Primary Supervisor: Dr Alicia Heath 

Primary Division: School of Public Health, Faculty of Medicine, Imperial 

It is crucial to identify breast cancer at an early stage, when treatment and survival outcomes are favourable. While screening is important for early detection, uptake rates are suboptimal, interval cancers remain a concern, and younger women are ineligible. There is an urgent need to find alternative tools for early detection of breast cancer. Proteomics has emerged as a promising area of study to identify biomarkers of disease. This PhD project aims to use large-scale proteomics data to identify protein biomarkers for early detection of breast cancer. Analyses will be primarily based on a case-cohort study within the European Prospective Investigation into Cancer and Nutrition (EPIC). Within the EPIC study, 7,363 plasma proteins have been measured among 970 incident breast cancer cases (including 231 premenopausal and 739 postmenopausal cases) and 2,490subcohort participants using the SomaScan 7k Assay. To focus on biomarkers for early detection, this project will utilise cases diagnosed within three years of blood sampling. Prentice-weighted Cox regression, with correction for multiple testing, will be used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between circulating proteins and breast cancer. Associations for identified proteins will be validated in the Atherosclerosis Risk in Communities (ARIC) study, which measured ~5,000 proteins in cases and non-cases using the SomaScan assay. Discrimination of the identified proteins will be assessed with the C-statistic. Gene set enrichment analyses and network analyses will explore potential molecular pathways involved in breast cancer. Integration with clinical studies at ICR will facilitate translation for clinical application. This multidisciplinary project combines cancer epidemiology, biochemistry, biomarkers, genetics and complex statistical modelling. This project offers scope to discover circulating proteins that could serve as biomarkers for early detection and provide insights into underlying molecular pathways involved in breast cancer. 

Primary Supervisor: Dr Rachael Natrajan 

Primary Division: Functional Genomics, Breast Cancer Division, ICR 

Overall Aims: This project will focus on detection of circulating tumour cells (CTC) and their molecular characterisation coupled with epigenetic profiling in circulating free (cf) DNA as biomarkers for monitoring metastatic ILC disease evolution.

Research Plan: Invasive lobular cancer (ILC) accounts for around 15% of invasive breast carcinomas and is characterised by loss of the cell adhesion glycoprotein E-cadherin. Most relapses still occur within the first 5 years of diagnosis, with a substantial proportion of women dying from metastatic disease during this time frame. ILCs differ in their driver gene repertoire and micro-environmental composition, and pattern of metastasis to invasive carcinomas of no special type (IC-NST), with a higher rate of spreading to serosal surfaces. Although circulating tumour DNA (ctDNA) assays are useful for monitoring cancer recurrence, they have limited ability to identify the transcriptional programs that govern cancer phenotypes and their dynamic changes during the course of disease. Measuring transcriptional and epigenomic features from CTC’s and cfDNA can provide a useful tool for monitoring the evolution of metastatic disease and provide a dynamic readout of transcriptional programs and cellular states. ILCs are known to shed a higher number of CTCs, but studies to date are small, and the molecular characteristics of ILC-derived CTCs are not known.

Aim 1: Investigate the utility of CTC capture for longitudinally monitoring of metastatic ILC disease evolution Focussing on a prospective cohort of patients presenting with detectable distant metastatic disease, the project will initially determine the number of CTCs detectable from blood samples from patients with metastatic ILC; if these occur in clusters and the cell type composition of the clusters.

Aim 2: Characterise the molecular alterations in the circulation that may predict therapy response Whilst mutational profiling of cfDNA is useful, it doesn’t capture the full molecular heterogeneity of the evolving disease. Using serial blood biopsies over the course of progression, the molecular subtype of the evolving metastatic disease will be characterised using cfChIP of H3K4me3 histone marks at gene promoters and H3K27ac atenhancers as a proxy of gene expression, which we recently optimised and have implemented in the lab, to assess i) subtype switching and ii) identify other recurrent gene expression alterations. Molecular profiling of CTC's using immunofluorescence staining of key markers (e.g. ER, PR, HER2, E and P and N Cadherin) will be used to further phenotypically characterise the CTCs that survive therapy.

Aim 3: Mapping the spatial location within primary tumours of enriched sub-clones Alterations identified in CTC's over time (Aim 2) will be assessed to see if these are pre-existing at initial diagnosis in primary ILCs using digital pathology based spatial profiling technologies and assess whether these could potentially provide useful prognostic and predictive markers for future evaluation. 

