缅北禁地

Starting in September 2027, we will fund one 4-year fully-funded studentship covering:

• Generous tax-free stipend (living allowance) of more than £22,000 per annum
• Tuition fees for Home status only (see Eligibility criteria)
• Project consumables funding (to enable the running of the PhD project and research development opportunities, including travel to international conferences/workshops)
• Mentoring, career support, leadership training and networking – led by the Windsor Fellowship and Black in Cancer, in addition to the support provided by the CRUK 缅北禁地 Cancer Centre Training Committee, to drive your career forward and realise your full potential to beat cancer.

The programme is aimed at students from Black heritage backgrounds pursuing a PhD in cancer-related fields.

This scheme is open to people who self-identify as being from a Black heritage background, including a mixed background, for example: Black African, Black Caribbean, Black Other, Mixed background (to include Black African, Black Caribbean or other Black backgrounds). You will need to submit an initial application to the Windsor Fellowship.

You must also meet the general entry requirements for the PhD programme at the University of 缅北禁地:

• Hold a first or upper-second class undergraduate honours degree or equivalent in a relevant subject (or equivalent from a non-UK university)
• Have appropriate research experience as part of, or outside of, an undergraduate or masters degree course in a relevant subject
• Meet English language requirements

Your application must be submitted by the deadline: 4 December 2026, noon

We should receive your references by 11 December 2026, noon. Your application may still be considered if references are not received by this deadline. However, no applicant will be invited to interview unless references have been received.

You will find out if you have been invited to interview for the programme before: 18 January 2027

Supervisors may contact you during the shortlisting period (December 2026 - mid-January 2027), to find out more about you and your interest in their project.

Information session for interviewees: 3 February 2027, 1pm to 2pm

Panel interviews will take place: week commencing 8 February 2027

Programme start date: September 2027

During the interview, candidates will be interviewed by a panel of CRUK 缅北禁地 Cancer Centre academics from across the Centre鈥檚 partners. Please note that only one project will be funded. Studentships will be awarded to the best applicant based on information submitted on the application form, references and performance during the interview.

Insight Session

The Windsor Fellowship is running an insight session for potential candidates:

Wednesday 14 October 2026 at 12:30 – 14:00 (GMT)

Potential candidates can register to attend the insight session .

Step 1 - 

Step 2 - CRUK 缅北禁地 Cancer Centre Application

Follow the above links for steps to submit your formal application for a place on the studentship programme at the CRUK 缅北禁地 Cancer Centre

Please remember that you will also have to complete Step 1

If you are shortlisted, you’ll be invited to attend an interview in February 2027

Primary supervisor: Prof Celine Cano

Background:

Prostate cancer accounts for 375,000 deaths per year worldwide. Targeting the androgen receptor (AR) using hormone therapy is the mainstay treatment for advanced prostate cancer and is often employed with radiotherapy in metastatic disease. Unfortunately, not all patients show durable responses; with many resistant to radiotherapy or acquiring mechanisms that overcome AR blockade. Hence, there is an urgent need to provide more effective and durable treatments for metastatic disease.

DNA-dependent protein kinase (DNA-PK) is a key component of the non-homologous end-joining pathway required to repair double-stranded DNA breaks. In advanced prostate cancer, DNA-PK expression is elevated and correlates with metastatic spread, and its kinase inhibition diminishes prostate cancer growth in vitro and in vivo. Importantly, we have demonstrated a kinase-independent pro-proliferative role of DNA-PK in prostate cancer which suggests that complete ablation of DNA-PK function would enhance anti-tumour efficacy. These findings provide a robust rationale for developing PROTACs to destabilise DNA-PK in PC and afford maximal levels of DNA-PK inactivation; quelling both, kinase-dependent and -independent functions of DNA-PK for maximal treatment efficacy for men with currently incurable metastatic disease.

Aims:

1. A proteolysis targeting chimeric molecule (PROTAC) will provide a proof of concept tool to test the hypothesis that DNA-PK can be targeted for degradation. The student will synthesise DNA-PK PROTACs that retain kinase domain binding capacity based on established DNA-PK inhibitors.  These will comprise a ligand for an E3 ligase protein attached by an appropriate linker to a ligand for DNA-PK. The initial PROTAC library will comprise a ‘traditional’ linker (alkyl, PEG) to a ligand for DNA-PK but we will also explore alternative linker strategies. Alkyne-containing linkers and heterocyclic scaffolds (e.g. piperazine/piperidines) will provide some rigidity but also, enable the modulation of the PROTAC physico-chemical properties in an attempt at reducing the gap between PROTACs and traditional drug-like chemical space.
2. The resultant PROTACs will enter an immunofluorescent-based assay pipeline, utilising a PC cell line stably expressing a green fluorescent protein (GFP)-DNA-PK fusion protein, to test the capacity of each compound to destabilise DNA-PK by confocal microscopy. It is anticipated that functional DNA-PK PROTACs will diminish levels of intracellular GFP-DNA-PK while parent DNA-PKIs lacking the PROTAC component will not impact DNA-PK protein abundance. The most effective PROTACs, as determined by their capacity to degrade DNA-PK, will then enter a comprehensive validation pipeline involving in vitro efficacy testing across a spectrum of DNA-PK-expressing PC cell lines and iPSC-derived organoids in comparison to controls. 

Methodological approaches:

In vitro analyses will involve assessing the impact of DNA-PK PROTACs on: (i) DNA-PK protein levels and downstream activation markers by western and immunofluorescence; (ii) DNA damage repair capacity using 飦�H2AX and Rad51 foci resolution assays; and (iii) cell proliferation and viability using live cell Incucyte imaging and annexin V-/caspase 3-based flow cytometry. Ultimately, we expect to develop DNA-PK PROTACs that have anti-tumour activity in multiple models of PC that are likely to be efficacious in other disease indications. 

Candidate background:

To be successful, candidates will demonstrate a strong foundation in synthetic organic chemistry, evidenced by a minimum 2:1 undergraduate degree in Chemistry.  

Potential research placement:

The student will undertake integrated Chemistry and Biosciences training within the NUCancer Drug Discovery and Prostate groups. Placements in Dr Gaughan’s laboratory will provide hands-on experience in cancer biology and biological assays, enabling direct evaluation of compounds. This training will link compound design/synthesis with biological evaluation and subsequent chemical optimisation.

References:

1. Adamson et al. The catalytic subunit of DNA-PK regulates transcription and splicing of AR in advanced prostate cancer. J Clin Invest.2023; :e169200.
2. Willoughby et al. .J Clin Invest. 2019;130, 1-14.
3. Kounatidou et al. A novel CRISPR-engineered prostate cancer cell line defines the AR-V transcriptome and identifies PARP inhibitor sensitivities. Nucleic Acids Research. 2019; 47, 5634-5647.
4. Watson et al. Targeting DNA-PK: medicinal chemistry insights into small-molecule inhibitor discovery and optimisation. RSC Med Chem. 2026; 17 (7), 3211-3230.
5. Cano et al. .J Med Chem.2013; 56 (16), 6386-6401.

Primary Supervisor: Dr Brian Ortmann

Background:

Oxygen-starved regions are among the hardest parts of a tumour to treat. Cancer cells within these hypoxic regions resist radiotherapy, chemotherapy and immune attack, enabling recurrence and metastasis. Yet few treatments specifically eliminate hypoxic cancer cells.

This challenge is particularly important in cancers carrying an unequal burden in Black communities. Black men have approximately twice the incidence of prostate cancer, while Black women are more frequently diagnosed with aggressive and late-stage breast cancers, including triple-negative breast cancer (TNBC). New approaches for targeting treatment-resistant cells within these tumours are urgently needed.

