CRUK CoL Centre MBPhD supervisors 2022
Potential CoL Centre MBPhD supervisors for the 2022 intake and information on their research area are provided below. Successful candidates may also be able to consider other CoL faculty as supervisors.
Great Ormond Street Hospital delivers the largest paediatric neuro-oncology service in the UK, and one of the largest in Europe. Our recent research has focused on the physiology and development of cerebellar mutism, on surgical strategy and outcomes in paediatric brain tumours, particularly posterior fossa tumours and craniopharyngiomas, and the radiomics of medulloblastoma and ependymoma. As the primary clinicians for most of these patients, our research is supported by extensive collaboration with oncologists, pathologists, and MRI physicists. Internationally we collaborate with European partners within SIOPE and the ITCC. We also have access to advanced MR techniques and intra-operative MR imaging. Visit our website.
Advanced quantitative neuroimaging in paediatrics
Prof Clark’s team specialises in the use of quantitative MRI for diagnosis and prognosis of paediatric brain tumours as well as tractography for neurosurgical planning. The student will join a multi-disciplinary team of imaging scientists and neurosurgeons to fully evaluate the accuracy of interventional MRI for paediatric brain tumour resection and to improve processes to optimise image quality leading to improved accuracy and reliability of the iMRI service at Great Ormond Street Hospital.
Novel therapeutic strategies for childhood brain tumours
As newly established Neuro-oncology Lecturer at UCL GOS-ICH, my research programme aims to enhance survival outcomes for paediatric medulloblastoma patients through the discovery of functional- and immuno-genomics, and the translation of immune biology into novel therapeutic strategies using optimal and clinically relevant primary and recurrent immune-replete animal models, improving the clinical potential of modern therapies for recurrent paediatric medulloblastoma.
Example of current translational projects:
1. The use of CRISPR-based functional genomics for the identification of combinatorial druggable and epigenetic vulnerabilities of recurrent medulloblastoma.
2. Investigating the use of epigenetic re-modelling combined with novel therapeutic strategies for the treatment of recurrent and metastatic medulloblastoma.
3. The use of novel radioimmunotherapy approaches for the treatment of recurrent, MYC-driven medulloblastoma.
4. Decoupling clonal evolution of relapse medulloblastoma
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Radiotherapy, treatment response prediction
My group develops novel radiotherapy approaches to enhance treatment efficacy and reduce toxicity for cancers of unmet need. We then translate these advances into clinical trials and routine clinical practice. Potential projects will involve the application of mathematical and statistical modelling to longitudinal imaging data in order to dynamically predict individual patient treatment responses over a course of therapy. We will then leverage these predictions to develop personalised, adaptive treatment protocols.
Basic and translational research in radiobiology and radiation therapy
As an academic radiation oncologist focused on improving treatments for patients with cancer my research group is interested in understanding how we can improve outcomes for those treated with radiation therapy or use radiotherapy in novel ways.
Our lab is interested in:
- Applying functional genomics to understand radiation resistance in animal and human model systems
- Using an evolutionary framework to understand how radiation resistant tumours evolve
- Understanding how the tumour microenvironment influences the response to radiation therapy
Adoptive immunotherapy for cancer – chimeric antigen receptor T cells
We work on chimeric antigen receptor (CAR) T cell therapies for cancer, with 3 particular interests:
1) Development of ?off-the-shelf? CAR-T
2) CAR-T for T cell leukaemias/ lymphomas
3) Novel engineering approaches to enhance CAR-T persistence and recruit endogenous immune cells
Students have the potential opportunity to develop a project all the way from concept, through detailed preclinical assessment, to clinical trial. They will develop broad skills, including in eg molecular biology, tissue culture, immunological techniques, small animal work.
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T cell engineering for cancer applications
My research is focused on engineering immune cells so they can be used to treat cancer. PhD projects tend to focus on synthetic biology / engineering approaches to solve complex problems to deal with specific cancers and their immune microenvironment. Skills learned include protein engineering, genetic engineering, functional immunology and small animal models of cancers and immune treatment. Projects appeal to students who are creative and like solving problems.