Primary Supervisor: Prof. Kamil Kranc 

Primary Division: Haemato-Oncology, Molecular Pathology Division, ICR  

AML is an aggressive clonal disorder of haematopoietic stem/progenitor cells which is driven by treatment-resistant leukaemicstem cells (LSCs). They display uncontrolled self-renewal and impaired differentiation, with the ability to initiate and propagate leukaemia. Conventional chemotherapies treatments target the AML bulk while damaging normal haematopoiesis but they often fail to eradicate LSCs, which cause fatal relapses. Furthermore, older patients are often unable to tolerate chemotherapy. There are at least 15 subtypes of AML, a number of which are associated with a poor prognosis and median survival of 6months. It is therefore critical to discover effective, well tolerated therapies which eradicate LSCs in those subtypes where current treatments fail. We discovered that enhancing stability of hypoxia-inducible factors (HIFs), which regulate cellular responses to hypoxia, is a promising therapeutic strategy (Lawson et al., Nature Cancer, 2024). We found that genetic and pharmacological inhibition of HIF prolyl hydroxylase enzymes (PHDs), which normally degrade HIF proteins, severely compromise AML without damaging normal haematopoiesis. Preliminary data indicate that this treatment is effective in AML subtypes with the poorest prognosis, and that inactivating factor inhibiting HIF (FIH), which prevents HIF target gene transcription, may potentiate the anti-leukaemic effect of PHD inactivation. Thus the central aim of this proposal is to test the hypothesis that combined PHD and FIH inhibition eliminates LSCs in AML.

To translate this research to the clinic, we will address the following questions:

1. Which AML subtypes are sensitive to PHD inhibition?

2. Does FIH inhibition synergise with PHD inactivation to eliminate LSCs?

3. What are the downstream molecular mechanisms through PHD/FIH inhibition eradicates LSCs?

4. How does combined PHD and FIH inhibition affect normal haematopoiesis and what is the therapeutic window foremploying this treatment?

This translational project will employ a combination of state-of-the-art murine and humanised AML in vivo models and mouse genetics with pharmacology, drug discovery and molecular biology approaches. By determining the impact of our novel PHD and FIH inhibitors on a variety of AML subtypes and normal haematopoiesis, and the underlying mechanisms, we will be well placed to harness this knowledge in clinical trials. 

Primary Supervisor: Dr Sung Pil Hong 

Primary Division: Surgery and Cancer, Faculty of Medicine, Imperial   

Oesophago-gastric (OG) cancer is the fifth most common cause of cancer in the UK, affecting over 11,000 people each year. Sadly, it has some of the worst clinical outcomes, with a five-year survival rate of only 17.5% for oesophageal cancer and22.2% for gastric cancer. A major reason for this high mortality is that OG cancers are often diagnosed at a late stage when they are typically incurable. Oesophago-gastro-duodenoscopy (OGD) is crucial for diagnosing OG cancer, providing the gold standard for direct mucosal visualisation and tissue acquisition. However, patients with suspected OG cancers often face delays in obtaining definitive diagnostic tests, resulting in the longest intervals between referral and commencement of treatment among all cancers. To address this, NHS England Cancer Alliances introduced a guideline for an OG cancer diagnostic pathway to meet the Faster Diagnosis Standard. However, the current guidelines do not adequately address the importance of high-quality OGD. A recent meta-analysis revealed that 11.4% of OG cancers are missed during the initial endoscopy, leading to what is termed Post-Endoscopy Upper GI Cancer (PEUGIC). Alarmingly, 71% of PEUGIC cases are considered avoidable. These statistics highlight significant inequalities in the quality of endoscopic procedures and emphasise the need for improved standards and practices to minimise the risk of missed diagnoses. Approximately 40% of PEUGICs are diagnosed in patients with Barrett's oesophagus, while intestinal metaplasia is the most common finding during initial OGDs inpatients with missed gastric cancer. This underscores the importance of high-quality OGDs for examining Barrett's oesophagus and detecting intestinal metaplasia. Despite British clinical guidelines that recommend quality standards for OGDs,there remains significant variability in performance, resulting in an alarming rate of missed cancer diagnoses. Artificial intelligence (AI)-based computer-assisted detection and diagnosis has shown promise in colonoscopy for identifying and characterising colon polyps, significantly reducing the miss-rate for adenomas and offering a cost-effective method to lower colorectal cancer incidence and mortality. However, AI applications in OG cancers are still in their early stages. Current research mainly focuses on detecting Barrett's dysplasia, with limited experience in diagnosing gastric cancers and intestinal metaplasia in Western countries. Prevenotics is an AI-powered autonomic detection and diagnosis software developed in South Korea, where OG cancers are among the most common cancers. High-quality OGDs in South Korea have demonstrated improved early-stage cancer detection and reduced mortality rates. Prevenotics has shown excellent diagnostic accuracy in detecting intestinal metaplasia and early gastric cancers. The software operates in real-time, automatically identifying key landmarks during OGDs to meet quality standards. However, its capability to detect Barrett's dysplasia still needs further development. This project aims to implement real-time AI-based endoscopy software in clinical practice to improve the detection of premalignant lesions and gastric cancers, while also focusing on enhancing its ability to detect Barrett's dysplasia. 

