Investigating the role of Cellular Prion protein (PrP C) in multi drug resistance (MDR) in schwannoma and meningioma tumours

Applications are invited for a three-year PhD studentship. The studentship will start on 1 October 2022.

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To apply please use the online application form. Simply search for PhD Medical Studies (and select the entry point of October 2022), then clearly state that you are applying for a PhD studentship and name the project at the top of your personal statement.

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For more information on the admissions process, please contact doctoralcollege@plymouth.ac.uk.

Director of Studies: Dr Sylwia Ammoun

2nd Supervisor: Professor Oliver Hanemann

3rd Supervisor: Dr Gyorgy Fejer

Applications are invited for a three-year PhD studentship. The studentship will start on 1 October 2022.

Project description

Deficiency of the tumour suppressor Merlin causes common tumours of the nervous system such as schwannomas and meningiomas occurring sporadically or as part of a genetic disorder Neurofibromatosis Type 2 (NF2). There are no effective drug treatments for NF2- related tumours and current therapies surgery and radiosurgery are not always fully effective or even possible and may result in complications. Meningiomas tend to recur over the years after surgery/radiosurgery, more frequently at higher grade.

Both tumours intrinsically overexpress Multi Drug Resistance protein 1 (MDR1, p-gp) which counteracts potential drug treatments. In this project we investigate and inhibit mechanisms involved in the development of intrinsic MDR in schwannoma and meningioma.

We already found that MDR1 protein overexpression in schwannoma is regulated by Cellular Prion protein (PrPC), which is overexpressed in schwannoma and meningioma (1). We also found that in schwannoma cells MDR1 increases after treatment with PDGFR/cRAF inhibitor Sorafenib and decreases after treatment with PI3K/pAKT inhibitor wortmannin. Importantly we found that combined treatment of Sorafenib and inhibitors targeting PrP or MDR1 potentiate efficiency of Sorafenib in schwannoma cells. Finally, we found strong abundance of M2 polarized macrophages in schwannoma and meningioma (3) tissues which may contribute to drug resistance via overexpression and release of MDR1 and PrPC.

This project builds on above and will aim to investigate: 1) MDR1 expression in all meningioma grades to see whether risk of MDR may change with tumour progression. 2) Mechanisms regulating MDR1 overexpression in schwannoma and meningioma cells. 3) The role of PrPC and MDR1 in drug resistance in schwannoma and meningioma and the mechanisms involved. 4) The role of M2 polarized macrophages in MDR in schwannoma and meningioma.

The supervisory team is part of our Brain Tumour centre of excellence and brings together expertise in brain tumour pathology, basic mechanisms of tumourigenesis and translation (2). Training will be provided for the development of both knowledge and technical skills to enable the trainee to conduct high-quality and independent research.

(1) Provenzano et al. Oncogene 2017 Nov 2;36(44):6132-6142.

(2) Ammoun et al. Jnn 2018-319713

(3) Adams et al. Int J Mol Sci. 2020 Feb 13;21(4):1273.

Eligibility

Applicants should have (at least) a first or upper second class honours degree in an appropriate subject and preferably a relevant MSc or MRes qualification.

The studentship is supported for three years and includes full Home tuition fees plus a stipend of £16,062 per annum. The studentship will only fully fund those applicants who are eligible for Home fees with relevant qualifications. Applicants normally required to cover overseas fees will have to cover the difference between the Home/EU and the overseas tuition fee rates (approximately £12,670 per annum, 2022/23 rate).

NB: The studentship is supported for three years of the four-year registration period. The fourth year is a self-funded ‘writing-up’ year.

If you wish to discuss this project further informally, please contact Dr Sylwia Ammoun.

Please see a list of supporting documents to upload with your application.

For more information on the admissions process generally, please contact doctoralcollege@plymouth.ac.uk.

The closing date for applications is 12 noon on 1 June 2022. 

Shortlisted candidates will be invited for interview week commencing 20 June. We regret that we may not be able to respond to all applications. Applicants who have not received a response within six weeks of the closing date should consider their application has been unsuccessful on this occasion.