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B cell immunology and lymphoma
The Tolar lab studies B cell immunity and pathology. This project will focus on mechanisms by which the B cell receptor for antigen (BCR) regulates pathogenesis of B cell lymphomas. The candidate will investigate novel BCR pathway mutations associated with specific lymphoma subtypes. The research will involve modelling of the mutations using CRISPR genetics in human cells and in mouse models and will focus on identifying pathways that can be harnessed for therapy.
Christian von Wagner
Behavioural science in early diagnosis of cancer
The role of social media in uptake of colorectal cancer screening. As part of the DHSC Policy Research Unit for Awareness and Early Diagnosis of Cancer, we have conducted a scoping review into the potential role of social media in early diagnosis of cancer. More recently we have begun a delphi exercise into developing a set of recommendations into the reporting of social media interventions. The next step will be to work with out clinical partners (e.g. St Mark’s Bowel Cancer Screening Centre) to develop and evaluate our own social media campaigns and interventions.
The role of community pharmacy in cancer screening. Together with academics and working community pharmacists we are planning to conduct research into self management of cancer symptoms using over the counter medication, and the development of online training to help community and other pharmacists and associated staff spot people with signs and symptoms of colorectal cancer.
Risk adapted colorectal cancer screening. the NHS Bowel Cancer Screening Programme has undergone many changes including the change from Guaiac to immunochemical testing, the rollout and decommissioning and flexible sigmoidoscopy screening and currently the age extension which will lower the start age to 50. The use of immunochecmial testing also enables a more personalised approach using the quantitative nature of the test. We are planning to tackle the behavioural aspects of risk adaption, including challenges to communicating individual results, people?s responses to different screening intervals and associated ethical issues.
Patient experience of at home capsule endoscopy. One of the potential consequences of risk adaptation is the possibility to offer different types of investigation according to the level of risk indicated by a combination of demographics, screening history and current FIT result. This opens the door to less invasive tests for people with intermediate risk of cancer who may not require a full colonoscopy visualization of the bowel. A similar logic is currently used in an NHSE pilot of colon capsule which has become popular in the pandemic due to its ability to reduce the need for patients to travel and visit the hospital. Colon capsule could in future replace much of the diagnostic load on colonoscopy and reserve the latter test predominantly for therapeutic interventions. We aim to understand awareness and attitudes of public, patients and health care providers to this new technology.
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Cancer computational genomics
Revolutionary technologies enable the sequencing of the whole genome of single cancer cells. These data provide a unique opportunity for better understanding the complex cancer evolutionary process and to identify evolutionary hallmarks of cancer to develop novel therapeutic strategies. Unfortunately, no computational methods currently exist to properly analyse such data. This project aims to address this limitation by developing a new generation of single-cell computational methods to investigate cancer evolution at the required cellular level.
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Queen Mary University of London
Pancreatic cancer, immune, radiotherapy
80% of pancreatic ductal adenocarcinoma (PDAC) patients are diagnosed with advanced disease and effective therapies are lacking. We have shown that targeting pancreatic stellate cells with all-trans-retinoic-acid (ATRA) reprograms pancreatic stroma to suppress PDAC growth. Stereotactic radiation therapy (SBRT) has shown promise in treating PDAC in the locally advanced setting. The efficacy of SBRT depends on direct DNA damage on the tumour, and modulation of stroma particularly the immune responses. We propose that combining SBRT with ATRA enhances antitumor response.
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DNA damage and repair in cancer, immunotherapy
PD-1 inhibitor, pembrolizumab. These findings have led to the first tissue-agnostic approval for anti PD-1 therapy for unresectable or metastatic solid tumours with MMR deficiency. However, it is becoming increasingly clear that many MMR deficient tumours fail to respond to anti-PD-1 therapy with approximately 50% refractory to treatment. Furthermore, in the proportion of those MMR-deficient patients that do respond, there is a wide diversity of clinical benefit. MMR-deficient tumours are clinically characterized by levels of microsatellite instability (MSI) and a recent study has revealed the degree of MSI is in part responsible for diverse response of MMR-deficient tumours to anti-PD-1 therapy. However why this is the case and how this can be clinically translated remains largely unknown.
