Targeting ERK5 to Treat Mesothelioma: A New Immunotherapy Approach?

University of Manchester

Faculty of Biology, Medicine and Health

Project Description

Malignant mesothelioma (MM) has an average survival time of less than 12 months post-diagnosis. There is an urgent need to develop novel therapies to treat MM. The fundamental cell-signalling protein ERK5 represents an ideal target to achieve this. We, and others, have shown that ERK5 drives progression of mesothelioma, prostate cancer, colorectal cancer and breast cancer both pre-clinically and in patients. Mechanistically, our lab has demonstrated ERK5 controls tumour progression by sustaining intra-tumoural macrophage populations and maintaining their pro-tumourigenic polarisation. This is crucial since MM is an inflammation-driven cancer with clinical evidence demonstrating that M2-macrophages are associated with decreased overall survival.

Pre-clinical studies demonstrated ERK5 inhibition (via shRNA) induces MM regression in vivo. However, these previous studies have two major caveats 1) they were conducted in models without an intact immune system, so the impact of ERK5 signalling on tumour-associated inflammation could not be properly assessed, 2) they employed shRNA to target ERK5, which is not a valid therapeutic strategy for patients.

Recently, our unpublished work has addressed the limitations of this previous work by using an immune-competent, orthotopic murine model of MM, to reveal as yet undiscovered roles of ERK5 in MM. We have also tested our novel, proprietary inhibitors of ERK5 in MM and we have found them to be very effective.

This project will build on that exciting new data. We will use in vitro model systems and in vivo models to understand underpinning mechanisms and test and understand our drug efficacy, evaluate scheduling regimes and the potential of our new drugs to augment existing standard of care for MM.

If successful, this project will have found a new immunotherapy approach for the treatment of MM, a cancer of huge unmet need, for which only no effective targeted therapies have been developed to date.

Funding Information

Applications are invited from self-funded students. This project has a Band 3 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

Eligibility Requirements

Candidates are expected to hold (or be about to obtain) a first class honours degree (or equivalent) in a Biosciences or a related subject. Candidates with experience in Cancer Biology, Biochemistry and Pharmacology are encouraged to apply.

Application Process

For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website here: Visit Website. Informal enquiries may be made directly to the primary supervisor. On the online application form select PhD Immunology.

Supplementary Information

For international students we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit here: International Page.

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

Finegan, K., Perez Madrigal, D., Hitchin, J., Davies, C., Jordan, A. & Tournier, C.ERK5 is a critical mediator of inflammation-driven cancer. 15 Feb 2015, In : Cancer Research. 75,4

Stecca B, Rovida E. Impact of ERK5 on the Hallmarks of Cancer. Int J Mol Sci. 2019 Mar 21;20(6):1426.

Shukla A, Miller JM, Cason C, et al. Extracellular signal-regulated kinase 5: a potential therapeutic target for malignant mesotheliomas. Clin Cancer Res. 2013;19(8):2071-2083

Wang H, Dai YY, Zhang WQ, et al. DCLK1 is correlated with MET and ERK5 expression, and associated with prognosis in malignant pleural mesothelioma. Int J Oncol. 2017;51(1):91-103

Giurisato E, Xu Q, Lonardi S, et al. Myeloid ERK5 deficiency suppresses tumor growth by blocking protumor macrophage polarization via STAT3 inhibition. Proc Natl Acad Sci U S A. 2018;115(12):E2801-E2810. doi:10.1073/pnas.1707929115

To apply for this PhD, please use the following application link: https://www.bmh.manchester.ac.uk/study/research/apply/

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