CRUK Black Leaders in Cancer PhD Scholarship Programme

Starting in September 2025, we will fund up to three 4-year fully-funded studentships covering:

• Generous tax-free stipend (living allowance) of £21,000 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: 6 December 2024, noon

We should receive your references by 13 December 2024, 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: 20 January 2025

Supervisors may contact you during the shortlisting period (December 2024 - mid-January 2025), to find out more about you and your interest in their project.

Information session for interviewees: 5 February 2025, 1pm to 2pm

Panel interviews will take place: week commencing 10 February 2025

Programme start date: September 2025

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 has ran two insight sessions this year:

2 October 2024 at 12:30 – 14:00 (GMT)

8 October 2024 at 12:30 – 14:00 (GMT)

The sessions are an opportunity for candidates interested in the PhD programme to find out more information and ask questions to our panel from the training centres, Cancer Research and Black in Cancer.

For recordings of the insight sessions, please visit the Windsor Fellowships website

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 2025

Primary supervisor: Dr Amir Enshaei  Co-supervisor: Prof Anthony Moorman

Acute lymphoblastic leukaemia is the most common form of childhood cancer with good risk genetic abnormalities accounting for 50% of B-cell precursor cases (1). Risk stratification and the development of intensified treatment protocols has dramatically improved the survival of these patients, resulting in cure rates >90% on contemporary protocols (1).  This success has resulted in a growing number of survivors of childhood ALL. However, patients often experience acute toxicities during treatment and the risk of dying from therapy is approximately the same as the risk of dying from the disease. In addition, survivors suffer long-term late effects and can expect to have at least one chronic condition by the age of 40 (2). Therapy-related complications are widespread and can affect many organ systems including cardiovascular issues, musculoskeletal problems, reproductive issues, and second cancers.

Historically, the focus of risk stratification has been to identify high-risk patients for treatment escalation but due to the high cure rates many researchers, including ourselves, are looking for methods to identify low-risk patients that could be eligible for treatment escalation (3).

However, there are very few studies that have objectively examined which treatment elements could be omitted from the standard 2-year treatment schedule protocol. A recent study showed that patients with ETV6::RUNX1 fusion could be treated less anthracyclines and without high-dose methotrexate. This study took a horizontal approach by examining several contemporaneous clinical trials and focussed on a single genetic subtype. In this PhD project we plan to leverage the unique data resource held by the LRCG to examine the treatment-genetic-outcome interaction among patients in the three good-risk genetic subtypes across consecutive UK clinical trials dating from 1990 to 2018.

The overarching hypothesis of this PhD project is that patients with specific genetic abnormalities will respond optimally to different, but specific, treatment combinations. Due to the rise in survival from 50% to >90% in paediatric ALL over the past 50 years, it is reasonable to assume that highly effective chemotherapy regimens for many genetic subtypes exist within historic clinical trial datasets.

The aim of this project is to identify treatment elements that are optimal for patients with an individual genetic abnormality to ensure that patients are given only the minimal dosages of drugs necessary in a patient’s therapy so that they are cured without unnecessary toxicity.

We are planning to do this, by harnessing the power of machine learning and deep learning methodologies to explore the genetic-treatment interactions in more depth. Recently we have established that traditional statistical methods fail to capture the whole complexity of treatment and outcome relation. This project will explore the state-of-the-art technologies such as transformers or/and Tsetlin machine to map the treatment path for each individual patient, and to identify a group of patients that have a fantastic outcome but with low intensity treatment. Furthermore, this project aims to explore the role of copy number alterations and optimal treatment pathways using neural networks such as auto encoders and/or convolutional neural network to identify and validate the patterns of alterations that significantly impacts the outcome.

Candidate background:

This is a data analysis project as a result, this project requires a candidate with background or interest in data science or programming or statistics and mathematics. Experience in machine learning is recommended.

Potential research placement:

A successful graduate will gain highly transferable skills and will be able to seek opportunities in translational cancer research institutes and/or clinical trial units. This project will equip the successful graduate to explore opportunities in wider drug discovery, clinical research or data analysis industries, outside of the academia.

References:

1. Moorman AV, et al (2022): Time to cure for childhood and young adult acute lymphoblastic leukemia is independent of early risk factors: Long-term follow-up of the UKALL2003 trial. J Clin Oncol 40:4228-4239, 2022.

2. Inaba, H. and Mullighan, C. G. (2020) 'Pediatric acute lymphoblastic leukemia', Haematologica, 105:2524-2539.

3. Roman E et al (2023).  Cohort profile: the United Kingdom Childhood Cancer Study (UKCCS) – a UK-wide population-based study examining the health of cancer survivors. BMJ Open 13:e073712. doi:10.1136/ bmjopen-2023-073712

4. Moorman AV et al (2024). Integration of genetics and MRD to define low risk patients with B-cell precursor acute lymphoblastic leukaemia with intermediate MRD levels at the end of induction. Leukemia. 38:2023-2026.

