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Precision Medicine DTP - Proteomic analysis of FAK function in human pancreatic cancer


Project Description

Background

In the United Kingdom, the 5-year survival rate for patients with pancreatic ductal adenocarcinoma (PDAC) is just 3% (Cancer Research UK statistics), and as a result pancreatic cancer is the 4th most common cause of cancer death in the UK and US. With increasing incidence and only small incremental improvements in treatment, it is predicted to become the 2nd most common cause of cancer death within the next decade. Immunotherapy has shown immense promise in the treatment of some cancers. However, it has had limited impact on the treatment of pancreatic cancer and patient prognosis remains poor. Therefore, understanding key molecular pathways that drive resistance to immunotherapy will enable development of new therapeutic strategies for this cancer of high unmet need.

Recently, our own work, and that of others, has identified a novel role for the non-receptor protein tyrosine kinase Focal Adhesion Kinase (FAK) in promoting immune evasion (Serrels et al, Cell, 2015) and resistance to immunotherapy in multiple tumour types, including pancreatic cancer (Jiang et al, Nat Med, 2016). These studies have led directly to ongoing clinical trials investigating the safety, tolerability, and anti-tumour efficacy of FAK inhibitors in combination with anti-PD1 immune checkpoint blockade in patients with pancreatic cancer. However, we still lack understanding of how best to utilize FAK inhibitors in combination with other immunotherapies, and which patients are most likely to benefit from targeting FAK.

Our current studies have identified a novel role for FAK in regulating the interferon (IFN) response in clinically relevant mouse models of pancreatic cancer. Functional IFN signalling is critical for the action of immune checkpoint inhibitors (Gao J, Cell, 2016), hence our findings may have important clinical significance. Specifically, we have identified that FAK suppresses the IFN-induced expression of antigen processing, transport, and presentation pathways in a subset of murine pancreatic cancer cells, and have shown that this contributes to immune evasion. Here, we aim to build on these findings by using proteomics approaches (e.g. quantitative expression proteomics, immunopeptidomics) to investigate FAK-dependent regulation of the IFN response in a panel of human patient-derived PDAC cell lines (approximately 30) that have already been classified using transcriptomics into one of the two major molecular subtypes (pancreatic progenitor and squamous) of human PDAC. Our overarching goal is to identify whether FAK regulates the type-II interferon response in human pancreatic cancer and in particular the antigen repertoire presented by human pancreatic cancer cells, and to define a clinically relevant prognostic signature that could be used to stratify pancreatic cancer patients most likely to show increased sensitivity to immunotherapy agents via FAK-dependent regulation of IFN signalling.

Aims

1) Undertake quantitative proteomic analysis of approximately 30 human PDAC cell lines +/- IFN-gamma +/- FAK inhibition.

2) Undertake extensive analysis of proteomic data to identify cell lines in which FAK expression suppresses IFN-gamma induced antigen processing/presentation pathways, and define prognostic signatures that correlate with FAK-dependent regulation of the interferon response.

3) Proteomic analysis of FAK-dependent regulation of the antigen repertoire / antigen diversity and extensive data analysis to identify of potential tumour neoantigens regulated by FAK.

Training Outcomes

1) Key lab-based skills, including cell culture, protein purification, immunoprecipitation, and sample processing/analysis for/by mass spectrometry. Supervision will be provided by Serrels and Kriegsheim.

2) A range of computational skills required for analysis of quantitative proteomics data, including network analysis, data clustering, statistical analysis and bioinformatics. Supervision will be provided by Byron and Kriegsheim.

3) Key skills in data interrogation, interpretation, presentation, and communication.

4) A comprehensive understanding of the biology of pancreatic cancer, cancer immunology, and the clinical challenges in treating this disease.

This MRC programme is joint between the Universities of Edinburgh and Glasgow. You will be registered at the host institution of the primary supervisor detailed in your project selection.

All applications should be made via the University of Edinburgh, irrespective of project location. For those applying to a University of Glasgow project, your application along with any supporting documents will be shared with University of Glasgow.

http://www.ed.ac.uk/studying/postgraduate/degrees/index.php?r=site/view&id=919

Please note, you must apply to one of the projects and you must contact the primary supervisor prior to making your application. Additional information on the application process is available from the link above.

For more information about Precision Medicine visit:
http://www.ed.ac.uk/usher/precision-medicine

Funding Notes

Start: September 2020

Qualifications criteria: Applicants applying for a MRC DTP in Precision Medicine studentship must have obtained, or will soon obtain, a first or upper-second class UK honours degree or equivalent non-UK qualification, in an appropriate science/technology area.
Residence criteria: The MRC DTP in Precision Medicine grant provides tuition fees and stipend of at least £15,009 (RCUK rate 2019/20) for UK and EU nationals that meet all required eligibility criteria.

Full eligibility details are available: View Website

Enquiries regarding programme:

References

1. Serrels A, Lund T, Serrels B, Byron A, McPherson RC, von Kriegsheim A, Gómez-Cuadrado L, Canel M, Muir M, Ring JE, Maniati E, Sims AH, Pachter JA, Brunton VG, Gilbert N, Anderton SM, Nibbs RJ, Frame MC. Nuclear FAK controls chemokine transcription, Tregs, and evasion of anti- tumor immunity. Cell. 2015 Sep 24;163(1):160-73. doi: 10.1016/j.cell.2015.09.001.

2. Jiang H, Hegde S, Knolhoff BL, Zhu Y, Herndon JM, Meyer MA, Nywening TM, Hawkins WG, Shapiro IM, Weaver DT, Pachter JA, Wang-Gillam A, DeNardo DG. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat Med. 2016 Aug;22(8):851-60. doi: 10.1038/nm.4123. Epub 2016 Jul 4.

3. Gao J, Shi LZ, Zhao H, Chen J, Xiong L, He Q, Chen T, Roszik J, Bernatchez C, Woodman SE, Chen PL, Hwu P, Allison JP, Futreal A, Wargo JA, Sharma P. Loss of IFN-γ Pathway Genes in Tumor Cells as a Mechanism of Resistance to Anti-CTLA-4 Therapy. Cell. 2016 Oct 6;167(2):397- 404.e9. doi: 10.1016/j.cell.2016.08.069. Epub 2016 Sep 22.

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