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Targeting ERK5 to enhance the DNA damage response to radiotherapy and chemotherapy


Project Description

ERK5 is a signalling protein that enables cells to transduce extracellular signals into responses. It is expressed in all tissues and is up-regulated in tumours. Up-regulated EKR5-signalling in patient samples (biopsies) correlates with poorer overall outcome and resistance to chemotherapy. Exactly how ERK5-signalling regulates cancer progression and therapy response is not known.
DNA damage response plays a central role in the development and progression of cancer and the response to therapy. In particular chemotherapy and radiotherapy, which elicit their effects via induction of DNA-damage.
Recent evidence suggests there may be a link between ERK5-signalling and proteins involved in the DNA damage response (particularly ATM). However, the impact of this interaction on tumour progression and chemotherapy and radiotherapy response has yet to be evaluated. The project will use triple-negative breast cancer (TNBC) as a model system to evaluate this interaction.
TNBC is an aggressive cancer which is routinely treated with chemotherapy and radiotherapy. We know from clinical studies that ERK5-signalling is frequently upregulated in TNBC and this upregulation of ERK5 signalling correlates with poorer outcome for patients and a decreased responsiveness to chemotherapy and thus it is likely targeting ERK5 will have significant impact in this scenario.
We have novel tools to evaluate ERK5 e.g. proprietary ERK5 inhibitors, ERK5-modified in vivo models. Using these models we will establish the impact of targeting ERK5 on DNA damage response in vitro and in vivo. Specifically, this project will 1) investigate the potential for ERK5 targeting to potentiate the effects of radiotherapy and chemotherapy in vitro and in vivo in TNBC models, 2) dissect the mechanisms underpinning the interactions, 3) evaluate the translational relevance of findings using patient samples, provided by the MCRC Biobank.
Together this data will give us a clearer idea of how best to target ERK5 for therapeutic gain in TNBC patients.

Training/techniques to be provided:
Cell culture systems and the evaluation of novel therapeutics therein. Cell based modelling of chemotherapy and radiotherapy responses. Biochemical assays – immunoblot, immunofluorescence, gene-expression analyses. In vivo tumour modelling and ex vivo analysis of material from in vivo tumour models
Molecular Biology techniques to manipulate key pathways in cells e.g. lentiviral-delivered expression systems or siRNA mediated knockdown

Entry 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 Biochemistry and Pharmacology are encouraged to apply.

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 http://www.internationalphd.manchester.ac.uk

Funding Notes

Applications are invited from self-funded students. This project has a Band 2 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).

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

1. 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
2. Angulo-Ibáñez M, Rovira-Clavé X, Espel E. ATM meets ERK5. Aging (Albany NY). 2017;9(2):299–300.
3. Stecca B, Rovida E. Impact of ERK5 on the Hallmarks of Cancer. Int J Mol Sci. 2019 Mar 21;20(6):1426..
4. Miranda M, Rozali E, Khanna KK, Al-Ejeh F. MEK5-ERK5 pathway associates with poor survival of breast cancer patients after systemic treatments. Oncoscience. 2015;2(2):99–101.
5. Mei Hua Jin, Do-Youn Oh, ATM in DNA repair in cancer, Pharmacology & Therapeutics,2019,107391

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