Abstract
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.
Highlights
Despite progress in the treatment of other cancers, the 5-year survival of esophageal adenocarcinoma (EA) remains low at around 15% [1]
Mucin glycoprotein 1 (MUC1) was linked to the progression to EA using gene set enrichment analysis (GSEA)
Within the Gene set enrichment analysis (GSEA) two groups of upper GI samples were compared; the comparison of non-dysplastic Barrett's esophagus (NDBE) to normal esophageal squamous epithelium (Sq) gave 47 pathways that were enriched in NDBE compared to Sq, of which 28 were significant and of these 21% included MUC1
Summary
Despite progress in the treatment of other cancers, the 5-year survival of esophageal adenocarcinoma (EA) remains low at around 15% [1]. Eradication of Barrett’s epithelium significantly reduces the risk of developing EA [4]. Identifying new therapeutic targets for Barrett’s epithelium and EA is of vital www.impactjournals.com/oncotarget clinical importance. Within the field of esophagogastric adenocarcinoma HER2 is the only therapeutic biomarker to be incorporated into widespread clinical practice. The HER2-targeting antibody Trastuzumab when used in combination with chemotherapy has been shown to improve progression-free and overall survival in HER2 positive gastric and gastroesophageal junction cancer patients [5]. 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
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