Meet us online this November to find out more about this course and all of our master’s degrees and research opportunities.
Pyrimidine-based chemotherapeutics remain central to cancer treatment, including 5-FU/capecitabine (colorectal), 5-FU + platinum (head and neck), capecitabine (metastatic or triple-negative breast), gemcitabine (NSCLC, pancreatic), cytarabine (AML), and azacytidine (haematological malignancies).
These drugs require intracellular phosphorylation for activation, but phosphorylated metabolites cannot cross cell membranes, making efficacy dependent on nucleoside transporters and kinases. To overcome this, NuCana developed ProTide derivatives that bypass these steps. Although benefit was expected in patients with low transporter expression, a clinical trial of the gemcitabine ProTide NUC-1031 (Acelarin) in advanced pancreatic cancer showed no overall survival improvement, due largely to a subgroup with both low hENT1 (transporter) and low RRM1 (gemcitabine target), in whom standard gemcitabine performed better.
Pyrimidine analogues act via DNA incorporation, causing double-strand breaks, and by inhibiting enzymes such as ribonucleotide reductase (RRM1) and thymidylate synthase. Gemcitabine exemplifies this dual mechanism. Resistance may arise from varying degrees of enzyme inhibition—partial inhibition allows ATM-mediated repair, while complete inhibition halts replication and triggers ATR-dependent survival. In low-transporter tumours, gemcitabine gives incomplete RRM1 inhibition, while Acelarin can fully suppress the enzyme when baseline levels are low. Gemcitabine-resistant pancreatic cell lines show abnormal RRM1 expression—some high, others low—yet both resist Acelarin, with low-RRM1 cells paradoxically more resistant at higher doses.
These findings suggest a “Goldilocks” model of sensitivity—requiring an optimal intracellular concentration balancing enzyme inhibition and DNA damage responses.
iCASE industrial partner web link: https://www.nucana.com/
A webinar will be held at 3.00pm on Wednesday 12th November to provide an overview of the studentship and allow prospective applicants to ask questions. Please register using the following link:
Aims and Objectives
This PhD will test the Goldilocks hypothesis and develop predictive models for personalised ProTide dosing. Specific objectives are to:
Experimental Approach
Resistant cell lines will be generated by dose escalation in ATM-positive and ATM-knockout backgrounds. Target expression and drug sensitivity will be assessed using GeoMX, single-cell transcriptomics, qPCR, Western blotting, and viability assays. Dose–response data will be modelled to identify optimal therapeutic windows and compared with clinical biomarker datasets to develop predictive resistance models.
Supervision and Training Environment
Supervision will be provided by Prof. William Greenhalf (https://www.liverpool.ac.uk/people/william-greenhalf) and Prof. Daniel Palmer (https://www.liverpool.ac.uk/people/daniel-palmer), experts in translational oncology, biomarker discovery, and clinical trial design. The student will join a multidisciplinary team with access to state-of-the-art facilities, one-to-one supervision, and training in experimental design, analysis, and research integrity.
Industrial Collaboration
NuCana plc will provide compounds, preclinical data, and input on experimental design. The student will undertake an industrial placement with NuCana, gaining experience in drug development and regulatory processes.
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, training opportunities or internships in science policy, science communication and beyond.
Further information on the programme and instructions on how to apply, including a link to the application portal, can be found on our website https://www.dimen.org.uk/
1. Ferguson R, Aughton K, Evans A, Shaw V, Armstrong J, Ware A, Bennett L, Costello E, Greenhalf W. Mutant K-Ras in Pancreatic Cancer: An Insight on the Role of Wild-Type N-Ras and K-Ras-Dependent Cell Cycle Regulation. Curr Issues Mol Biol. 2023 Mar 17;45(3):2505-2520. doi: 10.3390/cimb45030164. PMID: 36975534; PMCID: PMC10047412.
https://pmc.ncbi.nlm.nih.gov/articles/PMC10047412/
2. He J, Alhamwe BA, Sabroso S, Carrato A, Hidalgo M, Molero X, Iglesias M, Perea J, Farré A, Tardón A, Dominguez-Muñoz E, Barberà V, Muñoz-Bellvís L, Löhr M, Greenhalf W, O’Rorke M, Gress T, Crnogorac-Jurcevic T, Gayà A, Langtry A, Kleeff J, Lawlor R, Real FX, Renz H, Malats N; PanGenEU Study Investigators. Low type-2 immune effectors modulate atopic diseases’ protective role in pancreatic cancer risk. Int J Cancer. 2025 Aug 1;157(3):468-479. doi: 10.1002/ijc.35397. Epub 2025 Mar 18. PMID: 40098454.