Methylation is a remarkably versatile modification controlling almost every aspect of cell biology. By modifying DNA, RNA, histones and non-histone proteins, methylation regulates gene expression, RNA processing, DNA repair, signalling, metabolism and cell division. Protein methylation can alter protein activity, stability, localisation and molecular interactions, allowing it to rapidly reprogramme cellular behaviour. Intriguingly, methylation is tightly connected to oxygen because many demethylases require molecular oxygen for activity. Although histone methylation in hypoxia is well established, how non-histone methylation enables cancer cells to survive oxygen deprivation remains largely unknown.

Methylation enzymes are attractive therapeutic targets because their catalytic activity can be inhibited with drugs. Several methylation-enzyme inhibitors are approved or undergoing clinical trials, providing a realistic route from discovery to patient benefit. We hypothesise that prostate cancer and TNBC share methylation-dependent mechanisms that can be targeted to eliminate hypoxic tumour cells.

Aims:

1. Discover methyltransferases required for hypoxic survival.
2. Validate shared vulnerabilities and identify their protein targets in prostate cancer and TNBC.
3. Establish their clinical and therapeutic relevance.

Methodological approaches:

The student will use a focused CRISPR library targeting human methyltransferases to screen prostate cancer and TNBC cells under normal and low-oxygen conditions. Comparing the screens will reveal shared enzymes that become essential when oxygen is limited.

The two strongest candidates will be investigated using gene editing, molecular biology and inhibitors in cell-line and three-dimensional tumour models. PTM proteomics and mass spectrometry will identify their hypoxia-regulated protein substrates and methylation sites, revealing how individual modifications support tumour survival.

Clinical relevance will be assessed in prostate cancer and TNBC tissue microarrays. Immunohistochemistry will determine whether candidate enzymes and their targets are enriched in hypoxic regions and whether their expression associates with tumour progression or patient outcome. The lead vulnerability will then be tested through genetic or pharmacological inhibition in an in vivo tumour model.

The project will define a previously unexplored layer of oxygen-dependent cancer biology and reveal whether hypoxic prostate and breast tumours rely on shared methylation programmes. By connecting molecular mechanisms with patient tumours and preclinical models, it could identify biomarkers and druggable vulnerabilities for selectively eliminating treatment-resistant hypoxic cells, ultimately improving outcomes in cancers that disproportionately affect Black communities.

Candidate background:

The ideal candidate will be enthusiastic about cancer biology and interested in translating fundamental discoveries into new cancer treatments. They should be curious, self-motivated and enjoy developing their own research ideas while working as part of a collaborative team. Previous practical experience in molecular biology, cell culture or protein biochemistry would be valuable. Familiarity with gene editing, bioinformatics, proteomics or immunohistochemistry is welcomed but not required. Full training will be provided in CRISPR screening, hypoxia models, mass spectrometry and tumour tissue analysis.

Potential Research Placements:

University of Edinburgh: The student will have the opportunity to undertake an optional placement in Professor Alex von Kriegsheim’s group at the Institute of Genetics and Cancer. Professor von Kriegsheim is an internationally recognised expert in proteomics, using mass spectrometry to identify protein complexes, PTMs and understand how cellular perturbations reprogramme signalling networks. During the placement, the student will receive specialist training in PTMScan-based proteomics to identify methylated proteins regulated by the project’s candidate enzymes. They will also learn how to process, analyse and interpret complex proteomic datasets.

References:

1. Ortmann et al SET1B Drives Sustained HIF Activity and Disease Progression in Clear-Cell Renal Cell Carcinoma. Cancer Res. (2026)
2. Ortmann. Hypoxia-inducible factor in cancer: from pathway regulation to therapeutic opportunity. BMJ Oncol (2024)
3. Garnham, et al. ST3 beta-galactoside alpha-2,3-sialyltransferase 1 (ST3Gal1) synthesis of Siglec ligands mediates anti-tumour immunity in prostate cancer. Commun Biol (2024).
4. Kahn et al. JMJD5 regulates metabolism by hydroxylating ISY1, and regulating the Arginine Methyltransferase PRMT6. bioRxiv (2026)
5. Wu et al. Beyond histones - the expanding roles of protein lysine methylation. FEBS J (2017)

Primary Supervisor: Prof David Elliott

Background:

Prostate cancer is the most commonly diagnosed cancer in men in the UK and is a leading cause of cancer-related mortality worldwide. Black men are disproportionately affected by prostate cancer, experiencing a higher incidence, earlier onset, more aggressive disease, and poorer clinical outcomes compared with men from other ethnic groups. Despite these significant disparities, Black men remain underrepresented in large-scale genomic studies, limiting our understanding of the biological mechanisms that drive aggressive disease in this population.

Alternative RNA splicing is a fundamental regulatory process that generates diverse protein isoforms from a single gene. Dysregulation of splicing is now recognised as a hallmark of cancer and contributes to prostate cancer progression, metastasis, treatment resistance, and immune evasion. Emerging evidence suggests that alterations in RNA-binding proteins and splicing factors can drive aggressive prostate cancer phenotypes (1,2). Alternative splicing programmes differ between prostate tumours from Black and non-Black men (3,4), but why and whether these differences create novel opportunities for biomarker development and targeted therapeutic intervention is not well understood.

This project will use a newly derived prostate cancer cell line from a Black man (5) that we have available to increase understanding of racial disparities in prostate cancer. We will systematically investigate splicing alterations associated with aggressive disease in Black men and identify clinically actionable splicing events that may improve patient stratification and treatment selection.

Aims:

This project aims to define the role of alternative splicing in driving prostate cancer disparities in Black men. Specifically, we will:

1. Characterise alternative splicing landscapes in cell lines derived from Black and non-Black men by generating RNAseq datasets.
2. Identify key splicing factors, RNA-binding proteins and splice isoforms differentially expressed in Black men.
3. Characterise differentially expressed splice isoforms and their functional consequences as potential biomarkers/therapeutic targets.

Methodological approaches:

The project will combine computational and experimental approaches. We will generate global RNA sequencing datasets from prostate cancer cell lines, analyse these using bioinformatics pipelines, and identify differential alternative splicing events associated with ethnicity, tumour progression, and clinical outcome. Selected splicing events will be validated using RT-PCR, quantitative PCR, and long-read sequencing approaches. Functional studies will utilise CRISPR-based gene editing, siRNA-mediated knockdown, and splice-switching oligonucleotides to investigate the role of key splicing regulators and isoforms in tumour growth, invasion, treatment response, and metastatic potential.

This project is expected to generate the first comprehensive map of alternative splicing alterations associated with prostate cancer in Black men. The findings will improve our understanding of the molecular basis of prostate cancer disparities, identify novel biomarkers for patient stratification, and uncover new therapeutic opportunities targeting aberrant RNA processing pathways. The student will receive interdisciplinary training in cancer genomics, RNA biology, bioinformatics, molecular biology, and translational prostate cancer research within a multidisciplinary supervisory team.

Candidate Background:

The ideal candidate will have a strong interest in cancer biology, genomics, or RNA research and be motivated to address health inequalities through translational science. The project is suitable for a self-motivated student with experience in molecular biology, genetics, bioinformatics, or related biomedical sciences. Prior experience with RNA analysis, next-generation sequencing, cell culture, or computational data analysis would be advantageous but is not essential. Full training will be provided in transcriptomics, alternative splicing analysis, molecular techniques, and prostate cancer models.

Potential Research Placements:

University of Sheffield - An optional placement with collaborators specialising in prostate cancer metastasis and advanced pre-clinical models will provide training in in vivo and ex vivo approaches for investigating mechanisms of aggressive prostate cancer progression.

EMBL-European Bioinformatics Institute (or equivalent bioinformatics centre) - The student may undertake a short placement to gain advanced training in large-scale transcriptomic analysis, alternative splicing detection, machine-learning approaches, and integrative multi-omics analyses.

