Oncotarget

Research Papers:

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

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 and Laurence B. Lovat

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Oncotarget. 2017; 8:25080-25096. https://doi.org/10.18632/oncotarget.15340

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Abstract

Mohammed Adil Butt1,2,*, Hayley Pye1,*, Rehan J. Haidry2, Dahmane Oukrif3, Saif-U-Rehman Khan1, Ignazio Puccio1, Michael Gandy1, Halla W. Reinert1, Ellie Bloom1, Mohammed Rashid4, Gokhan Yahioglu5,6, Mahendra P. Deonarain1,5,6, Rifat Hamoudi1, Manuel Rodriguez-Justo3, Marco R. Novelli3, Laurence B. Lovat1,2

1Department for Tissue & Energy, University College London, London, UK

2Upper Gastrointestinal Service, University College London Hospitals NHS Foundation Trust, London, UK

3Department of Pathology, University College London, London, UK

4Department of Oncology, UCL Cancer Institute, London, UK

5Antikor BioPharma, Stevenage Bioscience Catalyst, Hertfordshire, UK

6Department of Chemistry, Imperial College London, London, UK

*These authors have contributed equally to this work

Correspondence to:

Mohammed Adil Butt, email: [email protected]

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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