5. Østergaard, A et al: (2024) 'ETV6::RUNX1 Acute Lymphoblastic Leukemia: how much therapy is needed for cure?', Leukemia, 38:1477-1487.

Primary Supervisor: Prof James Allan  Co-supervisor: Prof Julie Irving

Current methods for target identification in cancer drug development have an extremely high failure rate due to targets not validating in clinical trials. The aim of this project is to leverage real-world patient data to identify putative therapeutic targets for acute myeloid leukaemia (AML) and validate these using experimental models.

In a preliminary analysis, we have analysed survival data in conjunction with genetic data (650,000 genetic variants per patient) on over 1100 AML cases recruited via 5 independent clinical studies across Europe. This approach has identified numerous signals in the human genome that significantly associate with patient survival, where the association in consistently observed across all 5 studies. Critically, several of these signals localise to genes encoding proteins already established as determinants of response to chemotherapy and survival in AML, providing evidence that this approach has validity.

Methodological Approaches:

The current project includes three major objectives:

1. Supplement our preliminary dataset with additional AML survival and genetic data and perform a large-scale meta-analysis for genomic signals that significantly (and consistently) associate with patient survival.

James Allan (primary supervisor) leads an international consortium focussed on understanding how genetics impact on risk and prognostication of acute myeloid leukaemia (Lin et al, 2021). To increase statistical power, we will collate outcome data on cases already genotyped and recruited to our international AML consortium. We anticipate being able to perform a large-scale meta-analysis for genetic variants that associate with survival in >2000 AML patients, more than doubling the size of our preliminary analysis.

2. Use multiomic quantitative trait loci analysis and functional genomics techniques to identify local genes encoding tractable therapeutic targets.

Genetic variants that associate with response to treatment and survival will be interrogated for evidence impacting on expression/function of local cis-regulated genes. Specifically, expression quantitative trait loci (eQTL), splicing QTL (sQTL) and protein QTL (pQTL) analysis will be performed to identify functionally affected local genes. Genomic association signals will also be interrogated with chromatin and epigenetic annotations using high-density datasets that capture open regions (DNAse hypersensitivity or ATAC-sequencing), histone modifications (eg. H3K4me1, H3K4me3, H3K27ac and H3K27me3) and DNA methylation to identify regulatory activity affecting local genes.

3. Potential therapeutic targets will be selected for functional validation in vitro and in vivo, using appropriate genetically engineered AML cell lines and patient derived xenografts (PDX).

We will select potential therapeutic targets where the evidence suggests that their role in patient survival is via gain of an oncogenic function (rather than loss of a tumour-suppressor function) that is specific to the leukaemia cells or the local bone marrow environment. We will use RNA interference (RNAi) and/or CRISPR-mediated gene targeting to generate AML cell models (cell lines and PDX) with knockdown/knockout of candidate targets, with targeting vectors delivered via lentiviral transduction. Isogenic cell models (gene-targeted and non-targeted controls) will be evaluated for an effect on engraftment and proliferation in the bone marrow as well as response to AML chemotherapy in vitro and in vivo.

Candidate background:

The candidate should have an interest in biomedical research, including human genetics, molecular/cell biology and animal disease models. An interest in cancer therapeutics, including target identification and validation, would also be of value. Some experience of using genetic techniques to manipulate gene expression would also be useful. Regardless, we have considerable of using CRISPR and RNA interference to generate genetically engineered cell models and orthotopic disease models in animals, as demonstrated by our studies in CREBBP (Dixon et al, 2017), ATR (Fordham et al, 2018), and TET2 (Stolzel et al, 2023). As such, full training will be provided.

Potential Research Placements:

This project is supported by numerous collaborators across the United Kingdom and Europe There will be an opportunity for short placements at collaborating centres to collate primary clinical and demographic data from AML patients recruited to our international AML study (Lin et al, 2021).

References:

1. Lin W-Y et al (2021) Genome-wide association study identifies susceptibility loci for acute myeloid leukemia. Nature Communications: 12, 6233. PMID:34716350

2. Dixon ZA et al (2017). CREBBP knockdown enhances RAS/RAF/MEK/ERK signaling in Ras pathway mutated acute lymphoblastic leukemia but does not modulate chemotherapeutic response. Haematologica, 102: 736-745. PMID: 27979926

3. Fordham SE et al (2018) Inhibition of ATR acutely sensitizes acute myeloid leukemia cells to nucleoside analogs that target ribonucleotide reductase. Blood Advances, 2:1157-1169. PMID: 29789314

4. Stölzel F et al (2023) Biallelic TET2 mutations confer sensitivity to 5'-azacitidine in acute myeloid leukemia. JCI Insight, 8(2), e150368. PMID:36480300

Primary Supervisor: Dr Sam Orange  Co-supervisor: Dr James O’Hara

Background:

Oropharyngeal cancer (OPC) is a type of head and neck cancer that originates in the tonsils and back of the tongue. The incidence of OPC is rapidly increasing due to the Human Papillomavirus (HPV), with around 73% of cases being HPV-positive. Standard treatment is six weeks of high-dose radiotherapy and chemotherapy (termed “chemoradiotherapy”).

