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Title: Biomarkers in the pathogenesis of neuroendocrine tumours
Author: Mandair, D. S.
ISNI:       0000 0004 8498 1925
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2016
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Neuroendocrine tumours are a heterogenous group of tumours that arise in diverse anatomical locations and vary greatly in behavior and response to treatment. Currently available biomarkers are limited as predictive and prognostic tools. In exploring novel biomarkers, circulating tumour cells identified by the semi-automated platform CellSearch, have been found to predict worse outcome if present in NETs. However, the appropriate cut-off of for CTCs has not previously been substantively defined. In this thesis I have demonstrated in univariate and multivariate analysis the appropriate CTC cut-off in pancreatic NETs. I have demonstrated one CTC can predict progression with higher sensitivity and specificity than the currently used biomarker chromagranin A (CgA). I have investigated the potential of circulating endothelial cells as dynamic biomarkers. Although CECs as defined by CellSearch are not significantly elevated in NET patients, sub-groups of CECs could be investigated as biomarkers to measure response of molecular targeted drug therapy. Molecular characterization of CTCs can be used to "personalize therapy" and in effect CTCs can be considered a true "liquid biopsy". This is challenging due to the small numbers of CTCs found and difficulty in isolating single cells for genomic analyses. In Chapter 4, I demonstrated the ability of the novel CellCollector to capture CTCs, and in a direct comparison with CellSearch, found significantly more CTCs. I was able to confirm this is a safe, well-tolerated method for obtaining increased CTCs from a greater proportion of patients that can undergo further molecular analyses. In chapter 5, 5 I was able to successfully establish the isolation of single CTCs that had undergone enrichment with CellSearch using the novel DEPArray system. I was also able to obtain good quality DNA from these CTCs by whole genome amplification and demonstrate the potential for identifying somatic mutations. This thesis highlights robust evidence for the potential clinical application of CTCs to be incorporated into the management of pancreatic NET patients, as well as demonstrating the potential for new technologies enabling the utilization of CTCs as a true 'liquid' biopsy.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available