The identification of novel immune activating agents for rationalised combination therapy in breast cancer

Abstract

The DNA damage induced immune response (DDIR) signature was established to identify breast tumours with an intrinsic DNA damage repair defect that renders them susceptible to DNA damaging chemotherapy, anthracyclines and cyclophosphamide. This signature is characterised by activation of the cGAS/STING mediated innate immune response pathway and results in a classical type I interferon response, in addition it also activates immune checkpoint signalling. Taken together this suggests that activation of the DDIR may convert immunologically ‘cold’ tumours to ‘hot’ tumours, that may be responsive to immune checkpoint inhibition. This project aims to identify novel immune activating agents which have the potential for rationalised combination therapy with immune checkpoint blockade (ICB) in breast cancer. This project has incorporated two screening protocols, one smaller scale Broad Institute connectivity mapping directed screen utilising RT-qPCR assessment of interferon stimulated gene (ISG) expression. Then a second large sale high throughput screen of the ApexBio DiscoveryProbe FDA-approve compound library utilising an ELISA to detect CCL5 secretion. A total of 11 compounds were taken forward and validated using RNA sequencing to look at immune stimulated gene expression. The chicken chorioallantoic membrane (CAM) model was trialled as a method for assessing the immune activating potential of these compounds in combination with ICB. In doing this we hope to repurpose approved drugs for immune activation and rationalised combination therapy with ICB in breast cancer.

Thesis embargoed until 31 July 2029.

Date of Award	Jul 2024
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Julie Loughery
Supervisor	Stuart McIntosh (Supervisor) & Kienan Savage (Supervisor)