While the 5-year survival rate exceeds 80%, patients experience severe deconditioning that significantly impacts their quality of life and long-term health. Our preliminary data indicate a 17% reduction in cardiorespiratory fitness, 11% loss of skeletal muscle mass, and 9% reduction in muscular strength following six weeks of chemoradiotherapy, despite intensive feeding regimens via feeding tubes. These side effects have a life-changing impact on quality of life and predispose patients to accelerated biological ageing, multiple long-term conditions, and shortened life expectancy.

Trials aiming to reduce treatment intensity have not been successful, as modified protocols have led to worse survival. We propose an alternative strategy: delivering precision exercise and nutritional interventions alongside standard treatment to target and mitigate the adverse systemic effects of chemoradiotherapy.

We hypothesize that chemoradiotherapy results in systemic physiological changes that contribute to the adverse side effects experienced by patients. By uncovering the physiological signatures of chemoradiotherapy, we aim to guide the development of precision exercise and nutritional interventions and personalised risk stratification.

Aims:

This study aims to characterise the physiological changes that occur during chemoradiotherapy in patients with HPV-related OPC.

Methodology:

This prospective cohort study aims to recruit 30 patients with HPV-related OPC. All ethics and regulatory approvals are in place (IRAS ID: 334426). Patients will complete physiological tests and self-reported outcomes before, 2-weeks after, and 6-weeks after chemoradiotherapy. The primary assessment will be a cardiopulmonary exercise test (CPET), which measures gas exchange during a maximum incremental exercise test, providing a comprehensive evaluation of the pulmonary, cardiovascular, and skeletal muscle systems. Additional measures will include serum biomarkers of chronic inflammation, oxidative stress, and muscle contraction, body composition (fat mass, fat-free mass, muscle mass), strength, lung function, quality-of-life, fatigue, and physical activity.

Candidate Background:

Candidates should have a good honours degree in a relevant discipline, such as Biomedical Science, Exercise Science, Exercise Physiology, or Human Nutrition. A strong interest in exercise physiology and clinical (patient-facing) research is essential. We particularly encourage applications from candidates with a Master’s degree in a relevant field, prior experience as a Research Assistant, and/or experience working with patients. A bespoke training programme will be developed by the supervisory team and supported by Newcastle University’s Research Student Development Programme.

Potential Research Placements:

The candidate will join a dynamic, well-funded, and cross-disciplinary research team, providing ample opportunities to engage in various clinical research projects in Newcastle University’s Cancer Centre. There may also be opportunities to spend time working with external research groups, depending on the candidate’s interests and training needs.

References:

1. Mehanna H et al. Prevalence of human papillomavirus in oropharyngeal and nonoropharyngeal head and neck cancer--systematic review and meta-analysis of trends by time and region. Head Neck. 2013;35(5):747-755. doi:10.1002/hed.22015

2. Eldridge RC et al. Changing Functional Status within Six Months Post-treatment is Prognostic of Overall Survival in Head and Neck Cancer Patients: an NRG Oncology Study. Head Neck. 2019;41(11):3924-3932. doi:10.1002/hed.25922

3. Sharp L et al. Cancer-Related Fatigue in Head and Neck Cancer Survivors: Longitudinal Findings from the Head and Neck 5000 Prospective Clinical Cohort. Cancers. 2023;15(19):4864. doi:10.3390/cancers15194864

4. Vangelov B et al. The impact of HPV status on weight loss and feeding tube use in oropharyngeal carcinoma. Oral Oncol. 2018;79:33-39. doi:10.1016/j.oraloncology.2018.02.012

5. Sinclair R et al. The impact of neoadjuvant chemotherapy on cardiopulmonary physical fitness in gastro-oesophageal adenocarcinoma. Ann R Coll Surg Engl. 2016;98(6):396-400. doi:10.1308/rcsann.2016.0135

Primary Supervisor: Dr Emma Scott  Co-supervisor: Dr Jack Leslie

Background:

Castrate resistant prostate cancer (CRPC) remains a lethal disease with current standard treatments. As prostate tumours exist in a predominantly immunosuppressive state with few cytotoxic T cells, high levels of T cell exhaustion and impaired cytolytic activity of NK cells, their sensitivity to immune checkpoint inhibitors is poor. Both macrophages and neutrophil myeloid populations are abundant immune cell subsets in advanced prostate cancer. In 2023, striking results published from a clinical trial (NCT03177187) showed that blocking myeloid cell infiltration into prostate tumours had durable clinical benefit and re-sensitised patients to androgen receptor (AR)-targeting therapies1. Given the success of myeloid-targeting therapies in this study, further investigation into the mechanisms of myeloid-driven immune suppression in prostate tumours is crucial.

