CRUK Black Leaders in Cancer PhD Scholarship Programme

Starting in September 2026, 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 Newcastle 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 Newcastle:

• 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: 5 December 2025, noon

We should receive your references by 12 December 2025, 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: 19 January 2026

Supervisors may contact you during the shortlisting period (December 2025 - mid-January 2026), to find out more about you and your interest in their project.

Information session for interviewees: 5 February 2026, 1pm to 2pm

Panel interviews will take place: week commencing 9 February 2026

Programme start date: September 2026

During the interview, candidates will be interviewed by a panel of CRUK Newcastle Cancer Centre academics from across the Centre’s 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:

Tuesday 7 October 2025 at 12:30 – 14:00 (GMT)

Potential candidates can register to attend the insight session here.

Step 1 - Windsor Fellowship Application

Step 2 - CRUK Newcastle Cancer Centre Application

Follow the above links for steps to submit your formal application for a place on the studentship programme at the CRUK Newcastle 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 2026

Primary supervisor: Prof Fiona Oakley  Co-supervisor: Dr Erik Ramon-Gil

Background:

Hepatocellular carcinoma (HCC) develops in patients with chronic liver disease (CLD) including metabolic liver disease (MASLD/MASH). HCC is the 3rd leading cause of cancer-related mortality, with a poor 5-year survival rate of 18% due to late diagnosis. Systemic combination of atezolizumab plus bevacizumab is the standard-of-care treatment, but <30% of patients respond due to an immunosuppressive tumour immune-microenvironment (TIME). Second-line therapies (sorafenib/Lenvatinib) only extend median survival by ~6 months. Hence, novel systemic therapies are urgently needed to improve HCC treatment. PFKFB (6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase) are key glycolytic enzymes, and expression of the PFKFB3 subunit rapidly and potently stimulates glycolysis, a known modulator of tumour growth. PFKFB3 upregulation in CLD promotes metabolic reprogramming of hepatocytes and macrophages, implicating glycolytic reprogramming as a pathological driver of CLD. In human HCC, high PFKFB3 levels correlate with reduced patient survival. Therefore, PFKFB3 blockade represents a novel target for HCC.

Hypothesis: PFKFB3 inhibition will reduce tumour cell proliferation/survival and reshape the HCC-TIME to enhance immunotherapy response. 

Aims: 

1. Correlate PFKFB3 expression with pathological features of the TIME in mouse and human HCC.
2. Dissect the cell-specific activities of PFKFB3 in HCC using genetically modified mice.
3. Determine the therapeutic opportunities for PFKFB3 blockade in HCC, using complex 3D cell-culture models and mouse HCC models.

Methods: the student will be fully trained in all methodologies.

Human and mouse HCC Tissue Microarrays will be stained for PFKFB3, tumour, non-tumour and immune cell markers to create spatial maps of the HCC-TIME using imaging mass cytometry.  Image processing and bioinformatic analysis using established analysis pipelines (e.g. OPTIMAL) will reveal how cell-specific PFKFB3 expression influences the TIME.

The student will modulate PFKFB expression in the Hep53.4 murine HCC cell line using CRISPR to delete PFKFB3 (Hep53.4^PFKFB3-/-) and lentivirus to overexpress PFKFB3. PFKFB3 deletion/overexpression will be confirmed by western blot. Seahorse analysis will assess glycolytic reprograming.

The student will use our surgical orthotopic mouse HCC model that responds to immunotherapy but becomes resistant in mice with MASH to study the role of PFKFB3 in HCC and therapy resistance. Hep53.4 wildtype or Hep53.4^PFKFB3-/- orthotopic liver tumours will be generated in lean and obese (mimicking MASH-HCC) mice. To elucidate the cell-specific activities of PFKFB3 in HCC, orthotopic tumours will be generated in genetically modified mice, where PFKFB3 is deleted in hepatocytes, macrophages or fibroblasts. Changes to the HCC-TIME will be determined using established high-parameter flow cytometry panels and immunohistochemistry.

The student will interrogate the disease pathobiology in these models using Lipidomics and scRNA-seq with collaborators at Edinburgh University and Imperial College London.

To assess impact of PFKFB3 blockade on therapy response, precision cut tumour slices (PCTS) will be generated from Hep-53.4 orthotopic tumours from lean or obese mice and treated with PFKFB3 inhibitors +/- standard-of-care compounds.  Tumour growth (BrDU), viability (resazurin/ATP-glo), death (cell-tox green/caspase-glo) and metabolic activity (seahorse) will be quantified. Flow cytometry and immunohistochemistry will assess the PCTS-TIME as above. Lead therapeutic compounds and drug combinations will then be tested in primary human HCC lines, to increase the works translatability to patients.