References:

1. Munkley et al. Androgen-regulated transcription of ESRP2 drives alternative splicing patterns in prostate cancer. Elife. 2019 Sep 3;8:e47678. doi: 10.7554/eLife.47678.
2. Advani et al. Epithelial specific splicing regulator proteins as emerging oncogenes in aggressive prostate cancer. Oncogene. 2023; 42(43):3161-3168.
3. Wang et al. Alternative splicing promotes tumour aggressiveness and drug resistance in African American prostate cancer. Nat Commun. 2017 Jun 30;8:15921.
4. Al Abo et al. Genetic ancestry concordant RNA splicing in prostate cancer involves oncogenic genes and associates with recurrence. NPJ Precis Oncol. 2025; 9(1):30.
5. Badal et al. Novel Afro-Caribbean Prostate Cancer Model Reveals Ancestry-Specific Drug Vulnerabilities with Therapeutic Implications for Black Patients. Cancer Res Commun. 2025; 5(10):1758-1770.

Primary Supervisor: Dr Amir Enshaei 

Background:

Acute lymphoblastic leukaemia is a rare but complex disease, and high-quality research depends on access to detailed clinical, genomic, treatment and outcome data. However, healthcare datasets are often difficult to access and share because of privacy, governance and ethical constraints. These challenges can limit collaboration, reproducibility and the development and evaluation of new statistical and artificial intelligence methods.

This PhD will benefit from access to a unique resource of more than 20,000 acute lymphoblastic leukaemia patient records, providing an exceptional opportunity to develop and evaluate synthetic healthcare data methods at scale. The patient’s records are based on national clinical trials and include demographic, clinical, genetics, treatment and outcome data. Synthetic healthcare data—artificially generated data designed to preserve important characteristics and relationships within real patient data without directly representing individual patients—could enable safer data sharing and wider use of valuable healthcare data. However, important questions remain about whether synthetic data can adequately preserve complex clinical relationships, longitudinal treatment pathways, rare events and clinically important subgroups while maintaining patient privacy.

Aims:

This PhD will develop and rigorously evaluate methods for generating trustworthy synthetic healthcare data for acute lymphoblastic leukaemia research. The project will:

1. Develop and compare statistical, machine-learning and generative AI approaches for generating synthetic acute lymphoblastic leukaemia data.
2. Evaluate how well synthetic data preserve clinically important distributions, relationships, treatment pathways and outcomes, including rare events such as relapse.
3. Develop frameworks for assessing synthetic data in terms of utility, privacy, fidelity, fairness and clinical validity.
4. Examine whether synthetic data can support methodological research, hypothesis generation and reproducible statistical analysis.
5. Use teenagers and young adults (TYA) as an important case study, investigating whether synthetic data can reliably preserve the characteristics and outcomes of this clinically important subgroup.
6. Produce practical recommendations for the responsible generation, evaluation and use of synthetic healthcare data in childhood cancer research.

Methodological approaches:

The project will use the large-scale collection of more than 20,000 patient records as the basis for developing and evaluating synthetic data methods. The research will compare a range of approaches, potentially including probabilistic and statistical models, Bayesian methods, machine-learning approaches and modern generative AI models.

Synthetic datasets will be evaluated against the original data using complementary measures of statistical fidelity, analytical utility and clinical relevance. Evaluation will examine preservation of marginal distributions, correlations, clinically meaningful associations, longitudinal trajectories, survival and relapse patterns, and the reproducibility of key analyses.

A particular focus will be placed on the TYA population as an empirical case study. TYA patients may represent a relatively smaller and clinically distinct subgroup, providing an important test of whether synthetic data methods can preserve meaningful patterns in patient groups that may be under-represented in the overall dataset.

Privacy and disclosure risks will be assessed alongside data utility, including evaluation of the risk of re-identification or inappropriate inference about real patients. The project will also investigate potential biases and whether synthetic data maintain adequate representation of clinically important patient subgroups.

The overall goal is to establish robust, evidence-based principles for developing and validating trustworthy synthetic healthcare data, using acute lymphoblastic leukaemia—and particularly the TYA population—as a real-world setting for methodological innovation and empirical evaluation.

Candidate background:

We welcome applications from candidates with a background in statistics, data science, biostatistics, epidemiology, computer science, artificial intelligence, machine learning, or a related quantitative discipline. Applicants should have a strong interest in applying quantitative and computational methods to healthcare research. Experience with statistical programming (e.g., R, Python or Stata), data analysis, machine learning, or handling large and complex datasets would be advantageous. An interest in synthetic data, generative AI, privacy-preserving methods, or childhood cancer research is desirable, although training will be provided where appropriate.

References:

1. Eckardt et al. Artificial intelligence-generated synthetic data for cancer research and clinical trials. Nat Rev Cancer.2026; 26; 351–363.
2. Mansur et al. The genomic landscape of teenage and young adult T-cell acute lymphoblastic leukemia. Cancer Med. 2021; 10(14):4864-4873.
3. Rob et al. Relapse in Teenage and Young Adult (TYA) Patients Treated on a Pediatric Minimal Residual Disease (MRD) Stratified Protocol Is Associated with a Poor Outcome: Results from UKALL2003. Blood2015; 126 (23): 2493.

Primary Supervisor: Prof Lisa J Russell

Background:

Early life is a critical window during which environmental exposures can have lasting effects on human health across the life course. Factors including maternal nutrition, obesity, smoking, air pollution, infections, and chemical exposures are all linked to incidence of diseases including asthma, cardiovascular disease and cancer as a few examples. More specifically, maternal exposure to benzene and caffeine during pregnancy have been associated with increased risk of childhood leukaemia in offspring, whereas folate supplementation has been observed to be protective. Understanding the optimum environmental conditions during this critical window is likely to aid public health advice and interventions toward reducing childhood leukaemia risk.

While DNA methylation has been extensively studied as a molecular mechanism mediating early life exposures and disease outcomes, comparatively little is known about how early-life exposures alter broader epigenetic regulation, particularly:

• Histone modifications
• Chromatin accessibility
• Enhancer activity
• Three-dimensional chromatin organisation

These epigenomic changes regulate gene expression without altering the DNA sequence and may provide additional mechanistic links between environmental exposures and leukaemia susceptibility. Benzene, caffeine and folate levels during pregnancy are highly modifiable exposures associated with childhood leukaemia risk. All are associated with altered DNA methylation, with emerging evidence that they can influence other epigenetic marks including histone modifications, but this remains a considerable knowledge gap. Our experience of modelling these exposures together with contemporary epigenomic technologies such as ATAC-seq, CUT&Tag, and low input chromatin capture methods will enable genome-wide mapping of chromatin states and their influence on gene expression profiles. With proof of principle relationships between exposures and epigenetic regulation mechanisms in place, future population-based epigenomic studies will be increasingly feasible.

Hypothesis

Early-life environmental exposures induce persistent alterations in chromatin accessibility and histone modifications that modify gene regulatory networks, leading to long-term changes in gene regulation and increased susceptibility to genomic rearrangements.

The overarching aim is to determine whether common early-life environmental exposures induce epigenomic signatures that could underlie leukaemia susceptibility.

Aims:

1. Which early-life exposures produce the largest changes in histone modifications and chromatin accessibility?
2. What functions do exposure-altered genomic regions have in regulating gene expression?
3. Which biological pathways are disrupted?
4. Can epigenomic signatures identify any risk loci associated with the development of leukaemia?

Methodological approaches:

This PhD project follows a strategic pipeline to map epigenomic changes that may predispose regions of the genome to chromosomal rearrangements. During Years 1–2, immortalised haematopoietic cell lines will be used to optimise acute and prolonged exposure protocols for benzene, caffeine and folate. Comprehensive multi-omic datasets will be generated, including ATAC-seq for chromatin accessibility, CUT&Tag for histone modifications, and RNA-seq for transcriptomics. In Year 3, epigenomic signatures will be validated in primary human cells such as CD34+ve umbilical cord blood cells, thereby enhancing the translational relevance of identified mechanisms. Collectively, the research aims to uncover complex epigenomic networks driving responses to environmental stressors that have the potential to increase the risk of leukaemia development.