In recent years, bidirectional interactions between cancer associated fibroblasts (CAFs) and suppressive myeloid cells have been shown to promote immune suppression and tumour growth. In prostate cancer, CAFs directly contribute to disease progression and therapy resistance2. CAFs are highly heterogeneous in their phenotypes and functions and advances in single-cell technologies have identified multiple CAF subsets. The mechanisms through which CAFs shape the tumour immune microenvironment are yet to be fully identified and have the potential to form the basis of improved approaches for immunotherapy resistant tumours.

Recently, hypersialylation of CAFs has been identified as a new mechanism of tumour immune suppression, with sialoglycans on CAFs interacting with Siglec immunoreceptors on myeloid immune cells3,4. We recently described a role for Siglec receptors in driving immune suppression in prostate cancer and have demonstrated that hypersialylation ais modulated by common prostate cancer therapies5. Given our findings, we hypothesise that sialoglycans on CAFs will be altered in response to common prostate cancer therapies and contribute to immunotherapy resistance in prostate cancer.

Aims:

1. Profile sialoglycans in prostate stroma and CAF subsets in prostate cancer.

2. Study the effect of androgen receptor inhibition on CAF sialylation in vitro and in vivo.

3. Use mouse models to investigate the effects of targeting of stromal sialylation on the tumour immune microenvironment

Methodologies:

We will use multiplexed immunofluorescence to stain sialoglycans and fibroblasts in prostate cancer patient tissue from a range of disease stages. Flow cytometry on fresh prostate cancer tissue will be used to profile sialoglycans on CAF subsets. Primary human CAFs will be cultured ex vivo and treated with an AR-inhibitor (enzalutamide) with changes in sialoglycans profiled by flow cytometry. We will use a syngeneic mouse model to study the effect of AR-inhibition on CAF sialylation in vivo and will use immunohistochemistry and flow cytometry to study effects on the tumour immune microenvironment. Finally, we will use mice with fibroblast specific loss ST3Gal1 (enzyme responsible for sialylation) to assess the effects of targeting sialylation on the prostate tumour immune microenvironment using immunohistochemistry and flow cytometry. A successful candidate will receive broad training in histological analysis of patient tissue, primary cell culture techniques, high parameter flow cytometry and advanced mouse models of cancer.

Candidate background:

The ideal candidate should have a background in cell biology and immunology with wet lab experience in basic cell biology techniques. All training in the necessary techniques will be provided. Experience with tissue culture, histological analysis of tissue and flow cytometry will be advantageous.

Potential research placements:

The supervisory team has a broad network of national collaborators and there is potential for placements to support the prostate cancer and/or fibroblast biology aspects of the project.

References:

1. Guo, C. et al. Targeting myeloid chemotaxis to reverse prostate cancer therapy resistance. Nature 623, (2023).

2. Zhang, Z. et al. Tumor Microenvironment-Derived NRG1 Promotes Antiandrogen Resistance in Prostate Cancer. Cancer Cell 38, 279-296.e9 (2020).

3. Boelaars, K. et al. Pancreatic cancer-associated fibroblasts modulate macrophage differentiation via sialic acid-Siglec interactions Check for updates. doi:10.1038/s42003-024-06087-8.

4. Hannah Egan, A. et al. Targeting stromal cell sialylation reverses T cell-mediated immunosuppression in the tumor microenvironment. (2023) doi:10.1016/j.celrep.2023.112475.

5. Garnham, R., et al. ST3 beta-galactoside alpha-2,3- sialyltransferase 1 (ST3Gal1) synthesis of Siglec ligands mediates anti-tumour immunity in prostate cancer. (2024) doi: 10.1038/s42003-024-05924-0

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

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 using the ChromHMM package, to provide insights into structural changes 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 effort 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:

1. Russell LJ et al. Deregulated expression of cytokine receptor gene, CRLF2, is involved in lymphoid transformation in B-cell precursor acute lymphoblastic leukemia. Blood. 2009;114(13):2688-2698.

2. Yang H et al. Noncoding genetic variation in GATA3 increases acute lymphoblastic leukemia risk through local and global changes in chromatin conformation. Nat Genet. 2022;54(2):170-179.

3. Wang X et al. High-resolution genome-wide functional dissection of transcriptional regulatory regions and nucleotides in human. Nat Commun. 2018;9(1):5380

Primary Supervisor: Dr Kelly Coffey  Co-supervisor: Stuart McCracken

Prostate cancer in the most common cancer in males (1 in 8) with men of African heritage at the highest risk (1 in 4). A major deficiency in prostate cancer research is the lack of model systems that accurately reflect the disease in a patient. Being able to robustly test how the microenvironment can influence tumour growth is challenging. The idea of being able to consistently culture human tissue in the laboratory has gained traction in recent years with multiple methods reported to achieve this (1-3). The preferred method in the literature involves precision slicing MRI-guided biopsies of therapy naïve prostatectomy tissue to 300 mm and partially submerging the tissue, using supporting porous scaffolds, in growth media within 2 hours. However, this method is far from perfected, with contrasting observations being reported and several tissue characteristics such as altered metabolism unreported.