https://onlinelibrary.wiley.com/doi/10.1002/ijc.35397
3. Liew F, Efstathiou C, Fontanella S, Richardson M, Saunders R, Swieboda D, Sidhu JK, Ascough S, Moore SC, Mohamed N, Nunag J, King C, Leavy OC, Elneima O, McAuley HJC, Shikotra A, Singapuri A, Sereno M, Harris VC, Houchen-Wolloff L, Greening NJ, Lone NI, Thorpe M, Thompson AAR, Rowland-Jones SL, Docherty AB, Chalmers JD, Ho LP, Horsley A, Raman B, Poinasamy K, Marks M, Kon OM, Howard LS, Wootton DG, Quint JK, de Silva TI, Ho A, Chiu C, Harrison EM, Greenhalf W, Baillie JK, Semple MG, Turtle L, Evans RA, Wain LV, Brightling C, Thwaites RS, Openshaw PJM; PHOSP-COVID collaborative group; ISARIC investigators. Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease. Nat Immunol. 2024 Apr;25(4):607-621. doi: 10.1038/s41590-024-01778-0. Epub 2024 Apr 8. PMID: 38589621; PMCID: PMC11003868.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11003868/
4. McNamara MG, Bridgewater J, Palmer DH, Faluyi O, Wasan H, Patel A, Ryder WD, Barber S, Gnanaranjan C, Ghazaly E, Evans TRJ, Valle JW. A Phase Ib Study of NUC-1031 in Combination with Cisplatin for the First-Line Treatment of Patients with Advanced Biliary Tract Cancer (ABC-08). Oncologist. 2021 Apr;26(4):e669-e678. doi: 10.1002/onco.13598. Epub 2020 Dec 3. PMID: 33210382; PMCID: PMC8018303.
https://pmc.ncbi.nlm.nih.gov/articles/PMC8018303/
5. Middleton G, Palmer DH, Greenhalf W, Ghaneh P, Jackson R, Cox T, Evans A, Shaw VE, Wadsley J, Valle JW, Propper D, Wasan H, Falk S, Cunningham D, Coxon F, Ross P, Madhusudan S, Wadd N, Corrie P, Hickish T, Costello E, Campbell F, Rawcliffe C, Neoptolemos JP. Vandetanib plus gemcitabine versus placebo plus gemcitabine in locally advanced or metastatic pancreatic carcinoma (ViP): a prospective, randomised, double-blind, multicentre phase 2 trial. Lancet Oncol. 2017 Apr;18(4):486-499. doi: 10.1016/S1470-2045(17)30084-0. Epub 2017 Mar 2. PMID: 28259610.
https://linkinghub.elsevier.com/retrieve/pii/S1470-2045(17)30084-0
6. Lamarca A, Palmer DH, Wasan HS, Ross PJ, Ma YT, Arora A, Falk S, Gillmore R, Wadsley J, Patel K, Anthoney A, Maraveyas A, Iveson T, Waters JS, Hobbs C, Barber S, Ryder WD, Ramage J, Davies LM, Bridgewater JA, Valle JW; Advanced Biliary Cancer Working Group. Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2021 May;22(5):690-701. doi: 10.1016/S1470-2045(21)00027-9. Epub 2021 Mar 30. PMID: 33798493; PMCID: PMC8082275.
https://pmc.ncbi.nlm.nih.gov/articles/PMC8082275/
Applicants for postgraduate research study at Liverpool are normally expected to hold a UK first degree with a First Class or Upper Second Class degree classification, or a Second Class degree plus a Master’s degree. Equivalent international qualifications are also accepted, and their equivalence will be evaluated on the basis of the information provided by the European Network of Information Centres (ENIC) formerly NARIC as well as internal guidance based on our experience of a qualification’s suitability as a preparation for our programmes.
For applicants whose first language is not English, an IELTS score of 6.5 with no band score lower than 5.5, or an equivalent University of Liverpool acceptable English language qualification. For further details and other acceptable English language qualifications please see here: http://www.liv.ac.uk/study/international/countries/english-language/
Sueprvisors:
All applications are made via the application form accessed on the DiMeN website at www.dimen.org.uk/ Please read the full application guidance on the website before submitting an application.
Finally, register and apply online. You'll receive an email acknowledgment once you've submitted your application. We'll be in touch with further details about what happens next.
You should only follow this step if you’ve successfully completed the DiMeN application process
Studentships are fully funded by the MRC for 4yrs, including a minimum of 3 months working with an industry partner. Funding will cover tuition fees and an enhanced stipend (£23,280 for 2024/2025) and project costs. We have a very small number of funded studentships for exceptional international applicants. Please read additional guidance here: View Website
Have a question about this research opportunity or studying a PhD with us? Please get in touch with us, using the contact details below, and we’ll be happy to assist you.