.
authors.forename: Rifat
authors.initials: R
authors.lastname: Hamoudi
authors.affiliation: Department of Pathology, University College London, London, UK.
authors.forename: Manuel
authors.initials: M
authors.lastname: Rodriguez-Justo
authors.affiliation: Department of Pathology, University College London, London, UK.
authors.forename: Marco R
authors.initials: MR
authors.lastname: Novelli
authors.affiliation: Department for Tissue & Energy, University College London, London, UK.|Upper Gastrointestinal Service, University College London Hospitals NHS Foundation Trust, London, UK.
authors.forename: Laurence B
authors.initials: LB
authors.lastname: Lovat
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000074322:Antineoplastic Agents, Immunological / Q000494:pharmacology*; D015415:Biomarkers; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019295:Computational Biology; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology*; D007150:Immunohistochemistry; D008027:Light; D018396:Mucin-1 / Q000235:genetics* / Q000378:metabolism; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis
chemical_list: D000074322:Antineoplastic Agents, Immunological; D015415:Biomarkers; D006023:Glycoproteins; D018796:Immunoconjugates; C060192:MUC1 protein, human; D018396:Mucin-1
keywords: Barrett’s esophagus; antibody-drug conjugate; esophageal adenocarcinoma; mucins; photodynamic therapy