Using the above methodology, with the inclusion of perpetual movement through a 30-degree angle to improve nutrient exchange, we can successfully culture human prostate tissue in the laboratory for 96 hours. Indeed, we have used this model to demonstrate the impact of novel cancer therapeutics previously (4). However, we are restricted in the length of time the tissue remains viable and maintaining viability in high-grade cancerous samples remains particularly challenging.

The aim of this studentship is to improve culturing methods to extend tissue viability and accurately reflect tumour characteristics observed in vivo.

Methods:

This project will determine the optimal growth conditions to improve the longevity of cancer-rich samples. Current culturing methodology will be evaluated to improve growth conditions. Immunohistochemistry will be performed to assess cellular proliferation (Ki67), cell death (Cleaved caspase 3), hypoxia (CA9), AR signalling maintenance (AR/PSA), and cell type markers including AMACR (cancerous cells), p63 (basal cells), α-SMA (smooth muscle), vimentin (fibroblasts) and immune cell marker panels to monitor maintenance of the immune compartment. LDH ELISA assays will be used to monitor cell viability during the culturing.

Candidate background:

The candidate should understand theoretical molecular biology and biochemistry to degree level. They will be trained in all laboratory and academic skills required to complete the project. They should ensure they have vaccinations against Hepatitis B prior to beginning lab work.

Potential Research Placements:

In the process of setting up a national working group in collaboration with Prostate Cancer UK to facilitate the development of ex vivo prostate culturing. There will be opportunity for the student to attend working group meetings and get involved with collaborative efforts across multiple groups to improve our model systems and processes. Consequently, the successful candidate will be able to visit the labs of fellow collaborative members (including ICR, CRUK Scotland Centre and Cardiff University) to gain further experience of culturing methodologies but also to build their own network which is vital to become a future leader.

References:

1. Centenera MM et al. A patient-derived explant (PDE) model of hormone-dependent cancer. Mol Oncol. 2018;12(9):1608-22.

2. Figiel S et al. Functional Organotypic Cultures of Prostate Tissues: A Relevant Preclinical Model that Preserves Hypoxia Sensitivity and Calcium Signaling. Am J Pathol. 2019;189(6):1268-75.

3. Zhang W et al. Ex vivo treatment of prostate tumor tissue recapitulates in vivo therapy response. Prostate. 2019;79(4):390-402.

4. Bainbridge A et al. IKBKE activity enhances AR levels in advanced prostate cancer via modulation of the Hippo pathway. Nucleic Acids Res. 2020;48(10):5366-82.

Primary Supervisor: Dr Jack Leslie  Co-supervisor: Prof Derek Mann

Background:

Hepatocellular carcinoma (HCC) accounts for ~90% of primary liver cancers and has a 5-year survival rate of less than 20%. In 2020, the IMBrave150 trial led to combination immunotherapy becoming first line for advanced HCC. Whilst highly effective in a subset of patients, the majority (75%) of patients fail to respond1. Why only a small proportion of patients respond is a key unanswered questioned in the cancer field. We have previously shown that immunotherapy-resistant HCC can be sensitised by blocking neutrophil recruitment with the CXCR2 inhibitor, AZD50692. This led to the ongoing CUBIC phase I/II clinical trial combining AZD5069 with Durvalumab (anti-PD-L1) in advanced HCC patients, which has already observed benefits3. While this study provides a strong basis for neutrophils as rational targets for new immunotherapeutic approaches in HCC, simply blocking the entry of these cells to the tumour may not be the optimal strategy. Instead, we propose that reprogramming the phenotype of tumour myeloid cells from an immunosuppressive to immune stimulatory state maximises their therapeutic potential.

Siglec-7 and Siglec-9 are type-1 membrane proteins that contain immunoreceptor-tyrosine-based inhibitory motifs (ITIMs) which suppress immune function upon receptor binding to sialic acid-containing glycans (sialoglycans). We have previously shown that they are predominantly expressed by neutrophils and macrophages and promote an immunosuppressive phenotype in prostate cancer4. Targeting of Siglec receptors expressed on both macrophages and neutrophils has been shown to attenuate their immunosuppressive signalling, and therapeutic targeting of Siglecs has been shown to reduce immune suppression in a range of cancers including breast, lung, brain and colorectal tumours and has been used as a strategy to sensitise these tumours to immunotherapy.

We propose that Sigle7/9 are novel targetable myeloid checkpoints in HCC, that orchestrate an immunosuppressive immunotherapy resistance tumour microenvironment.

