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MRC DiMeN Doctoral Training Partnership: Liver Cancer – Developing DNA-PK as a predictive biomarker and clinical target


MRC DiMeN Doctoral Training Partnership

Prof Helen Reeves , Prof Daniel Palmer Wednesday, January 27, 2021 Competition Funded PhD Project (Students Worldwide)
Newcastle United Kingdom Biochemistry Bioinformatics Cancer Biology Cell Biology Immunology Molecular Biology Pathology Pharmaceutical Chemistry

About the Project

Primary liver cancer deaths are rising dramatically in Northern England, secondary to obesity, diabetes & alcohol related liver diseases.  Patients typically present at an advanced stage. Until recently, there haven’t been many treatments and those patients fit enough, with tumours confined to their liver, have received trans-arterial chemotherapy (TACE). In 30-50% this works well (median survival 24 months), but if it doesn’t, patients are rarely strong enough afterwards to consider any of the exciting immuno-oncology (IO) or other palliative treatments emerging – which can deliver dramatic benefits. We desperately need biomarkers to inform personalised treatment choices, either alone or in combination with TACE or other medical-/radio-therapies.

This student will study outcomes in patients with liver cancer, being treated with TACE or emerging treatments.  The patient samples will be used in tissues and liquid biomarker studies or pre-clinical models. A central focus will be on DNA-PK – a key enzyme that repairs DNA damage. Work by the primary supervisor team indicate that its amplification is associated with resistance to TACE/radiotherapy, as it repairs treatment induced damage. DNA-PK also has suspected roles in the anti-cancer immune response. DNA-PK inhibition (DNA-PKi) in conjunction with other treatments has tantalising therapeutic potential. An assay to detect its amplification in blood/serum will aid treatment stratification.

Supervisor team 1 (Newcastle – Helen Reeves, Hepatology; Steve Wedge - drug discovery; David Jamieson - pharmacodynamic biomarkers; Ruchi Shukla – Molecular Biology) has patients/tissues/resource/expertise needed to develop liquid biopsy tools & preclinical models.

https://www.ncl.ac.uk/research/cancer/

Helen Reeves

https://research.ncl.ac.uk/hunter/

https://research.ncl.ac.uk/drugdiscovery/

https://www.ncl.ac.uk/medical-sciences/people/profile/davidjamieson.html

https://www.ncl.ac.uk/medical-sciences/people/profile/ruchishukla.html

Supervisor team 2 (Daniel Palmer, Liverpool - oncology) leads highly relevant UK trials [TACE-3 study - TACE alone 1st line versus TACE+IO (Nivolumab); ARACHNID study - 1st line advanced HCC - IO alone (durvalumab+tremelimumab) or radiotherapy (SBRT/protons)], will support recruitment and the development/delivery of treatment stratification. 

Daniel Palmer

Clatterbridge Cancer Centre

https://www.lctu.org.uk/LCTU_NET/Frontend/Default.aspx?Data=W1tRMjl1ZEdWdWRFbEVdXVtNelEzXVtbYkc5allXeGxdXVtOQT09XQ%3D%3D

Supervisor team 3  (Mark J. O'Connor - Chief Scientist, Oncology, Head of DNA Damage Response Biology, Astra Zeneca) are an industry partner actively pursuing DNA-PK and associated strategies as therapeutic strategies, keen to provide inhibitors & test biomarker guided strategies in preclinical models. 

https://www.astrazeneca.com/our-company/our-people/mark-o-connor.html

Objectives, timeline and techniques

In addition to working closely with supervisory teams, the student will join the CRUK Hepatocellular Carcinoma Expediter Network (HUNTER), led by Reeves, presenting their own data and collaborating with other partners (London/ Cambridge/ Southampton/ Glasgow/ Barcelona/Rome/Milam/Parma)

1.  Validate DNA-PK/pDNA-PK as tissue biomarkers (Year1; Immunohistochemistry; Digital Image Analysis)

2.  Explore copy number variation (CNV) in plasma (Year1; array technology, focused on DNA-PK).

3.  Explore (1) and (2) with tumour stage, response to treatment, survival (Year2).

4.  Assess the impact of DNA-PKi in combination with cytoxic/IO/radiotherapies, in-vitro and in-vivo (Year 2-3; liver slices/organoids/printed tumour cells/immune cells).

5.  Develop predictive biomarkers (tissues/plasma) for clinical validation (Year3 – integration with clinical data/other datasets eg. Immune scores, hyperion mass-spec, RNA scope).

Broader implications/impact 

Given the rising deaths from liver cancer, this is a timely project, applying novel technologies to help guide treatment choice in what is a dynamic and rapidly changing field.  

The Discovery Medicine North Doctoral Training Partnership, is 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 & Sheffield) are internationally recognised as centres of research excellence & can offer you access to state-of the-art facilities for high impact research.

We are very proud of our student-centred ethos & committed to supporting students. We offer bespoke training in key skills sought after in early career researchers, & opportunities to broaden your career horizons in a wide range of sectors.

Funding by the MRC provides additional funding for research placements, international training, internships in science policy, science communication & beyond. See how current DiMeN students have benefited here

Further information


Funding Notes

Funded by the MRC for 3.5yrs, including a minimum of 3 months working within the industry partner.

Funding will cover UK tuition fees and an enhanced stipend (around £17,785) only. We aim to support the most outstanding applicants from outside the UK. We 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. Ogle LF, Orr JG, Willoughby CE, Hutton C, McPherson S, Plummer R, Boddy AV, Curtin NJ, Jamieson D, Reeves HL. Imagestream detection and characterisation of circulating tumour cells - A liquid biopsy for hepatocellular carcinoma? J Hepatol. 2016;65:305-13. doi: 10.1016/j.jhep.2016.04.014.
2. Willoughby CE, Jiang Y, Thomas HD, Willmore E, Kyle S, Wittner A, Phillips N, Zhao Y, Tudhope SJ, Prendergast L, Junge G, Lourenco LM, Finlay MRV, Turner P, Munck JM, Griffin RJ, Rennison T, Pickles J, Cano C, Newell DR, Reeves HL, Ryan AJ, Wedge SR. Selective DNA-PKcs inhibition extends the therapeutic index of localized radiotherapy and chemotherapy. J Clin Invest. 2020;130:258-271. doi: 10.1172/JCI127483.
3. Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, Verslype C, Zagonel V, Fartoux L, Vogel A, Sarker D, Verset G, Chan SL, Knox J, Daniele B, Webber AL, Ebbinghaus SW, Ma J, Siegel AB, Cheng AL, Kudo M; KEYNOTE-224 investigators. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018;19:940-952. doi: 10.1016/S1470-2045(18)30351-6. Clinical Trial

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