Candidate background:

The candidate must have a keen interest in cancer biology, and a desire discover new molecular mechanisms of liver cancer, to unlock novel therapeutics and test their potential to treat patients with HCC.

The candidate should have a background in basic science including cell and preferably cancer biology with some wet lab experience in basic cell biology techniques.  All training in the necessary techniques will be provided. While not essential experience with techniques experience with tissue culture, histological analysis of tissue and flow cytometry will be advantageous.

Potential research placement:

There is scope for two national placement at the laboratories of our collaborators;

Dr Zoe Hall, Imperial College London, to perform bulk and spatial lipidomics analysis on orthotopic tumour and non-tumour samples generated during the project.

Prof Prakash Ramanchandran, Edinburgh University to perform 10X fixed flex sequencing and bioinformatics analysis on orthotopic tumour and non-tumour samples generated during the project.

The student will also work with the supervisory team and collaborator laboratories to analyse and interpret the data generated from these placements using specialist software and informatics.

References:

Hepatocellular carcinoma. Nat Rev Dis Primers. 7, 6.

Leslie J et al. c-Rel orchestrates energy-dependent epithelial and macrophage reprogramming in fibrosis.  Nat Metab. 2, 1350 (2020).

Leslie J et al. CXCR2 inhibition enables NASH-HCC immunotherapy. Gut. 71, 2093 (2022).

Collins AL et al. Precision-cut tumor slices for modeling hepatocellular carcinoma enable at-scale drug screening. Hepatol Commun. 9, e0706 (2025).

Hall Z et al. Lipid Remodeling in Hepatocyte Proliferation and Hepatocellular Carcinoma. Hepatology. 73, 1028 (2021).

Primary Supervisor: Dr Lisa Russell  Co-supervisor: Dr Sarra Ryan

Background:

In 2009, we identified two cryptic rearrangements that result in deregulated expression of cytokine receptor‐like factor 2 by juxtaposition to IGH super-enhancers (IGH::CRLF2) or the promoter of purinergic gene, P2RY8 (P2RY8::CRLF2). Despite having genetically and clinically characterised these rearrangements (1,2), little is known about how and why these rearrangements occur in immature B-cell malignancies. This project will apply computational methods together with complementary laboratory experiments to characterise the epigenomic and 3D landscape of the PAR1 region to identify mechanisms that predispose this region to oncogenic rearrangements in immature B cells.

Aim 1 – (Re)analysis of publicly available/in-house generated epigenomic and chromosome conformation data to the PAR1 region. The candidate will realign histone ChIP-seq, ATAC-seq, DNase-seq and HiC data for healthy and malignant B-cell samples to the PAR1 region and using the ChromHMM package, will provide insights into the epigenomic landscape of the region that may contribute to leukaemia development.

Aim 2 – Confirm potential of large regulatory regions to control gene expression in PAR1. The candidate will quantify the activating capacity of enhancer regions within the PAR1 region of leukaemic B cells by conducting ATAC-STARR-seq (3) on patient derived models. This aim will lead to a detailed epigenomic map for the PAR1 region, providing insights into the mechanisms in place that regulate the expression of genes within this region, some that have confirmed links to cancer development.

Aim 3 – Experimentally investigate the regulation of CRLF2 and how this might predispose to oncogenic rearrangement events. The candidate will investigate how the expression and interaction between CRLF2 and confirmed regulatory regions promotes expression of CRLF2 and predisposes to deletion and gene fusion events in immature B-cells. Using CRISPR Cas9 technologies the candidate will: 1) Disrupt CTCF binding, a protein essential for forming DNA loops, between the promoter and regulatory regions and observe any changes in CRLF2 gene expression. 2)  Silence regulatory regions to assess their impact on CRLF2 gene expression. 3) Induce the formation of the fusion gene by using Cas9 to cut the DNA at recurrent breakpoint locations.

Candidate background:

We are looking for someone with a biology-based background who is interested in discovering novel mechanisms that underlie chromosomal rearrangements in cancer. 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 bioinformatic skills alongside existing wet lab skills 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 the UK that could offer placement opportunities. This includes experts in chromatin polymer physics (Edinburgh), protein homeostasis (York) and chromosome capture methods (Oxford).

