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MRC DiMeN Doctoral Training Partnership: Novel strategies for radioresistant head and neck cancers through targeting the DNA damage response in combination with high-precision proton beam therapy


MRC DiMeN Doctoral Training Partnership

Liverpool United Kingdom Biochemistry Cancer Biology Cell Biology Molecular Biology

About the Project

Background

Proton beam therapy (PBT) is increasingly being utilized worldwide for treatment of specific cancers, such as head and neck squamous carcinoma (HNSCC), as it precisely delivers the radiation dose to the tumour and limits irradiation of surrounding normal tissues. HNSCC is of significant importance to the North West region due to the high local incidence. The UK is particularly benefiting from new NHS PBT Centres in Manchester and London, which are in addition to the PBT facilities at the Clatterbridge Cancer Centre (CCC) NHS Foundation Trust that have been successfully treating patients with cancers of the eye for over 25 years. 

Despite this, there are still significant biological uncertainties of the molecular/cellular effects of PBT due to decreases in energy (increases in ionisation/linear energy transfer) at and around the Bragg peak where the radiation dose is deposited. This consequently leads to significant uncertainties in the use of PBT for the treatment of cancer patients in the clinic. Furthermore, identification of combinational strategies using drugs/small molecule inhibitors that can enhance sensitivity of radioresistant cancers, including subtypes of HNSCC, to PBT are unclear and maybe distinct from conventional (x-ray) radiation.

Objectives

This exciting DTP studentship will develop novel PBT research investigating key enzymes involved in the cellular DNA damage response (DDR), as targets for specific inhibitors (including those acquired in collaboration with AstraZeneca) to overcome radioresistance of HNSCC. This will be delivered through the use of established 2D cell lines, 3D spheroids and patient-derived organoids. The specific objectives are to:-

·      Analyse the impact of specific inhibitors targeting PARG (PDD00017273), ATM (AZD1390), ATR (AZD6738) and DNA-Pk (AZD7648) in sensitizing HNSCC 2D cell lines and 3D spheroids to PBT.

·      Perform mechanistic analysis to confirm action of targeted inhibitors in the inhibition of the cellular DDR following PBT.

·      Analyse the combination of targeted inhibitors with PBT on patient-derived 3D organoids.

Impact and training

This molecular and cellular biology-focussed research is timely given the increased use of PBT in the UK for cancer treatment, but is also the first to examine the effect of targeting DDR enzymes in combination with PBT in radiosensitising HNSCC 2D and 3D preclinical models. To enable this novel work that is at the interface of clinical and translational medicine, we have exclusive access to the clinical PBT centre at the CCC for cell irradiations, which is also equipped with unique on-site molecular and cellular laboratory facilities. The DTP student will actively drive this preclinical research and fully establish a collaborative partnership with Dr Parsons in Liverpool (https://www.liverpool.ac.uk/translational-medicine/staff/jason-parsons/) and Dr Bryant in Sheffield (https://www.sheffield.ac.uk/medicine/people/oncology-metabolism/helen-e-bryant) who are experts and have synergies in radiobiology, PBT and DNA repair/replication. This project has high translational potential in the establishment of more effective treatments for HNSCC using PBT.

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 and how to apply can be found on our website:

https://bit.ly/3lQXR8A 


Funding Notes

Studentships are funded by the Medical Research Council (MRC) for 3.5yrs. Funding will cover UK tuition fees and stipend only. We aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme. Please read additional guidance here: View Website
Studentships commence: 1st October 2021
Good luck!

References

1. Vitti, E-T., Kacperek, A., and Parsons, J.L. (2020) Targeting DNA double-strand break repair enhances radiosensitivity of HPV-positive and HPV-negative head and neck squamous cell carcinoma to photons and protons. Cancers., 12 (6):1490, doi: 10.3390/cancers12061490.
2. Carter, R.J., Nickson, C.M., Thompson, J.M., Kacperek, A., Hill, M.A., and Parsons, J.L. (2019) Characterisation of deubiquitylating enzymes involved in the cellular response to high-LET ionising radiation and complex DNA damage Int. J. Radiat. Oncol. Biol. Phys., 104 (3), 656-665, doi: 10.1016/j.ijrobp.2019.02.053.
3. Gravells, P., Neale, J., Grant, E., Nathubhai, A., Smith, K.M., James, D.I., and Bryant, H.E. (2018) Radiosensitization with an inhibitor of poly(ADP-ribose) glycohydrolase: A comparison with the PARP1/2/3 inhibitor olaparib. DNA repair., 61, 25-36, doi: 10.1016/j.dnarep.2017.11.004.

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