Candidate background:

We are looking for someone with a biology-based background who is interested in discovering how environmental exposures contribute to the development of chromosomal rearrangements in childhood leukaemia. Knowledge in areas such as cancer, genetics, epigenetics and bioinformatics would be advantageous. This project will apply computational methods together with complementary laboratory experiments, so a keen interest in developing bioinformatics and coding skills alongside existing wet lab capabilities is essential. Team science is a core value of the group so willingness to work organically with others is important.

Potential Research Placements:

We work with other leukaemia groups within 缅北禁地, including those that work in areas of hypoxia and long-read DNA sequencing. The student will also spend time training at Northumbria University to develop skills in exposure optimisation and organoid culture. We also work with other teams around the UK that could offer placement opportunities. This includes experts in chromatin polymer physics (Edinburgh), protein homeostasis (York) and chromosome capture methods (Oxford).

References:

1. Mikulasova et al. Epigenomic translocation of H3K4me3 broad domains over oncogenes following hijacking of super-enhancers. Genome Res. 2022; 32(7):1343-1354.
2. Rico et al. High-resolution simulations of chromatin folding at genomic rearrangements in malignant B cells provide mechanistic insights into proto-oncogene deregulation. Genome Res. 2022; 32(7):1355-1366.
3. Timms et al. DNA methylation as a potential mediator of environmental risks in the development of childhood acute lymphoblastic leukemia. Epigenomics. 2016 Apr;8(4):519-36. doi: 10.2217/epi-2015-0011.
4. Saville et al. Exploring the Role of Environmental Factors on Chromosomal Translocations Associated With Childhood Leukaemia. Cancer Med. 2026; 15(3):e71713. doi: 10.1002/cam4.71713.
5. Saville et al. The potential role of environmentally associated DNA methylation in childhood acute lymphoblastic leukaemia subtypes. Int J Cancer. 2025; 157(8):1600-1612.

Primary Supervisor: Dr Simone Webb

Background:

The bone marrow provides specialized microenvironments (niches) for haematopoietic stem and progenitor cells. Signals from these niches influence stem cell activity, including fate decisions such as whether to divide and differentiate into a mature blood cell or whether to remain quiescent. These signals contribute to lifelong maintenance of our blood and immune cell repertoire. However, in cancer, bone marrow niches can be co-opted and adapted by cancer cells to promote their growth and survival. In lymphoid leukaemia, niche cells can promote resistance to chemotherapy and dormancy, which ultimately leads to relapse after treatment. Modifications to the niche by leukaemia cells, such as fibrosis, limit access of immune cells and potentially reduce the efficacy of novel immunotherapies. Understanding this niche will fuel new therapeutic options in cancer.

The technologies needed to study bone marrow niches and their interactions with stem/progenitor or cancer cells are relatively recent. Through single cell RNA sequencing, we and others have characterized the diverse array of cell types in niches. Through spatial transcriptomics advances, the organization of these cell types can now be fully detailed. However, current transcriptomic references poorly represent the lymphoid niche, largely as these references are built from adult samples where lymphopoiesis is diminished. Insights from transcriptomic references are especially powerful when combined with in vitro or mechanistic studies. Organoid protocols now permit the recreation of human tissues in vitro, providing a vital platform for mechanistic studies and drug screening. However, many of these models do not yet faithfully replicate human physiology.

In this project, you will a generate a comprehensive single cell and spatial transcriptomic reference of the lymphoid niche in bone marrow, utilizing published data sets and integrating these with newly generated data. You will use conventional and AI-based analysis of these data sets to drive innovation in organoid protocols and identify pathways co-opted in acute lymphoblastic leukaemia.

Aims:

1. Define the niches that support lymphoid differentiation in healthy human bone marrow in steady state and during recovery from chemotherapy
2. Compare the above with lymphoid niches in bone marrow organoids to identify where current protocols could be made more physiological
3. Define niches that support acute lymphoblastic leukaemia, detailing interactions and simulating how perturbing these interactions would influence leukaemia cell survival

Methodological approaches:

This bioinformatic project will provide training in cutting edge-technologies and analytical methods that will equip the candidate for competitive post-doctoral training or employment opportunities. Data generation methods will include single cell RNA sequencing and spatial transcriptomics (e.g. Xenium). Data processing methods will include quality control and integration. Data analysis methods will include query-to-reference mapping, cell-cell communication inference and quantitative characterization of niches. You may also have exposure to experimental methods for data generation and organoid culture.

Candidate background:

We welcome an enthusiastic student committed to becoming a research leader with a competitive bioinformatic skill set. The candidate should have background knowledge of genomics (undergraduate module or equivalent), some experience in computational methods, and some experience of conducting independent research. Strong communication and teamwork skills are essential.

Potential Research Placements:

This project will inform ongoing collaborative work in bone marrow organoid optimisation. Short-term placement with local collaborators in chemistry, engineering or with our industrial partner can be arranged. Placement with collaborators at the Wellcome Sanger Institute may also possible.

References:

1. Jardine et al. Blood and immune development in human fetal bone marrow and Down syndrome. Nature 2021.
2. Bandyopadhyay et al. Mapping the cellular biogeography of human bone marrow niches using single-cell transcriptomics and proteomic imaging. Cell 2024.
3. Burt et al. Activated stromal cells transfer mitochondria to rescue acute lymphoblastic leukemia cells from oxidative stress. Blood 2019.
4. Shen et al. comBO: A combined human bone and lympho-myeloid bone marrow organoid for pre-clinical modelling of haematopoietic disorders. BioRxiv 2025.
5. Birk et al. Quantitative characterization of cell niches in spatially resolved omics data. Nature Genetics 2025.

Primary Supervisor: Dr Adriana Buskin

Background:

Prostate cancer disproportionately affects Black men, yet men of African ancestry remain underrepresented in experimental models. Diverse human models can help reveal how prostate cancer-associated genetic alterations influence disease biology.

BRCA2 and SPOP are altered in prostate cancer and affect different cellular processes. BRCA2 is important for repairing damaged DNA, while SPOP controls proteins involved in androgen receptor (AR) signalling and other cellular functions [1,2]. How these alterations affect the organisation and identity of prostate cells remains unclear.

Our group has developed a genetically manipulatable, xeno-free human induced pluripotent stem cell (iPSC)-derived prostate organoid platform containing epithelial and stromal populations [3]. Our preliminary studies show that cancer-associated genetic alterations can disrupt epithelial architecture and change cell states.

Through an ongoing research programme, we are generating genetically matched parental, BRCA2-altered, SPOP-mutant and combined BRCA2/SPOP organoids from iPSCs derived from men of African ancestry, alongside single-cell and spatial datasets. These complement our established models from donors of European ancestry, allowing us to explore which epithelial features are shared across models and which warrant further investigation in ancestry-diverse cohorts. This PhD will investigate how genetic alterations shape prostate cell organisation, identity and plasticity, particularly during treatment and recovery.

Aims:

The project will:

1. Determine how BRCA2 and SPOP alterations affect epithelial architecture and cell identity during organoid development.
2. Identify molecular pathways and cell interactions that regulate epithelial organisation and plasticity.
3. Determine how epithelial cell states change during treatment and recovery and test candidate regulators of plasticity.

Methodological approaches:

The student will generate prostate organoids from genetically defined iPSC lines. Longitudinal imaging and immunofluorescence will assess morphology, lumen formation, polarity, cell-cell junctions and basal and luminal cell distribution.

Single-cell transcriptomic datasets will be reanalysed to investigate epithelial differentiation, cell states and molecular programmes associated with tissue organisation. Findings will be integrated with existing spatial proteomic data generated using MACSima. MACSima measures many proteins while preserving their location within tissue, allowing us to examine how different cell states are organised within organoids. Targeted imaging and selected MACSima experiments will further investigate epithelial identity, polarity and cell–cell interactions. Dedicated imaging will determine whether changes in primary cilia, small signalling structures on the cell surface, are associated with altered epithelial organisation or identity.

