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Title: Targeting the PI3K/mTOR and ATR/Chk1 pathways to improve radiation efficacy for cancer therapy
Author: Fokas, Emmanouil
ISNI:       0000 0004 2734 871X
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2012
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The purpose of the present thesis was to better understand the effect of targeting key biological mechanisms in order to improve radiotherapy response. Two important and distinct pathways were targeted using novel agents: (1) the phosphoinoside-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway; (2) the ataxia telangiectasia-mutated-Rad3-related (ATR)/Chk1 pathway. The role of the PI3K/mTOR signalling pathway in tumour radiosensitivity and tumour microenvironment (TME) was examined using three, recently-developed signalling inhibitors obtained from Novartis Pharma: NVP-BEZ235 (dual PI3K/mTOR inhibitor), NVP-BGT226 (dual PI3K/mTOR inhibitor) and NVP-BKM120 (single PI3K inhibitor). The radiosensitising potential of NVP-BEZ235 and NVP-BGT226 was demonstrated in tumour and endothelial cells. Additionally, a thorough research into the effects of NVP-BKM120 and NVP-BEZ235 on TME showed that oncogenic signalling inhibitors can improve vascular morphology and increase tumour oxygenation and perfusion in tumour xenograft models, resulting in improved radiation response. Furthermore, a highly potent and selective ATR inhibitor, VE-822, that was obtained from Vertex Pharmaceuticals (Europe) Ltd, was tested in pancreatic ductal adenocarcinoma (PDAC) cells and tumour xenograft models. ATR inhibition by VE-822 resulted in sensitisation of tumour cells but not normal cells to radiation and gemcitabine. Similarly, VE-822 strongly enhanced radiation- and chemoradiation-induced tumour growth delay in tumour xenograft models. Importantly, VE-822 did not potentiate radiation-induced gastrointestinal tract epithelial damage. To summarize, the impact of targeting two distinct pathways in combination with radiation and chemoradiation was explored. Inhibition of the PI3K/mTOR and ATR/Chk1 signalling pathways increases response of tumours to radiotherapy they and might be promising targeting strategies for cancer treatment. These findings have considerable translational implications and future clinical trials should aim to validate these observations.
Supervisor: Muschel, Ruth J. Sponsor: Cancer Research UK ; Medical Research Council ; Oxford Cancer Imaging Centre ; NIHR Biomedical Research Centre, Oxford
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Radiobiology