Upregulation of Mucin Glycoprotein MUC1 in the Progression to Esophageal Adenocarcinoma and Therapeutic Potential with a Targeted Photoactive Antibody-drug Conjugate

Overview

Journal Oncotarget

Specialty Oncology

Date 2017 Feb 18

PMID 28212575

Citations 11

Authors

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

Affiliations

Soon will be listed here.

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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