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Unlocking oncogene dependent cell death in pancreatic tumours

Richards, Anna 2023. Unlocking oncogene dependent cell death in pancreatic tumours. PhD Thesis, Cardiff University.
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Summary Despite advances in our understanding of pancreatic ductal adenocarcinoma (PDAC) over the past few decades, it remains associated with a 5-year survival rate of less than 10% and accounts for over 90% of all pancreatic cancer cases. Non-specific symptoms result in patients presenting with advanced, often unresectable disease at diagnosis. In this setting, current standard-of-care treatment only extends survival by 10-12 months, highlighting an urgent need for the development of more targeted therapeutic approaches. Present in over 90% of all human PDAC tumours, mutant KRAS (mKRAS) represents a crucial target in the drive to improve therapeutic approaches. Amongst many malignant signalling roles, mKRAS hijacks apoptosis-inducing TRAIL-R signalling to instead drive non-canonical, pro-survival pathways in PDAC. The anti-apoptotic protein, cFLIP, suppresses canonical TRAIL-induced apoptosis. Using a combination of complete genetic deletion and small molecule inhibition, we aimed to determine whether cFLIP inhibition was sufficient to re-activate canonical TRAIL signalling and, therefore, specifically induce apoptosis within mKRAS PDAC cells. We demonstrated that human PDAC tumours expressing high levels of cFLIP, TRAIL and TRAIL-Rs were associated with significantly reduced survival. Moreover, cFLIP deletion (FLIPi) successfully sensitised a resistant panel of KRAS-mutant PDAC cell lines to TRAILinduced apoptosis in vitro. Similarly, tamoxifen-induced FLIPi within PDAC tumours in a novel, genetically engineered mouse model lead to increased levels of apoptosis in vivo. Whilst ex vivo FLIPi in tumour-derived organoids established from the same transgenic model resulted in significantly reduced organoid viability, particularly in combination with exogenous TRAIL. Finally, a novel small molecule cFLIP inhibitor, OH14, significantly increased apoptosis in the classical pdx1-Cre; LSL-KRASG12D; LSL-Trp53R172H (KPC) transgenic model of PDAC in vivo. Overall, these results support the further investigation of cFLIP inhibition as a therapeutic intervention specifically targeting KRAS-mutant PDAC tumours in the hope of improving the survival outcomes of this aggressive malignancy.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Biosciences
Subjects: Q Science > Q Science (General)
Funders: Pancreatic Cancer Research Fund
Date of First Compliant Deposit: 17 October 2023
Last Modified: 18 Oct 2023 09:49

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