Primary Supervisor: Prof. Maria Kyrgiou 

Primary Division: Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial   

Endometrial cancer is the commonest gynaecological cancer. Its incidence has risen by 10% over the past decade due to the obesity epidemic. Traditional histopathological classification of endometrial cancer has been insufficient for explaining the molecular heterogeneity of the disease and variation in clinical outcomes. The TCGA endometrial collaborative project described four distinct prognostic endometrial cancer subtypes based on genomic abnormalities (‘POLEmut’, mismatch repair-deficient (MMRd), p53abn, no specific molecular profile (NSMP) endometrial cancer). Molecular profiling using the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) algorithm has shown that molecular subtypes are strongly associated with prognostic significance in endometrial cancer and may better predict outcome than traditional histopathological classification alone. Furthermore, two clinical trials recently reported significantly improved progression-free survival from the universal use of immune checkpoint inhibitors as an adjunct to chemotherapy (in advanced/recurrent endometrial cancer) independent of molecular subtype and are likely to revolutionise management for endometrial cancer. However, currently transference of these two major advances to fertility-sparing management in young women remains inadequately explored, as does the potential for non-surgical therapies in women with early-stage endometrial cancer. Patient-derived organoids have been shown to represent an enhanced model of cancer biology compared to 2D cell culture and animal studies. Our team have been working with the ICR towards the development of benign and malignant endometrial (and cervical) organoids. We have successfully initiated work to demonstrate whether benign glandular and endometrial cancer organoids recapitulate the phenotypic features, epigenetic and metabonomic signatures of primary tissue. Organoids offer aunique opportunity to not only study key carcinogenic processes but also to further explore the potential of alternative and novel therapies During the fellowship we plan to investigate the effects of different therapies, such as checkpoint inhibitors,stratified by molecular profile and receptor status, for precision treatment of early endometrial cancer in fertility-sparing management and beyond. 

Primary Supervisor: Dr Alison Tree 

Primary Division: Radiotherapy and Imaging, ICR  

Building on the successful outputs of our previous CRUK PhD fellow, and our recently published paper in the New England Journal of Medicine on the long term cure rates of 5-fraction stereotactic body radiotherapy, we would like to offer an opportunity to continue this practice changing research. This project aligns with the ICR/RM CRUK Radiation Research Centre of Excellence. We were the first in the world to test 2-fraction MRI-guided adaptive radiotherapy for prostate cancer (the HERMES trial) and have also pioneered tumour-focussed radiotherapy whilst de-escalating dose to the normal prostate(DESTINATION 1). This project will lead the unifying successor to those trials, DESTINATION 2, which is a global collaborative project with one harmonised protocol. This trial will randomise to 2 fraction whole gland vs 2 fraction tumour-focussed radiotherapy, delivered with MRI-guided radiotherapy and a zero mm planning target volume margin. The UK component of this trial is led by Dr Alison Tree, sponsored by The Royal Marsden hospital. This candidate will lead on the dosimetric and technical feasibility analysis of this trial, focusing on the dosimetric implications of zero margin. Toxicity of these two novel schedules will be compared by the candidate and as part of the global collaborative, they will have a role in analysing the international component of this trial. Predictors and preventers of toxicity will be reported. Alongside this trial, the candidate will contribute to our work towards a simulation-free, MR-only workflow, speeding up cancer therapy for all patients and thereby improving the chances of cure. Their project will build on work already completed and seek to test whether this more efficient and effective way of delivering radiotherapy can be applied to the more complicated treatment pathways needed for the DESTINATION 2 trial. This project is well suited to a clinical oncologist who wishes to pursue a career in academic oncology. We will help you develop the skills needed to fund, design, run, analyse and publish academic oncology trials and will provide a springboard to the next phase of your career. 