Aims:

1. Quantify Siglec+ myeloid cells and their ligands in human and mouse MAFLD-HCC.

2. Understand how Siglec-7/9 contribute to macrophage and neutrophil immunosuppressive functions, assessing their contributions to MAFLD-HCC progression.

3. Generate proof-of-concept data on Siglec-targeting for the treatment of immunotherapy resistant liver cancer.

Methodological approaches:

This project will use an optimised Imaging Mass Cytometry panel to identify Siglec+ cells and their ligands in human and murine tissue and provide training in the downstream bioinformatic analysis. We will conduct orthotopic syngeneic liver cancer models in novel mice which have macrophage and neutrophil specific knock-out of Siglec receptors. We will measure tumour burden and assess the effects of Siglec-receptor knock-out on the tumour immune microenvironment using immunohistochemistry and flow cytometry.  Finally, using these mouse models, we will test anti-Siglec monoclonal antibodies in vivo, measuring tumour growth and profiling the tumour immune microenvironment using immunohistochemistry and flow cytometry.

Candidate background:

The ideal candidate should have a background in basic science including cell biology and immunology with some wet lab experience. While not essential experience with techniques such as flow cytometry, immunohistochemistry, and tissue analysis are an advantage. The candidate should have a keen interest in cancer immunology and a desire to explore novel therapeutic strategies targeting immune cells within the tumour microenvironment.

Potential Research Placements:

Through the HUNTER-HCC consortium, the supervisory team have a large network of national and international inter-disciplinary collaborators that we can access to support research placements for the successful candidate to provide additional training.

References:

1. Finn RS et al. N Engl J Med. 2020;382(20):1894-1905. doi:10.1056/NEJMoa1915745

2. Leslie J et al. Gut. 2022;71(10):2093-2106. doi:10.1136/gutjnl-2021-326259

3. Evans TRJ et al. Journal of Clinical Oncology. 2023;41(4_suppl):TPS631-TPS631. doi:10.1200/JCO.2023.41.4_SUPPL.TPS631

4. Garnham R et al. Communications Biology 2024 7:1. 2024;7(1):1-13. doi:10.1038/s42003-024-05924-0

Primary Supervisor: Dr Shelby Barnett  Co-supervisor: Prof Gareth Veal

In childhood cancer there are patient subpopulations who are particularly challenging to treat and represent a significant dilemma in terms of prescribing appropriate drug dosages(1). These patient groups include pre-term infants and neonates, children without functioning kidneys (anephric patients), those receiving high dose chemotherapy and obese patients. Patients may also have renal or hepatic toxicity from previous treatment, making the administration of additional chemotherapy particularly difficult. It is accepted that these patient groups require dosing adjustments, due to differences in exposure relating to how drugs are broken down and eliminated from the body, but there is commonly little scientific rationale to support dosing decisions made (1, 2). There are currently inconsistencies in dose reductions applied to many anticancer drugs, between tumour types and clinical trials, for each of these patient populations. Through an ongoing therapeutic drug monitoring (TDM) programme of work (TDM Study; ISRCTN 10139334), involving the real-time measurement of drug levels in the blood to help provide informed dosing decisions, we now have comprehensive pharmacokinetic datasets for a range of widely used anticancer drugs (13 drugs), providing previously unavailable clinical pharmacology information for these patient groups (1). The proposed project will focus on developing new assays using liquid chromatography and mass spectrometry for drugs that are highly requested for drug monitoring. These assays will then be utilised to measure drug levels in paediatric blood samples for TDM purposes, directly impacting on patient treatment. To assess factors associated with inter-patient variability of these selected anticancer drugs, TDM data will be used alongside clinical pharmacology data generated in standard paediatric populations to perform population-based pharmacokinetic modelling (Monolix and NONMEM) and provide a comprehensive overview of drug pharmacokinetics in paediatrics. This approach has already been initiated for vincristine and carboplatin, where marked differences in exposure have been observed for the neonate population, resulting in proposed changes to previously used dosing regimens (3-5).

The studentship will aim to:

1. Develop novel bioanalytical assays for chemotherapeutics where TDM may be of benefit to patient treatment.

2. Characterise the pharmacokinetics of widely used anticancer drugs in defined patient populations alongside appropriate pharmacodynamic biomarkers and clinical response/toxicity data.

3. Develop population pharmacokinetic models for individual drugs and patient populations to determine key factors influencing drug disposition.

4. Propose drug therapeutic windows based on appropriate pharmacological evidence and investigate optimal dosing regimens based on the data generated.

5. The student will gain a firm foundation in bioanalysis and pharmacokinetic modelling using real-world data, with the results generated providing experience of cutting edge translational clinical research. The studentship will lead to the publication of novel dosing guidelines to benefit the future treatment of these challenging paediatric cancer patient populations.

