Liquid biopsy of the liver to improve molecular targeted cancer therapy

分子靶向治疗已经彻底改变了肿瘤学。然而，虽然患者的预期寿命正在改善，但这些疗法存在对体内健康组织造成损害的风险，特别是对肝脏。根据肝损伤的严重程度，治疗剂量可能会减少甚至停止。如果肿瘤有反应，这就造成了严重的困境。不幸的是，目前肝损伤标志物的解释告诉我们损伤的程度并不简单，虽然人们普遍认为我们需要更好的肝损伤标志物，但这一领域的癌症药物安全性以前尚未得到广泛研究。这个博士项目的目的是改善这种情况，从而提高分子靶向癌症治疗的使用。博士将设在MRC药物安全科学中心（CDSS），成立于2008年，（https：//www.liverpool.ac.uk/mrc-centre-for-drug-safety-science/）和Twitter：@CDSS_利物浦也@3DbioNet）与主要主管Chris Goldring、第二主管Amy Chadwick和第三主管Francesco Falciani合作（全部显示在CDSS团队页面：https：//www.liverpool.ac.uk/mrc-centre-for-drug-safety-science/our-team/），并将在我们的工作基础上显示microRNA miR-122作为肝脏的生物标志物，并利用miRs作为生物标志物的特殊特性，以改善癌症治疗。该项目将涉及与外科医生和肿瘤学家以及我们的药物安全科学家团队的密切合作。它将涉及使用下一代测序（NGS）对来自大约10个供体的人类肝脏中的主要细胞类型进行miRNA分析（我们与当地教学医院的肝胆外科有很好的联系）。NGS分析将通过与一个名为Transbioline的大型国际学术制药行业联盟合作进行，该联盟资助我们到2024年研究肝损伤的生物标志物。该项目的这一部分将使成功的候选人与工业界的其他科学家建立联系和合作。该项目的结果将告诉我们新的肝脏生物标志物表达的个体间差异。结果还将告诉我们细胞表达的选择性-这将使我们能够在特定分子靶向治疗具有肝毒性时改善对细胞靶点的解释。该项目的最后一部分将涉及分离肝细胞的培养，并将使用一组相关疗法进行时间过程和剂量反应，以研究体外毒性，例如线粒体扰动-该项目的这一部分将由该领域的专家Amy Chadwick博士监督。体外研究将使我们更深入地了解这些疗法的毒理学机制，并有可能通过我们接触这些疗法的患者将结果转化为人类。

Molecular targeted therapies have revolutionised oncology. However, whilst patient life-expectancy is improving, these therapies carry a risk of causing damage to healthy tissues in the body, especially to the liver. Depending on the severity of liver injury, the therapeutic dose may be reduced or even discontinued. This poses a serious dilemma if the tumour is responsive. Unfortunately, the interpretation of current liver injury markers to tell us about the degree of damage is not straightforward, and whilst it is widely-accepted that we need better markers of liver injury, this area of cancer drug safety has not been previously widely studied. The objective of this PhD project is to improve this situation, and thereby to improve the use of molecular targeted cancer therapy. The PhD will be based at the MRC Centre for Drug Safety Science (CDSS), established in 2008, (https://www.liverpool.ac.uk/mrc-centre-for-drug-safety-science/), and Twitter: @CDSS_Liverpool also @3DbioNet) working with primary supervisor Chris Goldring, second supervisor Amy Chadwick and third supervisor Francesco Falciani (all shown on the CDSS team page: https://www.liverpool.ac.uk/mrc-centre-for-drug-safety-science/our-team/) and will build on our work showing microRNA miR-122 as a biomarker of the liver, and exploit the particular characteristics of miRs as biomarkers, in order to improve cancer therapy. The project will involve close collaboration with surgeons and oncologists, as well as our team of drug safety scientists. It will involve miRNA analysis using next generation sequencing (NGS) of the major cell types in human liver from around 10 donors (we have an excellent link to the hepatobiliary surgical unit at a local teaching hospital). The NGS analysis will be done through collaboration with a large international academic-pharmaceutical industry consortium called Transbioline, which fund us until 2024 to look at biomarkers of liver injury. This part of the project will enable the successful candidate to develop links and collaborations with other scientists in Industry. The results of the project will tell us about inter-individual variation in expression of new liver biomarkers. The results will also tell us about the selectivity of cell expression - this should allow us to improve interpretation as to the cellular target when a particular molecular targeted therapy is hepatotoxic. The final part of the project will involve the culture of isolated liver cells and will use a panel of relevant therapies to conduct time-courses and dose-responses to investigate toxicity in vitro, such as mitochondrial perturbation - this part of the project will be supervised by Dr Amy Chadwick, who is an expert in this area. The in vitro study will yield a deeper understanding of the toxicological mechanisms of these therapies, with potential for translating the results to humans through our access to patients on these therapies.