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MRC DiMeN Doctoral Training Partnership: Harnessing Autophagy for the Clinical benefit of Oropharyngeal Squamous Cell Carcinoma


Project Description

Oropharyngeal squamous cell carcinoma (OPSCC) accounts for 97,000 deaths annually worldwide with an increasing incidence attributed to human papillomavirus (HPV). Nevertheless, patients with HPV-positive OPSCC have a more favourable prognosis compared to their HPV-negative counterparts, stimulating a timely call for the re-evaluation of diagnostic, preventative and treatment guidelines and the potential to de-escalate treatment for HPV-positive OPSCC. Recent clinical trials of chemo-radiation versus cetuximab and radiotherapy for patients with HPV-related OPSCC however, showed no reduction in toxicity with inferior survival, reflecting the heterogeneity of this group of tumours. Consequently, there is an acute need for credible biomarkers to identify genuinely low risk HPV-positive tumour subsets as well as more effective personalised/precision based therapeutic strategies for high risk OPSCC.

The current iCASE PhD studentship will build upon exciting studies by the supervisory team, Professor Penny Lovat (https://www.ncl.ac.uk/icm/people/profile/pennylovat.html#background) and clinical academic pathologist, Dr Max Robinson (https://www.ncl.ac.uk/cohr/people/profile/maxrobinson.html#background) and the collaborating biotechnology company (AMLo Biosciences Ltd, https://amlo-biosciences.com/, https://twitter.com/AMLoBiosciences) demonstrating retention of the pro-autophagy regulatory protein AMBRA1 by primary OPSCCs is associated with reduced patient survival while HPV- induced degradation of AMBRA1 leads to the suppression of pro-survival autophagy and the increased susceptibility of OPSCC cells to drug-induced apoptosis. Using an immunohistchemical assay in development by AMLo Biosciences, a key aim of the studentship will be to validate and develop AMBRA1 as prognostic/treatment stratification biomarker for OPSCC, incorporating the analysis of pre-defined national and international OPSCC tissue cohorts and correlating expression with HPV status and clinical outcome. To determine the optimal strategy to harness autophagy modulation for the clinical benefit of high risk OPSCC, both pharmacological (using specific autophagy inhibitors or cannabinoid cyotoxic autophagy promoting agents) and genetic inhibition (using shRNA or CRISPR/Cas9) of autophagy and AMBRA1 expression will be performed in established OPSCC cell lines prior to determining the effects on tumour invasion/migration, clonagenicity, proliferation and cell death.

Training will be provided in both molecular biology and pathology and the student will work at the interface of academia and industry in an international and translational setting. Key skills will be attained in clinical biomarker development and validation, drug target development and bioscience research and enterprise including intellectual property, regulatory processes for manufacturing, product development and marketing. The studentship is particularly suited to graduates in the oncology field with an understanding and an appetite to develop his or her career in translational medical research in the academic and/or life sciences industrial sector.

Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme can be found on our website:
http://www.dimen.org.uk/

Funding Notes

iCASE Award: Industrial partnership project
Fully funded by the MRC for 3.5yrs, including a minimum of 3 months working within the industry partner. Enhanced stipend, tuition fees and budget for consumables, travel and subsistence.
Studentships commence: 1st October 2020.

To qualify, you must be a UK or EU citizen who has been resident in the UK/EU for 3 years prior to commencement. Applicants must have obtained, or be about to obtain, at least a 2.1 honours degree (or equivalent) in a relevant subject. All applications are scored blindly based on merit. Please read additional guidance here: View Website
Good luck!

References

Mehanna H, Robinson M, Hartley A, Kong A, Foran B, Fulton-Lieuw T, et al. (2019)
Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial.
Lancet 393:51–60.

Ellis R, Tang D, Nasr B, Greenwood A, McConnell A, Anagnostou ME, Elias M, Verykiou S, Bajwa D, Ewen T, Reynolds NJ, Barrett P, Carling E, Watson G, Armstrong J, Allen AJ, Horswell S, Labus M, Lovat PE.(2019)
Epidermal autophagy and beclin 1 regulator 1 (AMBRA1) and loricrin: a paradigm shift in the prognostication and stratification of the American Joint Committee on Cancer stage I melanomas.
Br J Dermatol. May 6. doi: 10.1111/bjd.18086. [Epub ahead of print]

Cosway B, Lovat PE (2016) The role of autophagy in squamous cell carcinoma of the head and neck. Oral Oncology 15: 433-9

How good is research at Newcastle University in Clinical Medicine?

FTE Category A staff submitted: 147.13

Research output data provided by the Research Excellence Framework (REF)

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