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Publication Detail
Upregulation of mucin glycoprotein MUC1 in the progression to esophageal adenocarcinoma and therapeutic potential with a targeted photoactive antibody-drug conjugate
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Article
  • Authors:
    Butt MA, Pye H, Haidry R, Oukrif D, Khan S, Puccio I, Gandy M, Reinert H, Bloom E, Rashid M, Yahioglu G, Deonarain M, Hamoudi R, Rodriguez-Justo M, Novelli M, Lovat L
  • Publisher:
    Impact Journals
  • Publication date:
    15/02/2017
  • Journal:
    Oncotarget
  • Status:
    Published
  • Print ISSN:
    1949-2553
  • Keywords:
    antibody-drug conjugate, mucins,, Barrett’s esophagus, esophageal adenocarcinoma, photodynamic therapy
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.
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Div of Surgery & Interventional Sci
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Department of Targeted Intervention
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Research Department of Pathology
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Department of Targeted Intervention
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Research Department of Pathology
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