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Development of biomarkers for the risk stratification and targeted therapy of Barrett's oesophagus and oesophageal adenocarcinoma

Butt, Mohammed Adil; (2018) Development of biomarkers for the risk stratification and targeted therapy of Barrett's oesophagus and oesophageal adenocarcinoma. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Barrett's oesophagus is the most important risk factor for the development of oesophageal adenocarcinoma (OA), but progression is unpredictable. Dysplasia predicts which Barrett’s patients are at greatest risk for OA but achieving the diagnosis can be challenging. Immunohistochemistry with p53 is recommended as an adjunct to assist with dysplasia diagnosis. This thesis will examine if replication licensing factors and DNA ploidy status are as good if not better than p53 to assist in the diagnosis of dysplasia. Overexpression of HER2 in foregut cancer is an indication for HER2 targeted treatments. Its influence on prognosis is less understood. The relationships between clinicopathological variables, HER2 overexpression and prognosis will next be evaluated. Current ablative techniques for Barrett’s neoplasia are limited to superficial disease. Photodynamic therapy was a treatment for Barrett’s that could penetrate more deeply into diseased tissue but was limited by the side effects of off-target photosensitivity. Combining targeting vehicles such as antibodies to newer and more deeply penetrating photosensitiser drugs, may overcome the previous limitations of this technology. A photosensitive ADC against HER2 will be created and its efficacy in vitro and in vivo evaluated. However, even the most effective ADC against HER2 will not treat the majority of cancers, as we will show HER2 is only expressed in the minority of foregut tumours. The final experiments will look to characterise the mucin MUC1 in Barrett’s and associated neoplasia. Studies have previously shown it to be present in up to 100% of cancers while others say far fewer. We will show proof of principle data for the development of a MUC1 targeting photosensitive ADC in vitro and postulate how it may in future enable treatment of locoregional invasive tumours endoscopically.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Development of biomarkers for the risk stratification and targeted therapy of Barrett's oesophagus and oesophageal adenocarcinoma
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Keywords: Barrett's, Oesophageal, Adenocarcinoma, Photodynamic, Antibody Drug Conjugate, Targeted therapy, Biomarker, Aneuploidy, PLK-1, Mucin, HER2, MUC1
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10059283
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