References:

Russell LJ et al. Deregulated expression of cytokine receptor gene, CRLF2, is involved in lymphoid transformation in B-cell precursor acute lymphoblastic leukemia. Blood. 114, 2688 (2009).

Yang H et al. Noncoding genetic variation in GATA3 increases acute lymphoblastic leukemia risk through local and global changes in chromatin conformation. Nat Genet. 54, 170 (2022).

Wang X et al. High-resolution genome-wide functional dissection of transcriptional regulatory regions and nucleotides in human. Nat Commun. 9, 5380 (2018).

Primary Supervisor: Dr Brian Ortmann  Co-supervisor: Dr Jack Leslie

Background:

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and a major cause of cancer-related death worldwide, with around 866,000 new cases and 759,000 deaths each year. A key barrier to treatment is tumour hypoxia, the reduced oxygen availability in the tumour microenvironment. Hypoxia promotes progression by driving angiogenesis, metabolic reprogramming, and resistance to cell death. It also reduces the efficacy of chemotherapy, radiotherapy, and targeted therapies, while enabling immune evasion1. Understanding how cells adapt to hypoxia therefore offers major opportunities for therapeutic advances.

Central to hypoxic adaptation is transcriptional reprogramming. Stabilisation of hypoxia-inducible factors (HIF-1 and HIF-2) activates survival and resistance programmes2. While HIF has long been an attractive therapeutic target, transcription factors are inherently difficult to inhibit, and HIF-2–specific inhibitors are limited by toxicity and systemic effects3. To make progress, we must move beyond HIF and define the broader signalling events driving cellular adaptation.

Recent evidence shows that hypoxia induces not only gene activation but also widespread transcriptional repression, conserving energy and prioritising essential pathways4,5. The mechanisms remain poorly understood. A targeted siRNA screen of chromatin regulators essential for hypoxic survival identified several methylases as key candidates. These enzymes repress transcription by depositing epigenetic marks that compact chromatin. This highlights transcriptional repression as a critical, yet underexplored, component of the hypoxic response. Notably, inhibitors of several methylases already exist, offering opportunities for therapeutic repurposing against hypoxic tumours.

Aims:

1. Validate the role of identified methylases in hypoxic cell survival.
2. Define the mechanisms underlying transcriptional repression under hypoxia.
3. Test the therapeutic potential of methylase inhibition in preclinical liver cancer models.

Methodologies:

We will first validate screen hits through cell viability and cell death assays, using immunoblotting and flow cytometry in liver cancer cell lines under normoxic and hypoxic conditions. Promising candidates will be prioritised for detailed analysis. To define the role of identified targets in transcriptional repression, we will combine ChIP-Seq to map epigenetic marks with RNA-Seq to correlate chromatin changes with transcriptional outputs, following genetic depletion (siRNA/CRISPR) or chemical inhibition (where possible). Mechanistic studies will employ biochemical analyses and proximity labelling with mass spectrometry (TurboID) to identify recruitment events, protein interactions, and cellular pathways involved in mediating transcrtpional repression in hypoxia. Finally, therapeutic relevance will be tested in mouse liver cancer models and ex vivo  liver slice cultures to determine whether genetic or chemical inhibition of identified methylases selectively enhances cell death in hypoxia. We will then comprehensively profile the tumour microenvironment using multiparameter flow cytometry and immunohistochemistry to define immune and stromal dynamics, including effects on anti-tumour immunity, following target inhibition.

The successful candidate will receive comprehensive training in next-generation sequencing (RNA-Seq, ChIP-Seq) and bioinformatics, advanced biochemical techniques including mass spectrometry, and in vivo and ex vivo liver cancer models providing an excellent platform for independent research development.

Candidate Background:

The ideal candidate will have a background in cell biology and a strong interest in transcriptional regulation and epigenetics, with hands-on experience in fundamental cell biology techniques. Full training will be provided in specialised methodologies and bioinformatics. Prior experience with tissue culture would be an advantage.

Potential Research Placements:

The supervisory team benefits from an extensive national network of collaborators, creating excellent opportunities for research placements and knowledge exchange. These collaborations will provide valuable exposure to complementary expertise, particularly in liver cancer research and bioinformatics, thereby broadening the scope and impact of the project while supporting the candidate’s career development.

References:

Ortmann BM.  Hypoxia- inducible factor in cancer: from pathway regulation to therapeutic opportunity. BMJ Oncology 3, e000154. doi:10.1136/ bmjonc-2023-000154 (2024).

Taylor CT, Scholz CC. The effect of HIF on metabolism and immunity. Nat Rev Nephrol 18, 573–587 (2022).