Candidate background:

For this clinically translational project, we are looking for a highly motivated student with a background in pharmacology/pharmaceutical sciences/biochemistry/bioanalytical sciences/pharmacokinetic modelling. This project can be flexible in terms of the amount of laboratory based and mathematical modelling research involved, depending on the background and interests of the student. However, candidates should be comfortable with the prospect of both working in a research laboratory and handling large packages of data.

Potential Research Placements:

During this PhD there will be an opportunity to collaborate with the Clinical Pharmacology Group at the Princess Maxima Centre in the Netherlands and participate in a research visit to gain intensive pharmacokinetic modelling experience. Our groups have collaborated on multiple projects and published numerous key manuscripts over the past few years.

References:

1. Barnett S et al. Perspectives and Expertise in Establishing a Therapeutic Drug Monitoring Programme for Challenging Childhood Cancer Patient Populations. Front Oncol. 2021;11:815040.

2. Nijstad AL et al. Clinical pharmacology of cytotoxic drugs in neonates and infants: Providing evidence-based dosing guidance. Eur J Cancer. 2022;164:137-54.

3. Barnett S et al. Vincristine dosing, drug exposure and therapeutic drug monitoring in neonate and infant cancer patients. Eur J Cancer. 2021.

4. Barnett S et al. Generation of evidence-based carboplatin dosing guidelines for neonates and infants. Br J Cancer. 2023;129(11):1773-9.

5. Millen GC et al. Utility of carboplatin therapeutic drug monitoring for the treatment of neonate and infant retinoblastoma patients in the United Kingdom. Brit J Cancer. 2024. https://doi.org/10.1038/s41416-024-02728-1

Primary Supervisor: Dr Luke Gaughan  Co-supervisor: Prof Craig Robson

Background:

Prostate cancer kills 12,000 men in the UK each year. Although the repertoire of therapeutics to treat prostate cancer has greatly expanded over the past decade, there remains major knowledge gaps in how best to apply the most effective treatments on a patient-by-patient basis. Critically, prostate cancers arising in Caucasian and Black men harbour common gene mutations which may make their tumours more sensitive to emerging or currently available drugs. Therefore, an improved biological understanding of common gene mutations in prostate cancer will allow us to define new and more effective treatments to give the best patient outcomes on a personalised level. In this project, you will study the biological consequences of mutations in the gene KMT2C in prostate cancer which occurs at a frequency of approximately 8% and 60% in Caucasian and Black men, respectively. Furthermore, by screening drug sensitivities in KMT2C mutant prostate cancer models, we will identify new therapeutics which could be applied clinically to improve prostate cancer treatment across a large cohort of men with the disease.

Aims:

The hypothesis of the study is that mutations in the KMT2C gene make prostate cancers more vulnerable to drugs that can be applied clinically to improve patient outcomes. The aims of the study are therefore:

1. To develop key KMT2C mutant prostate cancer models and assess the molecular alterations which enable tumours to grow.
2. To conduct a drug screening pipeline to assess drug sensitivities in KMT2C mutant prostate cancer models and validate treatments which stop growth of these tumours.

Methods:

The candidate will work alongside an experienced team to develop CRISPR-edited KMT2C mutant prostate cancer models which will be subject to key global ‘omics’ analyses to identify how the mutation drives prostate cancer progression. In parallel, an optimised drug screening pipeline will be conducted to define new therapeutics that can selectively kill KMT2C mutant prostate cancer.

Importantly, this project will provide and enhance key skills in both wet lab research and bioinformatics which will be vital for future career opportunities.

Candidate background:

At the time of starting their PhD, the student is expected to have attained a First or Upper Second Class BSc in a relevant subject (biomedical sciences, biochemistry, genetics, molecular biology).

Potential Research Placements:

The student will have the capacity to work alongside our in-house automation specialists who will conduct the drug screening pipeline using robotics systems.

References:

1. Walker L et al. (2024) Defining splicing factor requirements for androgen receptor variant synthesis in advanced prostate cancer. Molecular Cancer Research, https://doi.org/10.1158/1541-7786.MCR-23-0958.

2. Adamson B et al. (2023) Journal of Clinical Investigation DOI: 10.1172/JCI169200.

3. Buskin A et al. Engineering prostate cancer in vitro: what does it take? (2023) Oncogene. DOI: 10.1038/s41388-023-02776-6.

4. Bainbridge A et al. (2020) IKBKE Activity Enhances AR Levels in Advanced Prostate Cancer via Modulation of the Hippo Pathway. Nucleic Acids Research 48, 5366-5382. DOI: 10.1093/nar/gkaa271.

5. Kounatidou E et al. (2019) A novel CRISPR-engineered prostate cancer cell line defines the AR-V transcriptome and identifies PARP inhibitor sensitivities. Nucleic Acids Research 47, 5634-5647.

