Harnessing DNA damage repair and innate immune response in pancreatic cancer

Supervisors: David Chang, Nigel Jamieson (University of Glasgow), Jennifer Morton (CRUK Beatson Institute), Stephan Dreyer (University of Glasgow)

Pancreatic cancer (PC) is the 3rd most common cause of cancer related death, and is predicted to be the 2nd within a decade, therefore novel therapeutic strategies are urgently needed. While early data suggests novel targeted DNA damaging agents such as PARP inhibitors may be beneficial to PC harbouring DNA damage response deficiency (DDRd), its indication beyond DDRd is not well defined. We have recently shown the preservation of Type 1 interferon signaling in patient-derived cell line models demonstrating its cell-autonomous nature, and identified the link between DNA damage, inflammation, STING activation, leading to potential mechanisms of immune evasion through activation of PD-L1/2. This presents a rational for combinatorial PARP and immune checkpoint (IC) inhibition, especially single agent IC inhibitors have shown disappointing results in PC to date.

The overall aim for this clinical research fellowship will be to define the potential clinical utility of combinatorial PARP and IC inhibition in PC. The candidate will leverage the ongoing PRIMUS-002 trial (neoadjuvant treatment containing DNA-damaging agents) on the Precision-Panc platform, to interrogate the relationship between DNA damage, STING activation, and the evolution of immune landscape using serial temporal tumour samples pre- and post-treatment in both DDR deficient and proficient tumours. We will then use these findings to rationalise the putative biomarker of response of PARP and IC inhibition combination using the multi-omic data generated as part of PRIMUS-002. The hypothesis will be tested in vivo using syngeneic models of KPC, and KPC/BRCA1 and 2, with the ultimate aim to generate pre-clinical platform of evidence for early phase clinical trial design to be tested on the Precision-Panc platform.



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