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)/Chkl pathway. The role of the PI3K1mTOR signalling pathway in tumour radiosensitivity and tumour microerivlronment (TME) was examined using three, recently-developed signalling inhibitors obtained from Novartis Pharma: NVP-BEZ235 (dual PI3K1mTOR inhibitor), NVP-BGT226 (dual PI3K1mTOR 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 ofNVP-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 A TR inhibitor, VE-822, that was obtained from Vertex Pharmaceuticals (Europe) Ltd, was tested in pancreatic ductal adenocarcinoma (PDAC) cells and tumour xenograft models. A TR 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 PI3K1mTOR and ATRlChkl signalling pathways increases response of tumours to radiotherapy they and might be promising targeting strategies for cancer treatment. Our findings have considerable translational implications and future clinical trials should aim to validate these observations.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:572788 |
| Date | January 2012 |
| Creators | Fokas, Emmanouil |
| Contributors | Muschel, Ruth J. |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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