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Exploring the response of 3D cell models of head and neck squamous cell carcinoma to proton beam therapy for therapeutic gain

  • Full or part time
  • Application Deadline
    Sunday, March 03, 2019
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

Project Description: Bark Medal Studentship
A 3-year Bark Medal PhD Studentship is available in the research group of Dr Jason Parsons based in the Cancer Research Centre – University of Liverpool. The major goal of this project is to use newly established 3D cell models of head and neck squamous cell carcinoma (HNSCC) to examine their response to proton beam therapy, and to devise future, optimal strategies for the effective treatment of the tumour.

HNSCC is the 6th most common cancer worldwide, and highly prevalent in the North West region of the UK region. There has been a particularly rapid rise in the incidence of human papillomavirus type 16 (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) although interestingly these patients display improved survival rates, due to increased response to radiotherapy and chemotherapy, in comparison to HPV-negative patients whose outcome is very poor. Indeed we’ve recently demonstrated the same increased radiosensitivity of cultured cells from HPV-positive versus HPV-negative OPSCC, but discovered that this is a consequence of defects in the repair of radiation-induced DNA double strand breaks (Nickson et al., 2017). Despite this, acute and long term side-effects in HNSCC patients as a consequence of radiotherapy treatment are common. Therefore strategies to reduce or limit the adverse side effects, as well as improving the response of HPV-negative HNSCC to radiotherapy are actively being sought.

Over 70 proton beam therapy (PBT) centres are operational worldwide, with at least 50 more in construction (https://www.ptcog.ch) including two NHS facilities in Manchester and London which will be active this year and 2020, respectively. This demonstrates the current and future importance of PBT for treatment of solid tumours, such as HNSCC. PBT is a cutting edge technique that can directly target the tumour and spares the surrounding normal healthy tissues, leading to reduced side effects. However PBT results in variations in energy (via the Bragg peak) which can have a differential impact on the biological response of tumours, particularly mediated through DNA damage and its repair. Indeed we’ve recently demonstrated, utilising currently the only routinely used clinical PBT facility in the UK at the Clatterbridge Cancer Centre (CCC) in Bebington, the benefit of low energy protons in comparison to high energy protons in increasing HNSCC cell killing through formation of complex DNA damage, where multiple DNA lesions are in close proximity (Carter et al., 2018). We have also performed a novel siRNA screen identifying specific enzymes that when targeted can increase the efficacy of PBT in HNSCC cell killing (Carter et al., preprint available-http://biorxiv.org/cgi/content/short/453118v1). Despite this, the radiobiology of PBT is still not fully understood.

We have now established 3D spheroid models of HPV-negative HNSCC (from oropharynx, larynx, hypopharynx and oral cavity) and have acquired access to patient-derived organoids that more accurately reflect the structure and environment of the original tumour. The aim of this studentship is to use these 3D models to examine the impact of PBT (at CCC) at different energies on spheroid growth, and investigate how these effects are mediated through DNA damage and its subsequent repair. The impact of targeting specific DNA repair enzymes (through specific drugs and/or CRISPR-Cas9 gene knockouts) on the response of these models to PBT will also be explored. Furthermore, whole genome CRISPR-Cas9 screening will be used to identify novel genes that control HNSCC cell survival in response to PBT. The research will involve various molecular and cellular biology techniques (e.g. spheroid/organoid growth by light microscopy, quantitative DNA damage and DNA repair foci analysis by comet assays and immunofluorescence microscopy, CRISPR-Cas9 technology). The long term goal is the identification and development of optimal treatment strategies using PBT for effective HNSCC treatment.

To apply please send your CV including the names of two referees, and a covering letter stating the reasons for your interest in the studentship and why you feel your experience and qualifications make you a suitable candidate, to Dr Jason Parsons ().

For application enquires please also contact Dr Parsons.

Funding Notes

This 3-year PhD studentship part funded by a Bark Medal Endowment and covers tuition fees (UK/EU), and research support. There is no stipend. Living costs to be met through a student loan or self-funding.

References

1. Carter, R.J., Nickson, C.M., Thompson, J.M., Kacperek, A., Hill, M.A., and Parsons, J.L. Characterisation of deubiquitylating enzymes involved in the cellular response to high-LET ionising radiation and complex DNA damage. (preprint available-http://biorxiv.org/cgi/content/short/453118v1).
2. Carter, R.J, Nickson, C.M., Kacperek, A., Thompson, J., Hill, M.A., and Parsons, J.L. (2018) Complex DNA damage induced by high-LET α-particles and protons triggers a specific cellular DNA damage response. Int. J. Radiat. Oncol. Biol. Phys., 100 (3), 776-784.
3. Nickson, C.M., Moori, P., Carter, R.J., Rubbi, C.P., and Parsons, J.L. (2017) Misregulation of DNA damage repair pathways in HPV-positive head and neck squamous cell carcinoma contributes to cellular radiosensitivity. Oncotarget, 8 (18), 29963-29975.

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