Primary Supervisor: Prof. Anastasios Karadimitris 

Primary Division: Department of Immunology and Inflammation, Imperial  

Invariant NKT cells are a subset of innate-like, effector and immunoregulatory T cells that can exert direct or indirect anti-cancer activities. We pioneer development of iNKT cells as an allogeneic, 'off-the-shelf’ immunotherapy platform for the treatment of cancer. Our work has shown that CAR-iNKT outperform CAR-T cells in pre-clinical models of blood cancers in terms of efficacy, persistence and ability to kill CAR target-negative blood cancers in an NKG2D-dependent manner. Our transcriptional analysis of resting and activated iNKT cells shows that iNKT express the transcription factor FOXP3, the master regulator of the immunosuppressive conventional T-regulatory cells which among other functions, inhibit and limit anti-tumour T cell responses. In preliminary work, using intracellular flow-cytometry we confirmed that FOXP3 in expressed by ~5% of iNKT cells, i.e., same frequency as in conventional Tregs. The function of FOXP3 in iNKT cells and its impact on the efficacy of iNKT cell-based immunotherapy are not known. We hypothesise that the FOXP3+ fraction negatively impacts the anti-tumour activity of iNKT cells.

The aims of the project that will address this hypothesis will include:

1. Identification of FOXP3 gene targets in iNKT cells by combining ChIP-seq with transcriptome analysis after FOXP3 depletion using clinically validated FOXP3antisense oligonucleotides.

2. Impact of FOXP3 depletion and of iNKT cells expressing FOXP3 on effector functions(cytotoxicity, proliferation, cytokine secretion) of CAR-iNKT specific for AML (CD33), B cell lymphoma (CD19) and multiplemyeloma (BCMA) in vitro.

3. Impact of FOXP3 depletion on ability of CAR-iNKT to control the above blood cancers in vivo.

The project will combine regulatory genomics approaches with a number of in vitro and in vivo immunological assays relevant to tumour immunotherapy. Overall, this project as well as defining the role of FOXP3 in regulating the iNKT cell function, it might also provide insights that could be exploited to enhance the anti-cancer activity of the iNKT cell immunotherapy platform. 

Primary Supervisor: Dr Ed Johnston 

Primary Division: Radiotherapy and Imaging, ICR 

Despite the revolutionary impact of whole-body MRI upon the detection and staging of multiple myeloma (MM), tissue diagnosis still relies upon semi-random trephine bone marrow biopsy performed without image guidance. This is almost certainly a shortcoming because like almost all tumours, MM is a heterogeneous disease where certain clonal populations hold more prognostic significance than others. We know from other tumour types (e.g. renal, GI and prostate cancer) that inaccurate sampling results in disease misclassification with downstream negative impact upon treatment, which is why Interventional Radiology (IR) has a pivotal role in most multidisciplinary cancer teams. However, IR presence is curiously absent in MM. We are therefore looking to apply our collective expertise and develop new ways to better characterise MM using targeted multiregional biopsy, informed by functional imaging including whole-body MRI (which we call “smart biopsy”).

In a prospective study, the fellow will:

1. Explore available biopsy methods and technologies e.g., robotics, image fusion and cognitive registration, deciding whether a low-dose CT can assist targeting.

2. Develop a biopsy pipeline facilitating accurate targeting of focal lesions as demonstrated on whole-body MRI.

3. Decide how imaging signature is best used to select the most deterministic regions for biopsy, using advanced imaging techniques.

4. Conduct multi-regional sampling of different focal lesions.

5. Assess procedural feasibility, safety and sampling success.

6. Decide whether smart biopsy holds greater clinical potential than current practice (trephine biopsy).

7. Assess whether multiregional sampling provides more information than single site biopsy.

8. Assess acceptability of biopsy methods to both staff and patients.

9. Estimate procedural costs.

10.Explore the relationship between imaging and histological biomarkers, with a view towards characterising heterogeneous focal lesions using imaging alone (‘digital biopsy’).

11. Assemble a biobank of tissue samples for exploratory analysis of genomic and histological heterogeneity which guides treatment stratification.