Targeting the REF1/STAT3 axis to treat tuberous sclerosis

Champion, Jesse 2023. Targeting the REF1/STAT3 axis to treat tuberous sclerosis. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Mammalian target of rapamycin complex 1 (mTORC1) inhibitors have provided clear clinical benefit to tuberous sclerosis complex (TSC) patients. However, not all patients respond to mTORC1 inhibitors. Alternatives to mTORC1 inhibitors remains a significant unmet clinical need for the management of TSC. Elevated expression and activity of the transcription factors Hypoxia inducible factor 1 (HIF1α) and Signal transducer and activator of transcription 3 (STAT3) has been observed in TSC. The redox signalling protein Reduction-oxidation factor 1 (Ref-1) acts upstream of both STAT3 and HIF-1α to induce their transcriptional activity. This thesis seeks to investigate the efficacy of drug inhibition of the Ref-1/HIF-1α/STAT3 within TSC model cells and expand current knowledge of HIF-1α and STAT3 signalling within TSC. Research within this thesis identified drug blockade of Ref-1/HIF-1α/STAT3 activity reduced scores of tumorigenicity within TSC2 deficient cells. Additionally, inhibitors of Ref-1 and STAT3 were found to be effective at decreasing HIF-1α activity and pro-angiogenic factor expression within TSC2 deficient cells. The present work also developed the list of known STAT3 and HIF-1α targets dysregulated in cells upon the loss of TSC2, with analysis of their potential clinical relevance through comparison to data from TSC associated lesions. Mechanisms which lead to dysregulated STAT3 signalling were also elucidated within this work. Markers of oxidative stress were found to be elevated within TSC model cells, and the redox environment of TSC cells was shown to modulate markers of both HIF-1α and STAT3 activity. Finally, this thesis identifies the drug C188-9 as a potential therapeutic agent for the treatment of TSC. As C188-9 effectively repressed markers of STAT3 and mTORC1 activity within TSC2 deficient cell lines. Overall, this thesis provides a more developed understanding of mTORC1 and Ref-1/HIF1α/STAT3 signalling within the context of TSC, which hopefully will lead better therapeutic interventions for TSC patients.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	25 July 2023
Last Modified:	18 Apr 2024 01:05
URI:	https://orca.cardiff.ac.uk/id/eprint/161226

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