Investigating how driver mutations in pancreatic cancer impact early detection and chemopreventive and therapeutic strategies
Prof Jen Morton & Dr Alan Serrels
Lab: Preclinical Pancreatic Cancer; Tumour Immune Environment
Duration: 4 years, starting October 2025
Closing Date: Monday 25th November 2024
Interviews for this position will take place January/February 2025
Background
Pancreatic ductal adenocarcinoma (PDAC) is currently the fourth leading cause of cancer-associated mortality with <7% patients surviving for 5 years following diagnosis. This dismal prognosis is associated with late diagnosis, poor patient responsiveness to chemotherapy and a complex heterogeneous tumour microenvironment (TME) which influences tumour progression and response to therapy.
The majority of pancreatic cancer patients (~85%) are ineligible for surgery, their only potentially curative option, due to advanced disease at the time of diagnosis. However, current chemotherapy regimens are minimally effective. KRAS inhibitors may offer hope in this disease, however, how this heterogenous group of patients may respond is still not well understood, and some patients may still be too ill for meaningful therapeutic intervention. Thus, diagnosing patients and treating them at an earlier stage is critical to improving outcomes.
Comprehensive molecular profiling studies have revealed genetic driver events and enabled tumour subtyping based on gene expression and mutational profiles whilst also elucidating signalling pathways frequently modulated during disease progression. We hypothesise that both biomarkers of early disease, and response to targeted therapies, are influenced by the genetic background of the tumour and aim to understand how tumour genetics impact biomarker expression as well as responses to early intervention.The overarching goal of the project is to improve the devastating statistics currently associated with pancreatic cancer.
Research Question
The advent of mutant KRAS and pan-RAS inhibitors has the potential to be game changing in this disease, particularly now that inhibitors for the most commonly mutated forms in pancreatic cancer have been developed. However, we know very little about how the responses to KRAS inhibition may vary in patients with different combinations of gene mutations in addition to KRAS mutation (e.g., TP53, CDKN2A, SMAD4), and how these different mutations may affect biomarkers that could be used for earlier detection of tumours. The aim of this project is to address these questions.
We already have evidence of therapeutic efficacy of these agents in mice bearing Kras and Trp53 mutations, and some preliminary findings that early intervention can prevent the progression of preneoplastic lesions to pancreatic cancer. The student will expand on these findings by generating complex models representing these different patient subsets in which to test the efficacy of these agents in both the early intervention and chemotherapeutic settings. It is essential to investigate these aspects of tumour biology in vivo, in spontaneous tumours with a physiological microenvironment, so the student will use genetically engineered mouse models of PDAC that fully recapitulate human tumours in terms of genetic alterations and microenvironment. Since analysis of bulk tumour tissue provides no information on individual cell types, state-of-the-art molecular & digital pathology technologies will be used to spatially link molecular changes to therapeutic responses.
Earlier detection of pancreatic cancer will be vital to maximising therapeutic benefit of these novel agents, however, the presence of diverse driver mutations in a tumour may result in different markers in the blood that could be used for early detection. Therefore, the student will also use proteomic approaches to analyse potential biomarkers of disease in these different models.
Skills/Techniques that will be gained
The student will be fully supported by a team with nearly 20 years of experience working on preclinical models of pancreatic cancer and testing novel therapies. Training will be provided for both the technical and scientific skills needed for the projects, including working with physiologically relevant genetically engineered mouse models, preclinical imaging, preclinical trials, pancreatic cancer biology and pathology, and a variety of ex vivo techniques including proteomics, immunohistochemistry and multiplex immunofluorescence, spatial transcriptomics, as well as routine molecular biology techniques.
More generally, the Centre provides outstanding training opportunities for its students in state-of-the-art labs with access to the latest technologies. They will participate in the intellectual life of the Centre by attending/giving seminars and can also access University research and transferable skills training programmes.
At the end of their training, students should have a wide range of technical expertise, and the knowledge and understanding to be able to evaluate their own results, and test new hypotheses.
For questions regarding the application process, PhD programme/studentships at the CRUK Scotland Institute or any other queries, please contact phdstudentships@beatson.gla.ac.uk.
Closing date: Monday 25th November 2024
Applications are open to all individuals irrespective of nationality or country of residence.
Relevant Publications
Stoffel EM, Brand RE, Goggins M. Pancreatic Cancer: Changing Epidemiology and New Approaches to Risk Assessment, Early Detection, and Prevention. Gastroenterology. 2023;164(5):752-65.
Coffelt SB, Morton JP. LOXL2 in pancreatic tumourigenesis: the complexity of tumour-stromal crosstalk exemplified. Gut. 2023;72(2):221-2.
Kemp SB, Cheng N, Markosyan N, Sor R, Kim IK, Hallin J, et al. Efficacy of a Small-Molecule Inhibitor of KrasG12D in Immunocompetent Models of Pancreatic Cancer. Cancer Discov. 2023;13(2):298-311.
Wasko UN, Jiang J, Dalton TC, Curiel-Garcia A, Edwards AC, Wang Y, et al. Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer. Nature. 2024;629(8013):927-36.
Mahadevan KK, McAndrews KM, LeBleu VS, Yang S, Lyu H, Li B, et al. KRAS(G12D) inhibition reprograms the microenvironment of early and advanced pancreatic cancer to promote FAS-mediated killing by CD8(+) T cells. Cancer Cell. 2023;41(9):1606-20 e8.