Selected models will receive enzalutamide or radiotherapy to investigate responses to AR inhibition and radiation-induced damage. Imaging, molecular and spatial analyses will assess epithelial organisation and identity during treatment and recovery. Proliferation and cell death will also be assessed to distinguish changes in cell identity from changes caused by selective cell survival. Candidate mechanisms will be investigated through focused functional experiments.

This PhD will establish how genetic context influences prostate epithelial organisation and identity in human models derived from men of African ancestry and identify candidate mechanisms regulating plasticity during treatment and recovery. The student will gain training in organoid biology, imaging, single-cell transcriptomics, spatial proteomics and functional cancer biology.

Candidate background:

We welcome applicants with a background in biomedical sciences, cell biology, molecular biology, cancer biology, genetics or a related discipline. An interest in prostate cancer, human stem-cell models, tissue organisation or cancer health inequalities is desirable. Previous experience in cell culture, microscopy, molecular biology or computational analysis would be beneficial but is not essential, as training will be provided. The successful candidate should be motivated to develop both experimental and analytical skills within a multidisciplinary research environment.

Potential Research Placements:

The project is supported by extensive in-house expertise and a broad network of national and international collaborators, providing opportunities for specialist visits as appropriate to the student's research. The student will also be supported to undertake external training, including opportunities to attend a one-week EMBL-EBI bioinformatics course at Hinxton, Cambridge, complementing their training in single-cell and spatial data analysis.

References:

1. An et al. Destruction of Full-Length Androgen Receptor by Wild-Type SPOP, but Not Prostate-Cancer-Associated Mutants. Cell Rep.2014; 6, 657–669.
2. Fan et al. Homologous Recombination Repair Gene Mutations in Prostate Cancer: Prevalence and Clinical Value. Adv. Ther. 2024; 41, 2196–2216.
3. Shaikh et al. A xeno-free human iPSC-derived prostate organoid platform for multilineage differentiation and genetic manipulation. Cell reports methods. 2026; 101538.

Primary Supervisor: Dr Agnieszka K. Bronowska

Background:

Microsatellite instability-high (MSI) cancers remain in need of new precision treatments. WRN helicase is a validated therapeutic target for MSI cancers, with several inhibitors currently in Phase 1 clinical trials^1-3. Those WRN inhibitors include covalent (GSK_WRN3, VVD-133214, MOMA-341) and non-covalent modalities (HRO761, GSK4418959, NDI-219216), targeting different binding sites. Despite their considerable potential, understanding and addressing mechanisms of resistance to WRN inhibitors is crucial to maximise clinical benefit for patients. Currently, how MSI cancer cells adapt to WRN inhibitors, remains underexplored. Likewise, how identified WRN mutants respond to inhibitors, what drives resistance, and whether new modalities may be feasible for targeting mutated WRN which show resistance to existing inhibitors.

Recurrent somatic WRN mutations, including C727R, G729D, G729S, F730L, F730S, and I852F, were identified in all resistant cell models, which spontaneously emerged under the selective pressure of GSK_WRN3 and HRO761³. Many of the mutations are located at or adjacent to the reactive C727, which engages with covalent inhibitors. Among thousands of sample-specific mutations detected in resistant cells, WRN was the only gene that was recurrently mutated across all cell lines^3,4. These results provide a framework for interpreting emerging clinical data on WRN inhibitor resistance.

To mitigate impact of WRN inhibitor resistance, compounds targeting new druggable sites or showing unique modes of action, are being sought. The dynamic nature of WRN indicates that such novel binding sites may be identified. However, such a dynamic nature presents a major challenge for conventional structure-guided approaches, which rely on static protein structures and cannot target experimentally invisible yet “druggable” transient states in mutated WRN. This means that an effective way to identify and target transient conformations induced by on-target mutations in WRN helicase is currently missing.

Aims:

This project aims to enable development of precision medicines in collaboration with AstraZeneca (Cambridge).

Objective 1: Exploration the dynamic “pocketomes” of wild-type WRN and reported on-target mutants.

Objective 2: Explore trillion-size chemical spaces to identify novel chemotypes suitable for effective targeting identified sites.

Proposed project, which focuses on identification of unique “druggable” states using multiscale modelling approaches, may deconvolute mechanisms underlying resistance to WRN inhibitors, inform the design of next-generation inhibitors, and support patient stratification in the future. 

Methodological approaches:

This project will advance drug discovery against WRN by incorporating its conformational plasticity into early-stage hit discovery. The work will be driven by multiscale molecular dynamics simulations with enhanced sampling of a large, highly flexible WRN helicase (WP1, months 1-9). We will define distinct conformations populated in WRN mutants to reveal unique “druggable” sites (WP2, months 10-15). Massive chemical space docking against those sites may uncover a novel chemical matter (WP3, months 16-24), which will be validated by biophysical assays (ITC and nanoDSF) underpin by expression and purification, using the protocol established at AstraZeneca (WP4, months 25-36). The validation (WP5, months 37-48) will yield a dynamic “pocketome” model to enable structure-guided development of drugs targeting WRN mutants. This project will unlock new therapeutic opportunities in precision oncology by providing preparedness to drug resistance by WRN helicase.

Candidate background:

Candidates should have a 1^st class undergraduate degree in computational chemistry, biomedical sciences, biophysics, or related field (e.g. medicinal chemistry, pharmacy), with skills in protein modelling and molecular simulations of biomolecular systems. Experience using MD simulation software (e.g. Gromacs, Amber), macromolecular visualisation tools (e.g. UCSF Chimera, Pymol), structure-based development software (e.g. SeeSAR), and chemical space navigation tools (e.g. InfiniSee) is sought. Proficiency in data visualisation (xmgrace, R) is a bonus. Experience in scripting/programming (Python, bash) is an advantage. Wet-lab experience (e.g. recombinant protein expression, purification, biophysical assays, molecular biology, synthetic organic chemistry) is highly desirable.

Potential Research Placements:

The studentship will explore several computational approaches and will rely on validation of the models by biophysical assay requiring recombinant protein expression. Co-supervisor (Durham University), who will oversee practical training in protein production and biophysical assays monitoring target engagement, has connections and shared previous funding with AstraZeneca, providing a potential route to translate the findings of this project. Before the student/candidate will be interviewed, the formal agreement regarding the industrial placement will be sought.

References:

1. Kikuchi et al. Identification of VVD-214/RO7589831, a Clinical-Stage, Covalent Allosteric Inhibitor of WRN Helicase for the Treatment of MSI-High Cancers. J Med Chem. 2025; 68(24):25912-25938.
2. Picco et al. Novel WRN Helicase Inhibitors Selectively Target Microsatellite-Unstable Cancer Cells. Cancer Discov. 2024; 14(8):1457-1475.
3. Picco et al. On-target mutations confer resistance to WRN helicase inhibitors in Microsatellite Unstable Cancer Cells. BioRXiv, 2026,
4. Herranz-Ors et al. A tumour-derived organoid biobank maps cancer gene dependencies. Nature. 2026; 657(8132):765-774.

Primary Supervisor: Dr Kelly Coffey

Background:

Prostate cancer is the most common cancer in men in the UK. However, the burden of disease is not shared equally. Men of Black heritage are around twice as likely to develop prostate cancer, are often diagnosed at a younger age, are more likely to develop aggressive disease, and experience the highest mortality rates. Despite these striking disparities, the biological mechanisms responsible remain poorly understood. Emerging evidence suggests that prostate cancers arising in men of African ancestry possess distinct genetic features. Recent genomic studies have identified alterations in genes that control cellular signalling networks, including several protein kinases that regulate cancer growth and survival. For example, activating mutations in BRAF appear to occur more frequently in tumours from men of African ancestry and are associated with unique patterns of genomic change, including reduced frequencies of TMPRSS2-ERG fusions and alterations in PTEN and APC [1]. While these genomic discoveries provide important clues, they do not reveal how these genetic alterations affect cellular signalling pathways or influence response to treatment. A major knowledge gap therefore remains: we do not yet understand how ancestry-associated genetic changes reshape kinase signalling networks, drive tumour growth, or create vulnerabilities that could be exploited therapeutically.

