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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.
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Butt MA, Pye H, Haidry RJ, Oukrif D, Khan SU, Puccio I, Gandy M, Reinert HW, Bloom E, Rashid M, Yahioglu G, Deonarain MP, Hamoudi R, Rodriguez-Justo M, Novelli MR, Lovat LB,


Butt MA, Pye H, Haidry RJ, Oukrif D, Khan SU, Puccio I, Gandy M, Reinert HW, Bloom E, Rashid M, Yahioglu G, Deonarain MP, Hamoudi R, Rodriguez-Justo M, Novelli MR, Lovat LB, (click to view)

Butt MA, Pye H, Haidry RJ, Oukrif D, Khan SU, Puccio I, Gandy M, Reinert HW, Bloom E, Rashid M, Yahioglu G, Deonarain MP, Hamoudi R, Rodriguez-Justo M, Novelli MR, Lovat LB,

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Oncotarget 2017 02 15() doi 10.18632/oncotarget.15340
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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