Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.790356
Title: Targeted therapy for chordoma
Author: Jorgensen, M.
ISNI:       0000 0004 8497 6915
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2016
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Abstract:
Chordoma is a rare and slow growing but locally aggressive bone tumour with a poor prognosis and limited treatment options. Current treatment strategies include surgical resection and radiotherapy. There are no approved drugs for the treatment of chordoma. The aim of this thesis was to explore novel therapeutics approaches. Work presented within the thesis includes: A high throughput screen of more than 1100 compounds in three chordoma cell lines. This work identified 27 compounds selective for chordoma; 78% were EGFR/ErbB inhibitors. These data adds to existing evidence that EGFR inhibitors are potential therapeutic agents for treatment of chordoma. A gene therapy approach, using an Adeno-associated viral (AAV) vector for the delivery of RNAi targeting brachyury in vitro and in a xenograft model generated as part of the project. Chordoma cells were found to be permissive to AAV. Treatment with the brachyury-silencing vector resulted in tumour cell growth arrest. In addition, two biomarkers were assessed to establish the potential to monitor for disease and disease response to treatment in chordoma patients. Detection of a protein biomarker AKR1B10, which has shown promise in breast cancer, was assessed but was not detectable in plasma from chordoma patients. Circulating tumour DNA (ctDNA) has shown great promise in high grade and advanced cancer. The potential to detect ctDNA in plasma from patients with chordoma was assessed following genomic profiling for tumour specific mutations. Digital PCR was used for detection of tumour DNA from 4 chordoma patients. Low levels of ctDNA were detected in 3 patients, establishing proof of concept that with further optimisation this method can potentially be used for detection of disease recurrence and monitoring response to treatment. This work signposts the way towards further research into novel techniques to improve patient outcome for chordoma.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.790356  DOI: Not available
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