This project will address this challenge using cutting-edge molecular biology, genomics and drug discovery approaches. By focusing on models derived from men of African ancestry, the student will contribute directly to research aimed at reducing inequalities in prostate cancer outcomes and improving treatment options for Black men.

Aims:

This project seeks to improve our understanding of the biological factors that contribute to the increased burden of prostate cancer in men of Black heritage. Specifically, the student will (1) identify the contribution of kinase activity to the growth of prostate cancer in black men, (2) generate innovative models bespoke to African ancestry to determine how ancestry-specific signalling pathways influence response to treatment, (3) identify and prioritise novel therapeutic opportunities for pre-clinical testing.

Methodological approaches:

A high-throughput kinase library screen will identify ancestry specific, essential kinases using a panel of cell line models including MDA-PCA-2b (African American ancestry) and ACRJ-PC28 (Afro-Caribbean ancestry) [2, 3], CWR22Rv1 (mixed lineage) [4] and PC3 (European ancestry). Concurrently, publicly available RNA-Seq data will be evaluated to determine kinome expression differences, and mutations will be identified using whole genome sequencing data. This integrated approach will enable distinction between signalling changes driven by genetic mutations, altered gene expression, or broader network rewiring. Candidate essential kinases will be validated using cutting-edge functional cell biology assays including phenotypic response to kinase inhibitors, CRISPR-based knockout techniques and evaluation in tissue samples. Thirdly, new treatment opportunities will be identified using an FDA-approved drug screen to identify vulnerabilities in models derived from men of African ancestry.  This provides an opportunity to rapidly translate discoveries into clinically relevant therapeutic strategies through drug repurposing.

Students joining this project will have the opportunity to contribute to research with direct relevance to Black communities while gaining training in genomics, CRISPR gene editing, cancer biology, bioinformatics and translational drug discovery.

Candidate background:

The ideal candidate will have a passion for scientific research, be highly motivated and be willing to work collaboratively in a multicultural and diverse team environment. The candidate should have a background in molecular biology and/or biosciences at bachelor’s level as a minimum. Wet-lab experience is preferred but training will be provided in all techniques. A basic understanding of the R coding language and bioinformatics would be desirable, but training will be given. Peer and professional mentorship will be provided to support the successful student.

Potential Research Placements:

Multiple national placement opportunities are available ranging from collaborator laboratory placements to patient engagement opportunities. These will be discussed with prospective candidates upon enquiry and ultimately will be tailored to the successful candidate’s future career aspirations in addition to project development and support.

References:

1. Chehrazi-Raffle et al., Unique Spectrum of Activating BRAF Alterations in Prostate Cancer. Clin Cancer Res, 2023; 29(19): 3948–3957.
2. Badal et al., Novel Afro-Caribbean Prostate Cancer Model Reveals Ancestry-Specific Drug Vulnerabilities with Therapeutic Implications for Black Patients. Cancer Res Commun, 2025; 5(10): 1758–1770.
3. Valentine et al., Expanding the prostate cancer cell line repertoire with ACRJ-PC28, an AR-negative neuroendocrine cell line derived from an African-Caribbean patient. Cancer Res Commun, 2022; 2(11): 1355–1371.
4. Woods-Burnham et al., The 22Rv1 prostate cancer cell line carries mixed genetic ancestry: Implications for prostate cancer health disparities research using pre-clinical models. Prostate, 2017; 77(16):1601–1608.

Primary Supervisor: Prof Akane Kawamura

Background:

Despite major advances in drug discovery, many clinically validated targets remain inaccessible to traditional small-molecule therapeutics, particularly those that lack well-defined binding pockets or possess intrinsically disordered regions. This challenge is exemplified in castrate-resistant prostate cancer (CRPC), an advanced and lethal form of the disease, driven by persistent androgen receptor (AR) signalling despite androgen deprivation therapy.  CRPC frequently arises through AR amplification, point mutations, or expression of splice variants lacking the ligand-binding domain (LBD) targeted by current drugs. Among these, AR-V7 is associated with poor prognosis and remain difficult to target, due to its intrinsically disordered N-terminal domain and absence of tractable LBD, making it especially difficult to modulate with conventional approaches. Thus there is an urgent need for alternative chemical modalities to interrogate and target this challenging yet clinically important target / pathway in CRPC.

This PhD project aims to develop cyclic peptides as chemical tools to target challenging proteins, with a focus on AR and its co-regulators in CRPC. Cyclic peptides offer a promising alternative to small molecules due to their potency, selectivity and their ability to engage flat or extended protein surfaces that are typically inaccessible to traditional small-molecule ligands. These peptides can serve as both mechanistic probes and as starting points for therapeutic development.

In this project, the student will design and synthesise cyclic peptide libraries using solid-phase synthesis and display technologies. Biophysical assays will be used to confirm binders, and structural biology (X-ray crystallography / NMR studies) together with modelling will provide mechanistic insights and support the optimisation of cyclic peptides. Peptides will further be tested in cellular assays in CRPC models to evaluate their cellular effect on AR signalling.

The studentship will be supported by a collaborative team of experts in peptide chemistry, structural biology, target validation and cancer drug discovery. This project offers a unique opportunity to contribute to the development of next-generation chemical tools for challenging targets, with potential impact on prostate cancer treatment and broader drug discovery efforts.

*The aggressive nature of CRPC is particularly challenging in Black men who are twice as likely to be diagnosed with prostate cancer (1 in 4 Black men, 1 in 8 White men (1 in 13 Asian men), often at an earlier age and with death occurring at twice the rate as in white men (Prostate Cancer UK).

Candidate background:

We are seeking a highly motivated undergraduate or Master’s graduate with a 2:1 or above in chemistry, biochemistry, or a biology-related discipline. Experience in peptide chemistry, protein biochemistry, or chemical biology is desirable. The ideal candidate will have a strong interest in cancer biology, be proactive and enthusiastic, and keen to work across disciplines in a collaborative research environment.

References:

1. Tan et al. Androgen receptor: structure, role in prostate cancer and drug discovery. Acta Pharmacol. Sin. 2015; 36, 3–23.
2. Daniels et al. Therapeutic approaches to targeting androgen receptor splice variants. Cells. 2024; 13:104.
3. Lee et al. Structural mechanism underlying variations in DNA-binding by the androgen receptor. J. Steroid Biochem. Mol. Biol. 2024; 241:106499.
4. Serrano et al. Chapter 5: Cyclic peptides as chemical probes. Royal Society of Chemistry Book Series: Chemical Biology; The Discovery and Utility of Chemical Probes in Target Discovery. (ISBN: 978-1-78801-589-9; 2021) 100-123;
5. McAllister et al. Structural Diversity in De Novo Cyclic Peptide Ligands from Display Technologies. Peptide Science. 2020; 113:e24204

Primary Supervisor: Dr Jiabao He

Background:

Breast cancer diagnosis and treatment relies on effective clinical imaging techniques. However, most imaging characterises disease anatomy rather than functionality, providing no information on disease biology. Development of imaging methods sensitive to underlying disease processes would improve quality of care for patients by allowing better treatment stratification and response monitoring.. In contrast to the anatomical visualisation capability of conventional magnetic resonance imaging (MRI), advanced MRI methods allow essential physiological information, such as vascular function, tissue microstructure and metabolic function, to be encoded in the acquired images. Although the information derived from these new MRI methods is potentially valuable for the assessment of disease, their translation into clinical use is lagging behind fundamental research, because of the unique requirements imposed by clinical applications.

Oxygen is essential to the aerobic energy production, while anaerobic energy production is employed under insufficient oxygen supply. The anaerobic pathway is not only inefficient in terms of amount of energy produced, but also alters the pH, affecting normal immune function. Lactate dehydrogenase (LDH) overexpression is the central feature of tumour metabolism, with an associated hypoxia and elevated lactate production in the tumour core.

