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  • Upregulation of mucin glycoprotein MUC1 in the progression to esophageal adenocarcinoma and therapeutic potential with a targeted photoactive antibody-drug conjugate.

Upregulation of mucin glycoprotein MUC1 in the progression to esophageal adenocarcinoma and therapeutic potential with a targeted photoactive antibody-drug conjugate.

Oncotarget (2017-02-18)
Mohammed Adil Butt, Hayley Pye, Rehan J Haidry, Dahmane Oukrif, Saif-U-Rehman Khan, Ignazio Puccio, Michael Gandy, Halla W Reinert, Ellie Bloom, Mohammed Rashid, Gokhan Yahioglu, Mahendra P Deonarain, Rifat Hamoudi, Manuel Rodriguez-Justo, Marco R Novelli, Laurence B Lovat
ABSTRACT

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. 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). 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. 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
ExtrAvidin®−Peroxidase, buffered aqueous solution
Sigma-Aldrich
Anti-Human IgG (Fab specific)−FITC antibody produced in goat, affinity isolated antibody, buffered aqueous solution

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