Enhancing the neoadjuvant treatment of rectal cancer by targeting the Inhibitor of Apoptosis Proteins

Abstract

Total neoadjuvant therapy (TNT) has emerged as a standard approach for locally advanced rectal cancer, combining (chemo)radiation and systemic chemotherapy prior to surgery. This strategy improves tumour downstaging, increasing the likelihood of non-operative management, and reduces local and distant recurrence. However, most patients still require major surgery, and approximately 25% ultimately relapse. Enhancing tumour cell death during TNT may improve these outcomes.

Inhibitor of Apoptosis Proteins (IAPs) are upregulated in rectal cancer and are associated with treatment resistance and poor prognosis. Additionally, intratumoral bacteria such as Fusobacterium nucleatum may contribute to IAP-mediated resistance. This thesis investigates whether pharmacological inhibition of IAPs using the Smac-mimetic tolinapant can enhance responses to TNT.

Thesis is embargoed until 31 July 2027.

Date of Award	Jul 2026
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Wellcome Trust
Supervisor	Daniel Longley (Supervisor), Vicky Coyle (Supervisor) & Fionnuala Lundy (Supervisor)