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Understanding how ERK5 controls osteosarcoma development and response to treatment


Project Description

Osteosarcoma is the most common primary malignant tumour of the bone. A quarter of patients present with metastatic disease, which has a 20% survival rate past 5 years. Unfortunately, these survival rates have remained virtually unaltered for 30 years. Consequently, there is an urgent need for novel therapeutic strategies to treat osteosarcoma. A promising new therapeutic target for osteosarcoma is ERK5. A recent study of samples from osteosarcoma patients showed that high levels of ERK5 correlated with disease progression (87% of patients), resistance to chemotherapy (53% of patients), and was detected in 70% of metastases, where it correlated with decreased overall survival.

We have performed the first in vivo evaluation of the role of ERK5 in osteosarcoma (unpublished) and found that ERK5 loss impedes osteosarcoma growth in mouse models and prevents metastatic spread. This effect appears to be mediated by regulation of the immune cells in osteosarcoma tumours. However, several outstanding questions remain. How does EKR5 control osteosarcoma development? Can we target ERK5 to improve response to chemotherapy? Is EKR5 a potential new biomarker for osteosarcoma? Answering these questions is pivotal to finding new therapeutic targets and improving outcomes for osteosarcoma patients and is the objective of this PhD studentship. To achieve this, firstly we will use different molecular approaches to dissect out the impact ERK5 has on osteosarcoma cells and identify changes that indicate ERK5-driven function. Secondly, we will cross check whether the changes we have identified in mouse models translate to osteosarcoma patients, using patient biopsy material. Finally, we will evaluate if removing ERK5 in osteosarcoma mouse models can improve response to chemotherapy. It is important to note that via a parallel project, this project will have access to our novel class of ERK5 inhibitors, which when developed represent a promising new avenue for treatment of osteosarcoma patients.

Entry Requirements:
Applicants are expected to hold, or about to obtain, a minimum upper second class undergraduate degree (or equivalent) in Immunology or a subject relating to Cancer Biology, a Masters degree in a relevant subject and preferably practical experience in in vivo disease modelling and handling of patient samples. For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor.

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.

Funding Notes

This project is funded by Hannah’s Willberry Wonder Pony Charity (HWWPC). Studentship funding is for a duration of three years to commence in September 2019 and covers UK/EU tuition fees and a stipend (£15,009 per annum 2019/20). Due to funding restrictions the studentship is open to UK and EU nationals with 3 years residency in the UK. If you are interested please make direct contact with the Supervisor to discuss the project . You MUST also submit an online application form - choose PhD Cancer Sciences

References

1. Kansara, M., Teng, M.W., Smyth, M.J. & Thomas, D.M. Translational biology of osteosarcoma. Nat Rev Cancer 14, 722-35 (2014).
2. Finegan, K.G. et al. ERK5 is a critical mediator of inflammation-driven cancer. Cancer Res 75, 742-53 (2015).
3. Tesser-Gamba, F. et al. MAPK7 and MAP2K4 as prognostic markers in osteosarcoma. Hum Pathol 43, 994-1002 (2012).
4. Endo-Munoz, L., Evdokiou, A. & Saunders, N.A. The role of osteoclasts and tumour-associated macrophages in osteosarcoma metastasis. Biochim Biophys Acta 1826, 434-42 (2012).
5. Nithianandarajah-Jones, G.N., Wilm, B., Goldring, C.E., Muller, J. & Cross, M.J. ERK5: structure, regulation and function. Cell Signal 24, 2187-96 (2012).

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