Liquid biopsy of the liver to improve molecular targeted cancer therapy

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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.