B301: Characterisation of the mucin receptor MUC1 in the progression to oesophageal cancer and potential for antibody directed therapy.
1Department for Tissue & Energy, University College London, London, UK,2Upper Gastrointestinal Service, University College London, London, UK,3Antikor BioPharma, Stevenage Bioscience Catalyst, Stevenage, UK,4Antikor BioPharma, Stevenage Bioscience Catalyst, Stevenage, UK,5Department of Pathology, University College London, London, UK,6Genetics, Evolution & Environment, Division of Biosciences, University College London, London, UK,7Department of Oncology, UCL Cancer Institute, London, UK
The effectiveness and subsequent recommendation for the use of the antibody trastuzumab in the treatment of HER2-positive oesophagogastric and gastric adenocarcinoma generated interest in the introduction of other targeted agents for foregut cancers. Studies suggested Mucin receptor 1 (MUC1) to be up regulated in oesophageal adenocarcinoma (OA) but the literature is conflicting. The work presented highlights MUC1 to be involved in key pathways of OA development using gene set enrichment analysis. It characterises detection of the MUC1 receptor with immunohistochemistry and proposes the potential of antibody directed therapy for OA using the MUC1 targeting antibody HuHMFG1. HuHMFG1 is shown to bind the mucosal layer of oesophageal epithelium and be upregulated early at the metaplastic stage of progression to OA. In OA, HuHMFG1 binding is also shown to closely follow tumour invasion both locally and into lymph nodes, offering this target the potential to treat metastases. Binding of HuHMFG1 was confirmed on a panel of in vitro cell lines in the Barrett's to OA sequence and evidence for HuHMFG1 internalisation seen with confocal microscopy. A phototoxic ADC based on HuHMFG1 was designed and shown to have selective light-dependent cytotoxicity to the OA cell line, OE19. This study highlights the importance and potential of MUC1 as a target for OA, and has clarified conflicting data with regards to the expression of this antigen. This information will help guide the development of future antibody directed therapies against this epitope.