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

Published on Feb 15, 2017in Oncotarget
· DOI :10.18632/ONCOTARGET.15340
Mohammed A. Butt9
Estimated H-index: 9
(UCL: University College London),
Hayley Pye9
Estimated H-index: 9
(UCL: University College London)
+ 13 AuthorsLaurence Lovat36
Estimated H-index: 36
// Mohammed Adil Butt 1, 2, * , Hayley Pye 1, * , Rehan J. Haidry 2 , Dahmane Oukrif 3 , Saif-U-Rehman Khan 1 , Ignazio Puccio 1 , Michael Gandy 1 , Halla W. Reinert 1 , Ellie Bloom 1 , Mohammed Rashid 4 , Gokhan Yahioglu 5, 6 , Mahendra P. Deonarain 1, 5, 6 , Rifat Hamoudi 1 , Manuel Rodriguez-Justo 3 , Marco R. Novelli 3 , Laurence B. Lovat 1, 2 1 Department for Tissue & Energy, University College London, London, UK 2 Upper Gastrointestinal Service, University College London Hospitals NHS Foundation Trust, London, UK 3 Department of Pathology, University College London, London, UK 4 Department of Oncology, UCL Cancer Institute, London, UK 5 Antikor BioPharma, Stevenage Bioscience Catalyst, Hertfordshire, UK 6 Department of Chemistry, Imperial College London, London, UK * These authors have contributed equally to this work Correspondence to: Mohammed Adil Butt, email: adil.butt@nhs.net Keywords: antibody-drug conjugate, mucins, Barrett’s esophagus, esophageal adenocarcinoma, photodynamic therapy Received: August 11, 2016      Accepted: January 24, 2017      Published: February 15, 2017 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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