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/
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.
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.
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