MRC DiMeN Doctoral Training Partnership: Tyrosine kinase inhibitors: application of chemical and discovery proteomics to the problem of chemotherapeutic toxicity in cancer patients

Conventional chemotherapy for numerous cancers involves toxic and damaging drugs that cause severe side effects in patients. Scientists have for decades searched for the ‘magic bullet’ that would target only cancer cells, thereby reducing or eliminating the toxic effects of treatment. While this has yet to be fully achieved, huge strides have been made in the development of more specific drugs. One example of this is the group of tyrosine kinase inhibitors (TKIs).

Osimertinib is a TKI used to treat lung cancer in patients with mutations in their epidermal growth factor receptor (EGFR). The drug binds irreversibly to the receptor, thereby limiting EGF-stimulated proliferation. Despite the improved targeting of the drug compared to earlier therapies, many patients receiving TKIs develop severe liver and gastrointestinal (GI) toxicity, limiting the utility of the drug and impairing the quality of life for patients. Toxicity is believed to be a consequence of irreversible binding of the drug/metabolites to proteins other than the intended targets (off-target toxicity). This project will use cutting-edge technology to identify the off-target proteins, to decipher the consequences and potential mitigation of off-target binding, and to chemically engineer better drugs for the future.

The study will be carried out using human liver and GI organoids. These are mini organs-in-a-test-tube that mimic many of the functions of cells or tissues in the body. They are becoming increasingly vital to the study of disease and drug safety because they outperform conventional cell culture methods and they don’t require animal models. You will be trained on all aspects of organoid generation and maintenance.

Another pivotal technology for this project is mass spectrometry. You will have access to state-of-the-art instrumentation for identification of the drug-modified proteins, for profiling the changes in protein expression on exposure of organoids to different versions of the drug and searching for markers of toxicity that have been secreted by the organoids. You will receive training on sample preparation, fractionation techniques and mass spectrometry-based global proteomics. There is currently a global shortage of trained mass spectrometrists, so this project will equip you with expertise that is very attractive to both academia and Pharma.

Another key skill that you will gain from this project is the generation of Osimertinib chemical biology probe molecules including biotin (or acetylene) tagged derivatives. Once the drug has been applied to the organoids, the drug-modified proteins can be isolated by using the affinity of biotin for streptavidin. All the other unmodified proteins are then removed, enabling high-sensitivity detection of the off-target proteins. The structure of the drug may then be altered and the consequences for function and toxicity can be evaluated. This is a highly valuable tool in the drug development pathway.

During this exciting project, you will acquire skills that are in demand both in academic institutions and more widely in industry. There will also be the opportunity to gain experience in data processing, applicable to many fields outside biological research.

CDSS Bioanalytical Facility - Faculty of Health and Life Sciences - University of Liverpool

https://www.liverpool.ac.uk/systems-molecular-and-integrative-biology/staff/carrie-duckworth/

https://www.liverpool.ac.uk/systems-molecular-and-integrative-biology/staff/christopher-goldring/

https://www.liverpool.ac.uk/chemistry/staff/paul-oneill/

Benefits of being in the DiMeN DTP:

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), 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, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: https://www.dimen.org.uk/blog

Further information on the programme and how to apply can be found on our website: https://www.dimen.org.uk/how-to-apply