Courtney KD, et al. Phase I dose-escalation trial of PT2385, a first-in-class hypoxia-inducible factor-2α antagonist in patients with previously treated advanced clear cell renal cell carcinoma. J. Clin. Oncol. https://doi.org/10.1200/JCO.2017.74.2627 (2017).

Cavadas M, et al. REST is a hypoxia-responsive transcriptional repressor. Sci Rep 6, 31355 (2016).

Batie M, et al. Hypoxia and Chromatin: A Focus on Transcriptional Repression Mechanisms. Biomedicines. 6, 47 (2018).

Primary Supervisor: Dr Celine Cano  Co-supervisor: Dr Luke Gaughan

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.

Aim 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 (Cano).  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.

Aim 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.

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 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 (Gaughan). 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 placements:

The student will be based in a dynamic multidisciplinary drug discovery and translational research environment. The Newcastle Medicinal Chemistry Group is a fully integrated drug discovery group, consisting of 30 researchers. The group hosts regular group meetings to discuss progress, as well as medicinal and synthetic chemistry literature reviews. We also hold monthly multidisciplinary project reviews at which the student will be expected to present results to colleagues in Biosciences.

Each year, the PhD student will be able to undertake short (circa 2 months) placements within the biology labs (Dr Gaughan, Newcastle Centre for Cancer) to provide further multidisciplinary training.

References:

Adamson B et al. The catalytic subunit of DNA-PK regulates transcription and splicing of AR in advanced prostate cancer. J Clin Invest. 133 e169200 (2023).

Willoughby CE et al. Selective DNA-PKcs Inhibition Extends the Therapeutic Index of Localized Radiotherapy and Chemotherapy. J Clin Invest. 130, 1 (2019).

Kounatidou E et al. A novel CRISPR-engineered prostate cancer cell line defines the AR-V transcriptome and identifies PARP inhibitor sensitivities. Nucleic Acids Research 47, 5634 (2019).

Cano C et al. 1-Substituted (Dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-ones Endowed with Dual DNA-PK PI3-K Inhibitory Activity. Journal of Medicinal Chemistry 56, 6386 (2013).

Primary Supervisor: Dr Jennifer Munkley  Co-supervisor: Dr Kirsty Hodgson

Background:

Breast cancer is the most frequently diagnosed cancer in women worldwide. Black women are disproportionately affected by breast cancer, with greater diagnosis of aggressive and late-stage cancers, higher rates of hard-to-treat triple negative breast cancer (TNBC), and increased mortality rates compared to other ethnic groups. The gap in breast cancer incidence and outcomes in Black women is complex and multifactorial, and more research is needed to address this devastating racial disparity. Emerging studies suggest breast tumours in Black women have biological differences that may impact their cancer progression and response to therapy. An area of innovation in the search for new therapies for breast cancer is glycobiology, with exciting clinical trial data highlighting the huge potential to target glycans to improve outcomes for patients. Our research suggests breast tumours from Black women may have a different coat of glycans on their cell surface than tumours from other ethnic groups. Specifically, we have identified 3 glycans that are found at high levels in Black breast cancer tumours. We predict these glycans can be targeted to improve outcomes for Black women with breast cancer. However, to translate these findings into the clinic, we need a much better picture of how tumour-associated glycans change among breast cancer patients of different ethnicities and which glycans are best to target for Black breast cancer.

Aims: This project aims to exploit the tumour-associated glycans to develop novel targeted therapies that will specifically benefit Black women with breast cancer. We will aim to: 1) profile how glycans change in blood and tissue samples from breast cancer patients with different ethnicities, 2) discover the role of tumour-associated glycans in the growth and metastasis of Black breast cancer, and 3) use innovative models to perform pre-clinical evaluation of a panel of novel glycan-targeting drugs as new therapies for Black breast cancer.

Methods: ELISAs, immunohistochemistry, and novel glycan-profiling techniques will be used to monitor glycan signatures in tissue and blood samples from breast cancer patients with different ethnicities. Alongside this, utilising immune cell co-cultures, organoid models, and cutting edge pre-clinical syngeneic and metastasis mouse models, the student will discover the functional role of glycans in Black breast cancer, and test if novel glycan-targeting drugs can be developed as new therapies. The project will utilise a repertoire of recently developed glycosylation inhibitors (provided by collaborators or industrial partners), some of which are already being tested in clinical trials for other indications. Bioluminescence imaging, mass-spectrometry imaging and immune cell profiling of tumours will be used to monitor drug efficacy and assess therapeutic potential.

