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Targeting MTOR and metabolic pathways for anti-tumour therapy in a TSC2+/- mouse model

Jones, Ashley Thomas 2019. Targeting MTOR and metabolic pathways for anti-tumour therapy in a TSC2+/- mouse model. PhD Thesis, Cardiff University.
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Tuberous sclerosis (TSC) is a genetic tumour syndrome characterised by the formation of tumours in multiple organs, including the kidneys. TSC is caused by mutations in the TSC1 or TSC2 gene leading to aberrant activation of the mTOR signalling pathway. The mTOR signalling pathway regulates numerous biological processes such as cell growth, proliferation, metabolism and epithelial-to-mesenchymal transition (EMT). The mTOR inhibitor rapamycin (rapalogs) is effective for TSC-associated tumours. However, not all TSC-associated tumours respond to rapalogs and tumours usually regrow after treatment withdrawal. Therefore, this study aims to test alternative therapeutic approaches for treating TSC-associated renal tumours and to investigate mechanisms of tumorigenesis in Tsc2+/- mice. Firstly, this study presented a new model of EMT activation during tumour progression from cysts through papillary adenomas to solid carcinomas in the kidneys of Tsc2+/- mice. Effect on EMT and anti-tumour efficacy of the ATP competitive inhibitor of mTOR, AZD2014, was compared with rapamycin in these mice. Both AZD2014 and rapamycin inhibited EMT and significantly reduced tumour burden as indicated by number and size of tumours. Nevertheless, AZD2014 was not superior to rapamycin for these tumours, suggesting that the anti-tumour efficacy was probably achieved mainly through inhibition of mTORC1. Secondly, this study revealed that renal tumours of Tsc2+/- mice are metabolically active with the increased expression of enzymes associated with glycolysis and glutaminolysis. The dual inhibition of glycolysis and glutaminolysis with 3-BrPA and CB-839 significantly reduced renal tumour burden in these mice. However, this combination treatment was not as effective as rapamycin alone. These results suggest that dual inhibition of glycolysis and glutaminolysis is unlikely to offer better therapy than rapalogs for treating TSC-associated tumours. Finally, this study sought to investigate the role of the glycolytic enzyme, Pkm2, in renal tumourigenesis of Tsc2+/- mice using doxycycline-induced gene deletion. Pkm2 was successfully deleted in the epithelial cells of renal tubules and Pkm2 loss did not have significant effect on renal tumourigenesis. However, increased expression of Pkm1 was observed following Pkm2 deletion in renal tumour cells which may functionally compensate for Pkm2 loss to promote tumourigenesis.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 6 August 2019
Last Modified: 06 Aug 2019 09:28

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