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

在英格兰北方，原发性肝癌死亡率急剧上升，继发于肥胖、糖尿病和酒精相关的肝病。患者通常处于晚期。直到最近，还没有太多的治疗方法，那些肿瘤局限于肝脏的患者已经接受了经动脉化疗（TACE）。在30-50%的情况下，这种方法效果很好（中位生存期为24个月），但如果没有，患者很少有足够的能力考虑任何令人兴奋的免疫肿瘤学（IO）或其他姑息治疗-这可以带来巨大的好处。我们迫切需要生物标志物来提供个性化的治疗选择，无论是单独使用还是与TACE或其他药物/放射治疗相结合。将评估正在接受TACE或新兴治疗的肝癌患者的项目结局总结。患者样本将用于组织和液体生物标志物研究或临床前模型。一个中心焦点将是DNA-PK -一种修复DNA损伤的关键酶。主要主管团队的工作表明，其扩增与TACE/放疗的抗性相关，因为其修复治疗引起的损伤。DNA-PK在抗癌免疫应答中也有可疑的作用。DNA-PK抑制（DNA-PKi）与其他治疗结合具有诱人的治疗潜力。检测其在血液/血清中扩增的试验将有助于治疗分层。监督团队包括纽卡斯尔的Steve Wedge教授（药物发现）、大卫贾米森博士（药效学生物标志物专家）和Ruchi Shukla博士（分子细胞生物学专家）。来自利物浦克拉特布里奇癌症中心的丹尼尔帕尔默教授将是额外的主管，提供患者多样性和医学肿瘤学专业知识。Astra Zeneca是iCASE的合作伙伴，对评估DNA损伤修复途径的小分子抑制剂的影响感兴趣。 项目拟议大纲1。PDNA-PK/pDNA-PK作为组织生物标志物（第1年;免疫组织化学;数字图像分析）2.探索血浆中的拷贝数变异（CNV）（第1年;阵列技术，专注于DNA-PK）。3.探索（1）和（2）肿瘤分期、治疗反应、生存期（2年）。4.评估DNA-PKi与细胞毒性/IO/放射疗法组合的影响，体外和体内（第2-3年;肝切片/类器官/打印的肿瘤细胞/免疫细胞）。5.开发用于临床验证的预测性生物标志物（组织/血浆）（第3年-与临床数据/其他数据集整合，例如免疫评分、质谱、RNA范围）。

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).