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TGF-beta family members as potential therapeutic targets in pancreatic cancer


PhD Programme

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Dr C Hill , Dr R Wilkinson , Dr D Sarker No more applications being accepted Competition Funded PhD Project (European/UK Students Only)

About the Project

The project is focused on overcoming resistance to immune checkpoint inhibitors (ICIs) in pancreatic cancer by inhibiting the activity of particular ligands of the TGF-b family.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most rapidly progressive, difficult to treat and deadly malignancies worldwide [1]. The tumours are characterised by desmoplasia, which is the result of a dramatic increase in myofibroblast proliferation, and is associated with increased deposition of extracellular matrix (ECM) components. Desmoplasia makes drug delivery to the tumours difficult and contributes to resistance to standard-of-care chemotherapy and to novel immunotherapy approaches [2, 3]. Recent work in the Hill lab at the Francis Crick Institute has identified two closely-related TGF-b family members that are secreted by cancer-associated fibroblasts (CAFs) in both human PDAC and also in mouse models of PDAC. These ligands drive the production of ECM and are immune suppressive [4, 5]. We have recently demonstrated that secretion of these ligands leads to exclusion of immune cells in the tumours, which is a potential resistance mechanism in cancer patients who do not respond to ICIs. In collaboration with AstraZeneca we have developed a human antibody that is capable of neutralising these ligands, and we have exciting preliminary evidence that ligand neutralisation leads to higher infiltration of CD4+ and CD8+ T cells in tumours in a mouse model of PDAC. This suggests that combining this antibody with ICIs could be a promising approach for treating PDAC patients.

The proposed project has three main aims:

Firstly, the clinical fellow will generate a ‘high ligand signature’ by performing RNA-seq on normal fibroblasts treated ± the TGF-b family ligands, and also on CAFs from cancer patients, which we predict to express high levels of these ligands, treated in vitro ± neutralising antibody. We propose to use this bespoke signature to analyse tumours from patients before and after treatment with ICIs, across a number of indications, to determine whether it is capable of predicting which patients might respond to combination therapy comprising ICIs and the ligand neutralising antibody.

Secondly, the clinical fellow will use orthotopic mouse models of PDAC (which are ICI insensitive) to test the efficacy of combining ICIs with our neutralising antibody in reducing tumour growth and spread. They will address by high-content imaging and complex multicolour immunophenotyping by flow cytometry, whether the neutralising antibody modulates the immune infiltrate present in treated tumours, and thus whether the neutralising antibody can resensitise refractory tumours to the effects of ICIs.

Finally, our preliminary data has indicated that PDAC patients have elevated levels of ligands in their circulation compared with age-matched normal patients, and also we have detected high levels of these ligands in PDAC tumours. The clinical fellow will collect human PDAC samples and matched longitudinal bloods to understand how levels of ligand in tumours correlate with disease stage and different treatments, and also determine whether ligand levels in tumours correlate with circulating levels of ligand.

We are looking for a talented and motivated clinician with a strong academic track record, who is passionate about research and wants to pursue a career as an academic clinician in oncology. The applicant would be expected to have a medical degree, ideally some previous wet lab experience and continuous full General Medical Council (GMC) registration or equivalent national registration outside the UK.

The clinical fellow will have access to the state-of-the-art facilities at the Francis Crick Institute and AstraZeneca. They will gain expertise in human sample acquisition, and in analysis of signalling pathway components, ECM components and different stromal cell types using immunohistochemistry and immunofluorescence. They will learn next generation sequencing methods and analysis, and will gain experience in transgenic and syngeneic transplant tumour models in mice, and in high content immunophenotyping. The clinical fellow will also participate in regular project team meetings and gain knowledge of therapeutic development with AstraZeneca.

For details on how to apply please visit: https://www.colcc.ac.uk/crtf-recruitment-process/

For any informal enquiries on the project please contact Dr Caroline Hill: [Email Address Removed]

For any enquiries on the CRUK CoL Centre programme please contact Annabelle Scott: [Email Address Removed]

Funding Notes

We are looking for clinicians who are passionate about research, have a strong academic track record and hold full GMC registration or equivalent.

Applicants for this competitive programme are expected to have:
a medical degree
previous wet or dry lab research experience (desirable)
continuous full General Medical Council (GMC) registration or equivalent

Applications are welcomed from:
candidates from all medical and surgical specialities
Applicants should be in a training position (not necessarily with a training number). Candidates at consultant grade will not be considered.

Due to funding restrictions only UK / EU nationals are eligible to apply for this fellowship

References

1. Rossi, M. L., Rehman, A. A. and Gondi, C. S. (2014) Therapeutic options for the management of pancreatic cancer. World J Gastroenterol 20: 11142-11159.

2. Pereira, B. A., Vennin, C., Papanicolaou, M., Chambers, C. R., Herrmann, D., Morton, J. P., . . . Timpson, P. (2019) CAF Subpopulations: A New Reservoir of Stromal Targets in Pancreatic Cancer. Trends Cancer 5: 724-741.

3. Neesse, A., Bauer, C. A., Öhlund, D., Lauth, M., Buchholz, M., Michl, P., . . . Gress, T. M. (2019) Stromal biology and therapy in pancreatic cancer: ready for clinical translation? Gut 68: 159-171.

4. Wakefield, L. M. and Hill, C. S. (2013) Beyond TGFb: roles of other TGFb superfamily members in cancer. Nat Rev Cancer 13: 328-341.

5. Mariathasan, S., Turley, S. J., Nickles, D., Castiglioni, A., Yuen, K., Wang, Y., . . . Powles, T. (2018) TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554: 544-548.
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