Defining the impact of driver-gene heterogeneity on mechanisms of immune evasion and response to therapy in pancreatic cancer.

The CRUK Scotland Centre studentships are for 4 years and provide an annual tax-free stipend of £22,500 + 1.75% indexation in Year 2,3&4, university tuition fees and a consumables budget.

Students will be registered for their degree at either the University of Glasgow or Edinburgh, depending on the project they apply for. This scheme is open to both UK and international applicants.

PhD Studentships

The contribution of pancreatic cancer to global cancer-related mortality continues to rise, with an almost uniformly fatal outcome. At diagnosis, only a small minority of patients are eligible for surgical resection which remains the only treatment option with curative potential. Even after surgery, relapse is common and for most patients, current chemotherapy regimens have only modest activity despite significant toxicity. With objective response rates to standard-of-care chemotherapy approximately 30-40%, understanding mechanisms of resistance and identifying new therapies will be critical to improving patient outcomes.

Pancreatic cancer is a genetically heterogeneous disease. Activating mutations in the KRAS gene are near ubiquitous and are often accompanied by a loss-of-function mutation in at least one tumour suppressor gene, most commonly TP53, CDKN2A and/or SMAD4, resulting in a range of different combinations across the patient population. How this underlying heterogeneity impacts the tumour microenvironment (TME) and mechanisms of immune evasion is not clear. To explore this, we have used CRISPR-Cas9 genome editing to generate new isogenic cell-based models of pancreatic cancer by engineering the most common driver-gene expression states found in human PDAC into genetically pristine murine primary acinar cells. Extensive benchmarking of the TME in these models against the human disease has identified CD8 T-cell enriched sub-tumour microenvironments, similar to those observed in human PDAC. What immune regulatory pathways are expressed within these CD8 T-cell enriched sub-TMEs to drive immune evasion is unknown. Similarly, what immune regulatory mechanisms drive CD8 T-cell exclusion from other regions of the tumour is also not clear.

Combining our new models with the analysis of human PDAC tissue, we have used spatial transcriptomics to interrogate mechanisms of immune evasion in CD8 T-cell enriched sub-TMEs and immune desert (lacking CD8 T-cells) regions enriched for cancer cells, macrophages or cancer-associated fibroblasts. This has enabled us to identify spatially restricted mechanisms of immune evasion that are conserved between human PDAC and our novel mouse models, and their association with the loss of CDKN2A and/or SMAD4. Leveraging this information, we now aim to develop and test novel therapeutic combinations coupled with patient stratification hypotheses to identify new treatment options for this disease of unmet clinical need.

Current treatment options for patients diagnosed with advanced disease are limited, with most eligible patients receiving either FOLFIRINOX or a combination of Gemcitabine and Abraxane. Using our model systems, we have identified that tumour driver-gene expression impacts response to FOLFIRINOX and plays an important role in dictating how FOLFIRINOX treatment reprograms the TME and mechanisms of immune evasion. Therefore, understanding the interplay between tumour driver-gene expression and treatment-associated TME reprogramming will be important in identifying downstream treatment options following the onset of resistance and disease relapse. Recently, a number of KRAS inhibitors have entered clinical trials in PDAC, with initial data suggesting robust anti-tumour efficacy but the rapid onset of resistance. Therefore, we propose to build on our current findings by leveraging our model systems to address the impact of CDKN2A and SMAD4 expression on response to KRAS inhibition. Specifically, we aim to understand how KRAS inhibition impacts mechanisms of immune regulation within CD8 T-cell sub-TMEs and immune desert regions, and how this is influenced by CDKN2A and SMAD4 expression status. In doing so, we seek to identify immunotherapeutic opportunities emerging as a consequence of resistance to KRAS inhibition.

This project will use mouse models of PDAC in combination with spatial transcriptomics, immunohistochemistry, multiplex immunofluorescence, and computational biology to identify, develop and test novel immunotherapy approaches and patient stratification hypotheses for the treatment of pancreatic cancer.

The supervisory team already has extensive expertise in the model systems and techniques to be used and will support the candidate with all required training needs.