Outcomes: The outcome of the project is expected to lead to a functional readout of the cancer-associated glycans for Black breast cancer that will aid patient stratification and lead to new life-saving personalised treatments for Black women. The project offers a unique opportunity for a student to be trained in a range of novel cutting-edge techniques under the supervision of a multidisciplinary team with complementary expertise in cancer glycobiology, pre-clinical drug testing, and clinical breast cancer research.

Candidate background:

This ideal candidate for this PhD project will have a strong interest in breast cancer research and be passionate about translating scientific discoveries into patient benefit. The candidate should enjoy focusing on their own studies whilst also engaging with wider related cancer research projects. The PhD project will suit a self-motivated student, driven by curiosity for cancer biology, with prior research experience using molecular biology and cell culture techniques. Experience with flow cytometry and immunohistochemistry is desirable, however, experienced team members will support and train the student in all of the required experimental techniques.

Potential Research Placements:

Sheffield Hallam University: Our project also includes an optional placement at the Centre for Mass Spectrometry Imaging (CMSI) at Sheffield Hallam University. Here, the student will be trained in novel mass spectrometry imaging techniques to profile the glycomic landscape of Black breast cancer tissue and monitor response to therapy in tumours in our vivo models.

Leicester Cancer Research Centre: The student will have the opportunity to visit Dr Ning Wang’s research group in Leicester for expert training in innovative in vivo and ex vivo models to study breast cancer bone metastasis.

References:

Hirko KA, et al The impact of race and ethnicity in breast cancer-disparities and implications for precision oncology. BMC Med. 20, 72 (2022).

Yao S, et al. Breast Tumor Microenvironment in Black Women: A Distinct Signature of CD8+ T-Cell Exhaustion. J Natl Cancer Inst. 113, 1036 (2021).

Hodgson K, et al. Sialic acid blockade inhibits the metastatic spread of prostate cancer to bone. EBioMedicine. 2024;104:105163.

Mereiter S, et al. Glycosylation in the Era of Cancer-Targeted Therapy: Where Are We Heading? Cancer Cell. 36, 6 (2019).

Scott DA, Drake RR. Glycosylation and its implications in breast cancer. Expert Rev Proteomics. 16, 665 (2019).

Primary Supervisor: Dr Gordon Strathdee  Co-supervisor: Prof Linda Sharp

Background:

Survival rates in childhood cancer have improved dramatically but treatment is associated with significant toxicity and serious long-term health problems. Long-term follow up of childhood cancer survivors has revealed many experience severe adverse late health effects and premature ageing-associated diseases, such as heart disease and second cancers; significantly impacting quality-of-life and life expectancy. Thus, there is an acute unmet need to identify (i) the molecular basis of late effects in childhood cancer survivors and (ii) quantitative biomarkers to inform strategies to reduce risk, frequency and/or severity of late effects and improve quality-of-life for cancer survivors. Such strategies might include less toxic treatments or personalised biomarker-driven post-treatment management. Discovery of reliable biomarkers will be crucial in enabling optimisation of long-term personalised follow-up and potential intervention studies.

This studentship will be nested within an existing collaborative team consisting of four research groups from Newcastle University, St Jude’s Research Hospital, the leading North American institute working in this area, and Northumbria University. It will build upon the team’s past work which determined that exposure to anticancer therapies induces frequent, reproducible changes in DNA methylation in normal tissues. These alterations persist many years later when survivors reach adulthood and associate with adverse outcomes. We further determined that childhood cancer survivors demonstrate clear epigenetic age acceleration (defined by so called DNA methylation “clocks” that are measured by assessing genome-wide DNA methylation patterns) that is progressive over time. Moreover, using genome-wide DNA methylation studies, we found that specific methylation markers in adult survivors can predict late adverse health effects.

Thus, the overall aim of this studentship is to investigate the utility of methylation based markers and epigenetic age acceleration to identify survivors at high risk of serious late health effects. The ultimate goal is to use these methylation based markers to enable improved targeted care and potential interventional studies aimed at improving long-term health outcomes for childhood cancer survivors.

Specific objectives:

1) Utilising methylation markers to assess whether reduced intensity treatment results in reduced molecular damage/aberrant DNA methylation.

2) Investigating the potential of methylation-based biomarkers for personalised prediction of serious late effects in childhood cancer survivors.

3) Determining whether health behaviours in adult survivors of childhood cancer (e.g. smoking) interact with methylation changes to influence risk of late effects.

