Article
作者: Rodriguez-Justo, Manuel ; Deonarain, Mahendra P. ; Bloom, Ellie ; Oukrif, Dahmane ; Lovat, Laurence B. ; Puccio, Ignazio ; Novelli, Marco R. ; Butt, Mohammed Adil ; Haidry, Rehan J. ; Pye, Hayley ; Rashid, Mohammed ; Reinert, Halla W. ; Hamoudi, Rifat ; Gandy, Michael ; Khan, Saif-U-Rehman ; Yahioglu, Gokhan
BACKGROUNDMucin 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.RESULTSMUC1 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).METHODSGene 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.CONCLUSIONSMUC1 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.