MRI is a promising powerful non-invasive method for assessing tissue oxygen level. Since deoxyhaemoglobin is paramagnetic, generating local magnetic field disturbance within tissues, both the rate of signal dissipation (R2*) and the rate of tissue re-magnetisation (R1*) increases with the concentration of deoxyhaemoglobin. However, these methods are qualitative in nature, with R1* measurement influenced by imperfections of the scanner hardware. Recently, a method based on the employment of inspiration of oxygen-enriched air in conjunction with the observation of R1* was successfully developed and demonstrated in an animal model, allowing quantitative assessment of the oxygen extraction fraction1. However, R1* measurement is lengthy compared to R2* assessment and humans can only be exposed to oxygen-enriched air for a limited time, while several acceleration methods are available (namely Look-Locker, fast reordering and DESPOT1 methods)2.

Aims:

This project aims to translate, optimise and extend quantitative oxygen extraction fraction mapping based on oxygen enriched air inspiration and magnetic resonance (MR) relaxometric imaging for human application. This underpinning imaging method will be pivotal in the non-invasive assessment of mitochondrial function and abnormal metabolism, fundamental in the understanding and treatment of cancer.

Methodological approaches:

The project includes three workpackages:

1. Development and optimisation of R1* and R2* acquisition schemes to estimate sensitivity and specificity.
2. Development and optimisation of data feature extraction algorithms for the effective combination of R1* and R2* data.
3. Implementation and validation of this new acquisition approach on our clinical MRI scanner.

The investigation team has extensive experience and strong track record in the development and clinical application of novel MRI methods, including hardware development, image analysis and programming. The successful candidate will be guided by Dr Jiabao He on MRI method development, Dr Simon Lowes on clinical application, and Dr Sai Man Cheung on clinical study management, as well as being supported by a network of former and current students in academic and healthcare domains.

Candidate background:

We are seeking a highly-motivated student with a background in a quantitative discipline such as physics, mathematics, engineering or computing science to join our cancer imaging team.  Instruction in MRI physics can be provided through a taught MSc module.

At the end of the PhD, the student will have acquired transferable skills including numerical simulation, image data analysis, clinical study management and MRI scanner programming, essential for the next stage in their career development. The student will benefit from a set of internal training programmes, specially designed to support the success of scientists working in the clinical environment.

Potential Research Placements:

The three investigators are from 3 academic and NHS organisations, allowing wide choices of placement. We have strong ongoing research collaboration with Francis Crick Institute, and 3 students have previously conducted multi-week placement on collaborative research project yielding first author publications.

References:

1. Cheung et al. Lipid Composition in the Breast of Premenopausal BRCA1/2 Genetic Mutation Carriers Using MRI. IJMS. 2026; 27: 8472.
2. Cheung et al. Editorial: Breast cancer imaging: clinical translation of novel methods. Frontiers in Oncol. 2025; 15:1581169.
3. Nkonde et al. Understanding cellular proliferation activity in breast cancer using multi-compartment model of transverse relaxation time mapping on 3T MRI. Frontiers in Oncol. 2025; 15:1482112.
4. Ayoub et al. Differentiation of Histological Calcification Classifications in Breast Cancer using Ultrashort Echo Time (UTE) and chemical shift encoded imaging (CSEI) MRI. Frontiers in Oncol. 2024; 14:1475090.
5. Cheung et al. Peri-tumoural lipid composition and hypoxia for early immune response to neoadjuvant chemotherapy in breast cancer. IJMS. 2024; 25(17): 9303.

Primary Supervisor: Dr Debbie Hicks

Background:

Medulloblastoma (MB) is the most common malignant paediatric brain tumour, with 5-year survival now exceeding 75%. Despite these improvements, survivors remain at high risk of developing severe treatment-related late effects. Craniospinal irradiation and multi-agent chemotherapy remain essential components of therapy for non-infant patients, but can result in endocrine dysfunction, secondary malignancies, ototoxicity, reduced physical function, and neurocognitive impairment. Neurocognitive dysfunction is particularly debilitating, with many survivors experiencing reductions in intelligence quotient, academic attainment, processing speed, memory, and executive function. As previous efforts have primarily focussed on developing novel anti-tumour therapies, there are currently no pharmacological interventions that prevent or reverse treatment-induced neurotoxicity in widespread clinical use.

Our previous research has identified several germline single nucleotide polymorphisms (SNPs) associated with an increased risk of neurocognitive impairment in MB survivors, and further functional investigation is required to characterise their ability to modulate treatment-induced injury. In addition, using our clinically relevant murine model of MB radiotherapy, we have developed a single-cell transcriptional atlas that has identified key perturbations in microglia and oligodendrocyte progenitor cells.

The aim of this studentship is to investigate the biological mechanisms underpinning radiation- and chemotherapy-induced injury and understanding why some individuals are more susceptible to neurocognitive decline than others, with a particular focus on identifying potential targets for neuroprotection.

Aims:

1. Characterise the biological response to clinically relevant radiation and chemotherapy exposure, within a suite of biological relevant cell lines.
2. Explore the roles of microglia and oligodendrocyte lineage cells in mediating treatment-induced neurotoxicity.
3. Determine how germline genetic modifications, associated with neurocognitive impairment, influence cellular injury responses.
4. Identify candidate therapeutic targets that may mitigate treatment-related brain injury.

Methodological approaches:

The project will build upon our clinically relevant murine model of MB radiotherapy, from which we have generated a single-cell transcriptional atlas identifying radiation-induced perturbations within microglia and oligodendrocyte progenitor cells (OPCs), two cell populations increasingly recognised as critical mediators of neurocognitive outcomes. The student will utilise human inducible pluripotent stem cells (iPSC), and characterise the acute and late neurotoxicity induced by radiation and chemotherapy within specific brain cell types.

Our previous research has also identified several germline single nucleotide polymorphisms (SNPs) associated with an increased risk of neurocognitive impairment in MB survivors. To investigate their functional significance, CRISPR/Cas9 genome editing will be used to generate isogenic cell lines harbouring our panel of SNPs. Molecular biology techniques will be employed to explore their ability to modulate radiation and/or chemotherapy-induced injury, in particular assessing DNA damage, oxidative stress, neuroinflammation, mitochondrial dysfunction, senescence, and cell death.

This work will provide fundamental insight into the cellular biology of treatment-induced neurotoxicity and establish how genetic variation modifies vulnerability to treatment-induced injury. The project will identify key biological targets for neuroprotective therapies for children treated for medulloblastoma and provide a platform to assess potential pharmacological interventions prior to their appraisal within our developed in vivo models.

Candidate background:

The candidate should have a background in cancer and/or neuroscience, with experience in molecular biology laboratory techniques, particularly tissue culture.

This project will involve training in tissue culture, immunoassays, bioinformatics and statistical analyses. Complete training will be provided throughout the duration of this project in the Paediatric Brain Tumour Group. 

References:

1. Taylor et al. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol. 2012; 123(4):465-72. 
2. Castle et al. In vivo modeling recapitulates radiotherapy delivery and late-effect profile for childhood medulloblastoma, Neuro-Oncology Advances, 2024; 6, Issue 1, vdae091.

Primary Supervisor: Dr Sara Luzzi

Background:

Androgen signalling via the androgen receptor (AR) is a major driver of prostate cancer. Consequently, hormone therapy that blocks either androgen production or AR function is a highly effective and widely used therapeutic approach. However, this intervention significantly increases the risk of cardiovascular disease and, critically, cardiovascular mortality.

The mechanisms by which inhibiting androgen signalling induces cardiovascular disease remain poorly elucidated. Therefore, assessing and mitigating cardiovascular risk in men with prostate cancer remains a major clinical challenge. Furthermore, whether susceptibility to these cardiovascular side effects resulting from prostate cancer hormone therapy differs across ethnicities is unclear. Recent clinical studies report contrasting findings, with some cohorts observing a higher incidence of cardiovascular events among Black men receiving hormone therapy compared to White men, while others found similar or lower rates.

