Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.711863
Title: Discovery and investigation of novel radiosensitising genes
Author: Tiwana, Gaganpreet Singh
ISNI:       0000 0004 6061 4813
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2015
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Abstract:
Radiotherapy is second only to surgery in the curative management of patients with cancer, and yet the molecular mechanisms that determine the sensitivity of tumours to radiation remain largely unclear. A high-throughput radiosensitivity screening method based on clonogenicity was developed and a siRNA library against kinase targets was screened. The gold standard colony formation endpoint was chosen for determining reproductive cell death after radiation treatment, since effects on proliferation often do not reflect survival. Thiamine pyrophosphokinase-1 (TPK1), a key component of Vitamin B1/thiamine metabolism, was identified as a target for radiosensitisation. TPK1 knockdown caused significant radiosensitisation in cancer but not normal tissue cell lines. Other means of blocking this pathway such as knockdown of thiamine transporter-1 (THTR1) or treatment with the thiamine analogue pyrithiamine hydrobromide (PyrH) caused significant tumour specific radiosensitisation. There was persistent DNA damage in cells irradiated after TPK1 and THTR1 knockdown or PyrH treatment. Thus this screen allowed the identification of thiamine metabolism as a novel radiosensitisation target that affects DNA repair. Short-term modulation of thiamine metabolism could be a clinically exploitable strategy to achieve tumour specific radiosensitisation. Three additional genes, signal recognition particle-72 kDa (SRP72), glycogen synthase 3-beta (GSK3β) and MAP/Microtubule Affinity-Regulating Kinase 2 (MARK2) were also investigated. Knockdown of these genes radiosensitised both tumour and normal tissue cell lines and expression of two of them, GSK3β and SRP72 were found to be associated with poor recurrence-free survival in early breast cancer patients.
Supervisor: Higgins, Geoffrey Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.711863  DOI: Not available
Keywords: Radiation-sensitizing agents ; High throughput screening (Drug development) ; Small interfering RNA
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