Primary Supervisor: Dr Pasquale Rescigno  Co-supervisor: Dr Christoph Oing

Background:

Worldwide, approximately 550,000 people are diagnosed with bladder cancer (BC) each year and 200,000 die of the disease [1]. The standard treatment for muscle-invasive BC (MIBC) is cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy or upfront radical cystectomy for cisplatin-ineligible patients. Patients ineligible for or who refuse radical cystectomy are offered a trimodal approach with transurethral resection of the bladder tumour (TURBT) followed by chemo-radiotherapy. While these treatments may be curative, a significant proportion of patients will develop distant recurrence and will ultimately succumb to metastatic disease [2]. It is, however, challenging to assess treatment response in this setting or to detect early disease relapse.

Circulating tumor DNA (ctDNA) refers to circulating DNA fragments derived from tumour cells [2]. These fragments carry gene mutations, deletions, insertions, rearrangements, copy number alterations, DNA methylation, etc. Hence, ctDNA may be used for early tumour detection, detection of tumour progression/recurrence, response prediction, and personalized treatment. Thus, it is critical to detect ctDNA for clinical applications [3] [4].

Aims:

1. To define the clinical relevance of ctDNA in locally advanced bladder cancer undergoing chemo-radiation with radical intent;
2. To assess ctDNA samples both quantitatively and qualitatively in order to study the possible association between ctDNA levels, genomic characteristics, and disease recurrence.

Methods:

We aim to recruit 70 patients with locally advanced bladder cancer/MIBC (T2-T4) undergoing curative-intent chemo-radiotherapy (based on hospital feasibility). We estimate that 25-30 patients will relapse within 3 years from the start of the treatment with the majority of them expected to have detectable ctDNA at time of radiologically confirmed relapse, or earlier.

Patients will have bloods taken for ctDNA prior to the start, after neo-adjuvant chemotherapy, at completion of chemo-radiation, at progression or at the end of the 3 years observation (whatever occurs first), along with restaging scans for 3 years (as per standard of care) at Newcastle Hospitals.

Associations between relevant genomic aberrations and relapse will be determined by Fisher’s exact tests. Multivariate logistic regression models will be used to jointly account for different genomic events on relapse risk in the whole cohort.

We developed a bespoken assay to detect (presence or absence) and quantify ctDNA exploiting genomic features such as allelic imbalance to enhance detection sensitivity, starting from <5ml of plasma. The method developed and validated in prostate cancer by Prof Demichelis and an international consortium (PMIDs: 35664542, 38197680) and recently applied to the Biomarker Study of the PRESIDE Phase 3b Trial [5] would be extremely useful in this subset of bladder cancer patients.

This project will explore the feasibility of cfDNA analyses for the first time in this setting (chemo-radiotherapy for locally advanced bladder cancer), potentially offering multiple advantages such as the non-invasive nature of the test, the identification of residual disease/early relapse and offering precious information on aggressive cancers likely to recur after radical curative-intent treatment.

Candidate Background:

This project would suit motivated candidates with strong backgrounds in clinical/translational research in urogenital cancers. They will receive comprehensive training in genomic through international collaborations and clinical research (trial design, management of clinical data, and recruitment of cancer patients within clinical trials).

Potential Research Placement:

The Newcastle University Centre for Cancer is one of 15 Cancer Research UK and ECMC Centres in UK (Prof Plummer is clinical lead for both) which provides excellent, well-funded infrastructure to support our clinical and translational research, including sequencing facilities. Strong links exist with the Clinical Trials Unit and Oncology departments of the Newcastle Hospitals to source and profile bladder material under an established ongoing protocol.

Prof Demichelis is full professor of the Department of Cellular, Computational and Integrative Biology – CIBIO, Trento Italy. She has expertise in the area of cancer genomics that builds on more than ten years of interdisciplinary work with focus in the field of urological cancers. Since 2011 she leads the Computational and Functional Oncology Laboratory (University of Trento) with 10 members (fully funded through competitive grants) including both computational and experimental wet laboratory post-docs and PhD students. Her research focuses on the characterization of cancer evolution and progression and on the identification of germline and somatic diagnostic and prognostic cancer biomarkers. 

References:

1. F. Bray et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA Cancer J Clin, 68 (2018), pp. 394-424

2. International Bladder Cancer Nomogram Consortium, Bochner BH et al. Postoperative nomogram predicting risk of recurrence after radical cystectomy for bladder cancer J Clin Oncol, 24 (2006), pp. 3967-3972.

3. Huang T et al. Liquid Biopsies: Methods and Protocols, 2023. E-booK, https://doi.org/10.1007/978-1-0716-3346-5

4. Christensen E et al (2017) Liquid biopsy analysis of FGFR3 and PIK3CA hotspot mutations for disease surveillance in bladder cancer. Eur Urol 71:961–969.

5. Ruiz-Vico M et al. Liquid Biopsy in Progressing Prostate Cancer Patients Starting Docetaxel with or Without Enzalutamide: A Biomarker Study of the PRESIDE Phase 3b Trial. Eur Urol Oncol. Published online September 10, 2024. doi:10.1016/j.euo.2024.08.006