Experimental Approach:

The student will perform genome wide DNA methylation analysis, using samples from childhood cancer patients, to assess the molecular damage caused by anti-cancer therapies and if this is lessened by new reduced intensity treatment schedules. To investigate how this altered methylation impacts childhood cancer survivors, the student will then utilise data from very large survivor cohorts, including extensive clinical information, follow-up data and key modifiable lifestyle factors, and apply bioinformatic and statistical approaches to analyse these data. Quantitative genome-wide DNA methylation data will be generated from Illumina methylation arrays, which will also be used to measure premature ageing using multiple methylation clocks. The project will also utilise our novel ‘Meet-in-the-Middle’ approach to strengthen understanding of potential causal links between methylation changes and survivor outcomes.

Candidate background:

The ideal candidate will be strongly motivated to work in cancer research and to contribute to improving patient outcomes, especially for childhood cancer patients. In addition, a willingness to engage in multi-disciplinary research and to work and contribute as part of a team is essential. Some training or knowledge of quantitative methods would be an advantage but is not essential as the overall team has extensive experience to support the prospective student in all facets of the project, maximising the training opportunity.  A desire to learn to use big data approaches to address complex biological problems will be essential.

Potential Research Placements:

The student will have the potential for placements with the other members of the collaborative group. This will include the opportunity to spend time at St Jude in Memphis, working with Dr Wang. St Jude is the largest centre of research on childhood cancer survivorship and his will give the student a chance to gain a greater appreciation of the breadth of research in this area. In addition, the student will have the opportunity for a placement at Northumbria University working with Dr McKay to gain a deeper understanding of the meet in the middle approach that can identify potential molecular mediators to be identified from epidemiological data.

References:

Chen C, et al. Race and Ethnicity, Socioeconomic Factors, and Epigenetic Age Acceleration in Survivors of Childhood Cancer. JAMA Netw Open. 7, e2419771 (2024).

Lalchungnunga H, et al. Deconvolution of cancer methylation patterns determines that altered methylation in cancer is dominated by a non-disease associated proliferation signal. Br J Cancer (in press).

Robinson N, et al. Anti-cancer therapy is associated with long-term epigenomic changes in childhood cancer survivors. Br J Cancer. 127, 288 (2022).

Meng X, et al. Epigenetic Age Acceleration Mediates Treatment Effects on Cardiometabolic and Cardiovascular Risk in Childhood Cancer Survivors. JACC CardioOncol. doi: 10.1016/j.jaccao.2025.06.001 (Online).

Brown MC, et al. Protocol for the 'Supporting Young Cancer Survivors who Smoke' study (PRISM): Informing the development of a smoking cessation intervention for childhood, adolescent and young adult cancer survivors in England. PLoS One. 19e0299321 (2024).

Primary Supervisor: Dr Laura Jardine  Co-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

Methodology:

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 will be supported by direct supervision in Newcastle and via collaborative networks at the Wellcome Sanger Institute. An independent bioinformatics mentor will be tailored to the individual.

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 is also possible.

References:

Jardine L, et al. Blood and immune development in human fetal bone marrow and Down syndrome. Nature 598, 327 (2021).

Bandyopadhyay S, et al. Mapping the cellular biogeography of human bone marrow niches using single-cell transcriptomics and proteomic imaging. Cell 187, 3120 (2024).

Burt R, et al. Activated stromal cells transfer mitochondria to rescue acute lymphoblastic leukemia cells from oxidative stress. Blood 134, 1415 (2019).

Shen Y et al. comBO: A combined human bone and lympho-myeloid bone marrow organoid for pre-clinical modelling of haematopoietic disorders. BioRxiv (2025).

Birk S, et al. Quantitative characterization of cell niches in spatially resolved omics data. Nature Genetics 57, 897 (2025).

Primary Supervisor: Prof Akane Kawamura  Co-supervisor: Prof Ian Hickson

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.

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.

Potential Research Placements:

N/A

References:

Tan ME, et al.  Androgen receptor: structure, role in prostate cancer and drug discovery. Acta Pharmacol. Sin. 36, 3–23 (2015).

Daniels VA, et al. Therapeutic approaches to targeting androgen receptor splice variants. Cells 13:104 (2024).

Lee XY, et al. Structural mechanism underlying variations in DNA-binding by the androgen receptor. J. Steroid Biochem. Mol. Biol. 241:106499 (2024).

Serrano L, 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.

McAllister TE, et al. Structural Diversity in De Novo Cyclic Peptide Ligands from Display Technologies. Peptide Science (2020) 113:e24204.