Liver Cancer - Developing DNA-PK as a predictive biomarker and clinical target

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Background Primary liver cancer deaths are rising dramatically in Northern England, secondary to obesity, diabetes and 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. Summary of project Outcomes in patients with liver cancer, being treated with TACE or emerging treatments will be assessed. 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. The supervisory team includes Professor Steve Wedge (Drug Discovery), Dr David Jamieson (Pharmacodynamic Biomarkers expertise) and Dr Ruchi Shukla (Molecular Cell Biology Expert) in Newcastle. Professor Daniel Palmer from the Clatterbridge Cancer Centre in Liverpool will be an additional supervisor, providing patient diversity and medical oncology expertise. Astra Zeneca are an iCASE partnership, with an interest in assessing the impact of small molecular inhibitors of the DNA damage repair pathways. Proposed outline of project 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).