Development of novel therapeutics for the treatment of pancreatic cancer

Abstract

Pancreatic cancer is a highly drug resistant cancer with a dismal prognosis. Despite intensive research efforts and advancements in treatment options, the 5-year survival rate remains around 5%. This is primarily due to the late-stage diagnosis of the majority of cases, rendering potentially curative surgical resection impossible. Current first-line combination chemotherapy in the form of FOLFIRINOX comes with significant toxicities for patient, which render many patients physically unsuitable for this regime.

As resistance to chemotherapy-induced cell death is a major cause of drug resistance, this thesis examined apoptotic signalling in several pancreatic cancer cell lines focussing on the extrinsic apoptotic pathway regulated by the TNF-related apoptosis- inducing ligand (TRAIL) receptor 2/ death receptor-5 (DR5). Activation of TRAIL-R2 by natural or therapeutic ligands results in formation of the Death Inducing Signalling Complex (DISC), at which procaspase 8 is activated, leading to downstream executioner procaspase 3/7 activation and subsequent apoptosis. A key anti-apoptotic inhibitor of this pathway is FLICE-inhibitory protein (FLIP), a paralog of procaspase 8 that inhibits DISC-mediated activation of procaspase 8 and subsequent activation of procaspases 3 and 7, and thus inhibits the induction of apoptosis.

Previous studies have shown FLIP to be upregulated in pancreatic cancer, compared to expression levels in healthy pancreatic tissue. Therefore, this thesis examines the role of this pathway in regulating apoptosis in pancreatic cancer and whether this pathway could be utilised for novel therapeutic treatments, via analysis of the response to the latest DR5 agonists and a novel small molecule inhibitor of FLIP.

In summary, this work confirmed DR5 mediated apoptosis to be an interrogatable mechanism in pancreatic cancer and that the proprietary first-in-class FLIP inhibitor currently under development at QUB is an exciting development towards therapeutic targeting of a previously undruggable protein. Collectively, these results show that exploitation of the DR5 pathway, in combination with downregulation of key overexpressed inhibitors of apoptosis, such as FLIP, form a promising therapeutic rationale for poor prognostic pancreatic cancer.

Thesis is embargoed until 31 December 2026.

Date of Award	Dec 2023
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	US-Ireland R&D Partnership Programme
Supervisor	Christopher Scott (Supervisor) & Daniel Longley (Supervisor)