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 Weihe Reinert; Ellie Bloom; Mohammed Rashid; Gokhan Yahioglu; Mahendra P. Deonarain; Rifat Hamoudi; Manuel Rodriguez-Justo; Marco R. Novelli; Laurence B. Lovat

doi:10.18632/oncotarget.15340

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 Weihe Reinert, Ellie Bloom, Mohammed Rashid, Gokhan Yahioglu, Mahendra P. Deonarain, Rifat Hamoudi, Manuel Rodriguez-Justo, Marco R. Novelli, Laurence B. Lovat

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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=0.0022)

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.

Original language	English
Pages (from-to)	25080-25096
Number of pages	17
Journal	Oncotarget
Volume	8
Issue number	15
DOIs	https://doi.org/10.18632/oncotarget.15340
Publication status	Published - 15 Feb 2017
Externally published	Yes

Keywords

Pharmacology
MUC1
Esophogeal adenocarcinoma
antibody drug conjugate
ADC
Photodynamic therapy
Biomarkers

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.18632/oncotarget.15340

Upregulation of mucin glycoprotein MUC1 in the progression to esophageal adenocarcinoma and therapeutic potential with a targeted photoactive antibody-drug conjugateFinal published version, 4.5 MBLicence: CC BY

Cite this

Butt, M. A., Pye, H., Haidry, R. J., Oukrif, D., Khan, S. U. R., Puccio, I., Gandy, M., Weihe Reinert, H., Bloom, E., Rashid, M., Yahioglu, G., Deonarain, M. P., Hamoudi, R., Rodriguez-Justo, M., Novelli, M. R., & Lovat, L. B. (2017). Upregulation of mucin glycoprotein MUC1 in the progression to esophageal adenocarcinoma and therapeutic potential with a targeted photoactive antibody-drug conjugate. Oncotarget, 8(15), 25080-25096. https://doi.org/10.18632/oncotarget.15340

@article{9e96a08d2153422a835950ba66a9be1b,

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

abstract = "Background: Mucin glycoprotein 1 (MUC1) is a glycosylated transmembrane protein on epithelial cells. We investigate MUC1 as a therapeutic target in Barrett{\textquoteright}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=0.0022)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.",

keywords = "Pharmacology, MUC1, Esophogeal adenocarcinoma, antibody drug conjugate, ADC, Photodynamic therapy, Biomarkers",

author = "Butt, {Mohammed Adil} and Hayley Pye and Haidry, {Rehan J.} and Dahmane Oukrif and Khan, {Saif U. Rehman} and Ignazio Puccio and Michael Gandy and {Weihe Reinert}, Halla and Ellie Bloom and Mohammed Rashid and Gokhan Yahioglu and Deonarain, {Mahendra P.} and Rifat Hamoudi and Manuel Rodriguez-Justo and Novelli, {Marco R.} and Lovat, {Laurence B.}",

year = "2017",

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day = "15",

doi = "10.18632/oncotarget.15340",

language = "English",

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Butt, MA, Pye, H, Haidry, RJ, Oukrif, D, Khan, SUR, Puccio, I, Gandy, M, Weihe Reinert, H, Bloom, E, Rashid, M, Yahioglu, G, Deonarain, MP, Hamoudi, R, Rodriguez-Justo, M, Novelli, MR & Lovat, LB 2017, 'Upregulation of mucin glycoprotein MUC1 in the progression to esophageal adenocarcinoma and therapeutic potential with a targeted photoactive antibody-drug conjugate', Oncotarget, vol. 8, no. 15, pp. 25080-25096. https://doi.org/10.18632/oncotarget.15340

TY - JOUR

T1 - Upregulation of mucin glycoprotein MUC1 in the progression to esophageal adenocarcinoma and therapeutic potential with a targeted photoactive antibody-drug conjugate

AU - Butt, Mohammed Adil

AU - Pye, Hayley

AU - Haidry, Rehan J.

AU - Oukrif, Dahmane

AU - Khan, Saif U. Rehman

AU - Puccio, Ignazio

AU - Gandy, Michael

AU - Weihe Reinert, Halla

AU - Bloom, Ellie

AU - Rashid, Mohammed

AU - Yahioglu, Gokhan

AU - Deonarain, Mahendra P.

AU - Hamoudi, Rifat

AU - Rodriguez-Justo, Manuel

AU - Novelli, Marco R.

AU - Lovat, Laurence B.

PY - 2017/2/15

Y1 - 2017/2/15

N2 - 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=0.0022)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.

AB - 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=0.0022)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.

KW - Pharmacology

KW - MUC1

KW - Esophogeal adenocarcinoma

KW - antibody drug conjugate

KW - ADC

KW - Photodynamic therapy

KW - Biomarkers

UR - http://dx.doi.org/10.18632/oncotarget.15340

U2 - 10.18632/oncotarget.15340

DO - 10.18632/oncotarget.15340

M3 - Article

SN - 1949-2553

VL - 8

SP - 25080

EP - 25096

JO - Oncotarget

JF - Oncotarget

IS - 15

ER -

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

Abstract

Keywords

UN SDGs

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