We have found that AR inhibition disrupts redox homeostasis and calcium handling in cardiovascular cells. Intriguingly, previous studies report baseline differences in endothelial redox biology between Black and White donors. Whether these pathways contribute to ethnic variations in vascular response to prostate cancer hormone therapy is unknown.

Aims:

1. Investigate ethnic differences in the endothelial response to androgen signalling inhibition
2. Identify the mechanisms driving cardiovascular vulnerability to AR signalling inhibition in different ethnic groups
3. Determine whether these identified mechanisms can be targeted to either predict or mitigate the cardiovascular toxicity of prostate cancer hormone therapy

Methodological approaches:

The student will expose human aortic endothelial cells (HAoECs) from both White/Caucasian and Black/African male donors to AR signalling inhibitors to assess cell function and redox homeostasis (Aim 1). They will employ a robust panel of functional assays including ATP and nitric oxide measurements, flow cytometry, immunostaining, RT-qPCR, Western blotting, endothelial-to-mesenchymal transition and vessel formation assays. To distinguish between true androgen-dependence and off-target drug effects, the student will utilise siRNA-mediated AR knockdown and androgen-depleted culture conditions. Next, the student will employ RNA sequencing to characterise differences in transcript levels and RNA processing in HAoECs exposed to AR inhibitors and will assess how these translate to changes to the proteome by SWATH mass spectrometry (Aim 2). Finally, the student will integrate functional, transcriptomic and proteomic datasets to select up to three high-priority targets. These targets will be modulated via over-expression or inhibition to evaluate their capacity to rescue endothelial function during AR inhibition (Aim 3).

Outcomes This project will determine if endothelial responses to prostate cancer hormone therapy differ between ethnic groups, and identify molecular signatures to reduce treatment-induced cardiovascular toxicity. The student will acquire a comprehensive skillset spanning wet-lab experimental biology and computational bioinformatics, developing highly marketable expertise in the rapidly growing field of cardio-oncology.

Candidate background:

We seek a motivated candidate with a strong foundation in biological sciences and a keen interest in cancer biology or cardio-oncology. Applicants should possess a background in molecular biology or genetics, alongside practical wet lab experience including cell culture techniques and nucleic acids handling. Basic knowledge of bioinformatics is advantageous but not essential as training in all the required experimental and computational workflows will be provided.

Potential Research Placements:

We have an extensive network of collaborators. The student will undertake a placement at Durham University for SWATH mass spectrometry, with further optional placement opportunities at Sheffield Hallam University and the University of Leeds to utilise advanced multicellular vascular models for this project. Additionally, the student will have the opportunity to interact with collaborators in Oxford, Glasgow, Manchester, London and Amsterdam to integrate their project into the wider ongoing research work carried out in the supervisory groups.

References:

1. Saigal et al. Androgen deprivation therapy increases cardiovascular morbidity in men with prostate cancer. Cancer. 2007: 110(7):1493-1500.
2. Demissei et al. Social determinants of health mediate racial disparities in cardiovascular disease in men with prostate cancer. JACC CardioOncology. 2024; 6(3):390-401.
3. Moul et al. Real-world analyses of major adverse cardiovascular events and mortality risk after androgen deprivation therapy initiation in black vs. white prostate cancer patients. Prostate Cancer Prostatic Dis. 2025; 28(4):946-952.
4. Kalinowski et al. Race-specific differences in endothelial function: predisposition of African Americans to vascular diseases. Circulation. 2004; 109(21):2511-2517.
5. Vidotto et al. Multiomic reference map of endothelial mechanosensitive pathways under athero- and erosion-prone flow. J Am Heart Assoc. 2026; 15(13):e048290.

Primary Supervisor: Prof Gareth Veal

Background:

Advances in the treatment of childhood cancer over the past several decades have been achieved through a combination of developing intensive chemotherapy regimens, predominantly involving high doses of traditional cytotoxic drugs, alongside the introduction of novel agents. While survival rates have increased considerably for many malignancies, this is associated with a high incidence of treatment-related side-effects and long-term toxicities. In this respect, it is estimated that approximately two-thirds of all childhood cancer survivors experience long-term health issues which impact quality of life. As cumulative dose is associated with increased risk of late-effects of treatment, we need to generate a better understanding of relationships between individual patient dose, drug exposure, clinical response and toxicity. The project will focus on blinatumomab and venetoclax, drugs that have recently been introduced in a childhood leukaemia setting (B-cell acute lymphoblastic leukaemia (B-ALL) and acute myeloid leukaemia (AML), respectively). Currently very limited paediatric pharmacokinetic data exist on which to base dosing regimens for childhood patients. Blinatumomab is a novel immunotherapeutic, with recent data showing a significant improvement in disease-free survival for children with standard-risk B-cell ALL with an average/higher risk of relapse, as compared to chemotherapy alone. Data from adults have indicated an association between blinatumomab concentrations and clinical response, providing good evidence for investigating pharmacokinetics in a paediatric population. Similarly, venetoclax exposure has been shown to be significantly associated with probability of achieving response in adult CLL patients, again providing evidence that pharmacokinetics should be studied in a paediatric setting.

Aims:

1. Develop and validate assays for the quantification of blinatumomab and venetoclax in clinical samples.
2. Generate pharmacokinetic data on blinatumomab and venetoclax in a clinical trial setting alongside outcome and toxicity data.
3. Develop Population Pharmacokinetic models for blinatumomab and venetoclax to investigate factors associated with pharmacokinetic variability and predict drug clearance and exposure.
4. Use the models developed to propose dosing regimens based on a clear clinical pharmacological rationale.

Methodological approaches:

The 缅北禁地 Cancer Centre Pharmacology Group has vast experience of developing assays for a wide array of anticancer drugs, including small molecules, bicyclic peptide drug conjugates, pegylated drugs and monoclonal antibodies, with several novel assays published from early phase clinical trial work. Analytical assays to be taken forward as part of the current proposal will include liquid chromatography-mass spectrometry (LC/MS) and enzyme-linked immunosorbent assay (ELISA) approaches, which will be developed and fully validated according to internationally accepted recommendations for bioanalytical method validation provided by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). This will include the development of formal assay validation plans with experimental approaches designed to investigate assay recovery, selectivity, matrix effect, anticoagulant comparison, lower limits of detection and quantification, linearity and range, intra- and inter-day precision and accuracy, dilutional integrity, carryover, short- and long-term stability, freeze-thaw stability, and incurred sample reproducibility (ISR). Acceptance criteria are provided for each of these assay parameters in the aforementioned EMA and FDA guidance documents. 

Candidate background:

This project is highly translational and we are looking for a motivated student with a background in pharmacology/pharmaceutical sciences/biochemistry/bioanalytical sciences who has an interest in pharmacokinetics.

Potential Research Placements:

The project will include collaborative work with a research group at the Princess Maxima Hospital in the Netherlands and may include an optional training period in pharmacokinetic modelling in Amsterdam.

References:

1. Astley et al. Development and validation of a LC-MS/MS method for the quantification of the E-type prostanoid receptor 4 antagonist HTL0039732 in human plasma, for a Phase I/IIa clinical trial. Bioanalysis 2026; (In press)
2. Brandon et al. Population pharmacokinetics and dose-response relationships of mitoxantrone in children with acute myeloid leukaemia. British Journal of Clinical Pharmacology 2026; 92: 1760-1770
3. Whitaker et al. Development and validation of a LC-MS/MS method for the quantification of novel therapeutic TT-478, a selective adenosine receptor 2B antagonist, for a phase I/II clinical trial. Bioanalysis 2025; 17: 1105-1112
4. Mohmaed Ali et al. A population pharmacokinetic study to evaluate doxorubicin exposure across all age groups. Clin Pharmacokinet 2024; 63: 1711-1722
5. Millen et al. Utility of carboplatin therapeutic drug monitoring for the treatment of neonate and infant retinoblastoma patients in the United Kingdom. Br J Cancer 2024; 131: 491-497