Our research has focused largely on the use of synthetic lethal approaches to target loss of MMR in tumour cells (Martin et al., EMBO Mol Med 2009; Mendes-Pereira et al., EMBO Mol Med 2009; Martin et al., Cancer Cell 2010; Martin et al., Cancer Res 2011; Hewish et al., Br. J Cancer 2013; Locke et al., Cell Reports 2016; Guillotin et al., Clin Cancer Res 2017; Rashid et al., Cell Death & Disease 2019). Due to our significant experience in MMR biology, we are now interested in understanding the role of MMR loss in the cellular response to immune checkpoint inhibition. Our exciting preliminary data suggest that loss of specific MMR genes results in a differential increased expression of the immune checkpoint molecule, PD-L1. Therefore, we have evidence that loss of specific MMR genes can trigger differential expression of PD-L1 and we hypothesize that it is this differential expression that may in part determine sensitivity to anti-PD-1 therapy. In this PhD proposal, we will use both CRISPR-Cas9 generated MMR deficient cancer cell lines and in vivo models to elucidate the precise genetic determinants upon MMR loss that may predict response to immune checkpoint blockade.
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Evolution of metaplasia to cancer and the role of stem cells
We are actively seeking clinical fellows for projects in the following areas of Dr McDonald’s research programmes;
Evolution to Cancer:
Barrett?s is the replacement of the normal squamous oesophageal epithelium with a columnar phenotype and is the major precursor condition of the development of oesophageal adenocarcinoma. All patients with Barrett’s undergo routine and lifelong endoscopic surveillance to detect cancer but the majority of patients never progress to cancer. There are no effective predictive biomarkers for cancer risk and we believe this is because we do not fully understand the evolution to cancer in this condition. My lab has two major CRUK-funded programmes to study different aspects of the progression to cancer. 1) Programme foundation awards to study the diversity of different Barrett’s oesophagus gland types and clonal evolution in the progression to cancer and response to treatment to predict dysplasia risk and therapeutic response. 2) Grand Challenge: To investigate how the stromal reprogramming can prevent and revert inflammation-associated cancers (STORMing Cancer team with Prof Thea Tlsty, University of California San Francisco). Specifically, my lab studies how the stroma changes over time in Barrett’s particularly in patients the progress to cancer.
Stem cells and cancer
Epithelial tumours, namely carcinomas, are responsible for >90% of all human malignancies, and intuitively we believe that most, if not all carcinomas, have their origins in normal adult stem cells.Despite a great deal of work in animals, we are still largely ignorant about the nature and location of the stem cells in most epithelia. Thus, there is a great need for a robust technique to identify clonogenic cells and their descendants, particularly in human tissues.
Our laboratory has developed methods to identify clonal proliferative units in human epithelia, and we are now extending these studies to precisely identify the clonogenic cells, their location and nature (multipotential capacity), the cells that are the likely founders of much premalignant disease. We are currently working on the stem cell dynamics of Barrett?s oesophagus using next generation bisulphite sequencing and in the human liver using mitochondrial next generation sequencing, developing molecular clock models to determine stem cell dynamics.
Other interests focus around;
- The cellular origins of Barrett?s oesophagus
- Field cancerisation of the human stomach
- Clonal expansion in ductal carcinoma in situ of the human breast
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Investigation of the molecular mechanisms regulating tissue growth, invasion, metastasis and tumour heterogeneity
Our research group uses the fruit fly Drosophila to uncover the mechanisms regulating tissue growth, metastasis and tumour heterogeneity. This particular project aims to define the functional role of glioblastoma EGFR variants in the context of tumour heterogeneity. For this, we will use our newly generated genetic system for studying tumour heterogeneity and combine it with in vivo and in vitro models of glioblastoma, including the fruit fly Drosophila and mammalian organoid cultures.
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Acute Lymphoblastic Leukaemia, evolution of treatment resistance using functional xenograft modelling and high throughput genomics
Research in the Wrench laboratory aims to better understand the biological pathways that allow for persistence of ALL cells after potentially curative therapy. We apply multifaceted programmes composed of several projects running in parallel with an overarching aim to identify recurrent genetic and/or non-genetic mechanisms underpinning ALL persistence and survival following initial therapy. The PhD project will study the dynamic process of ALL resistance, using longitudinal genomic and transcriptomic (bulk and single cell) datasets generated during in vivo chemotherapy treatment of patient derived xenografts and from clinical samples. Applying state of the art bioinformatic tools, the student will describe biological relationships and evolutionary trajectories contributing to the stages of disease progression and identify microenvironmental precipitants. The project builds on local collaborations (Professor Trevor Graham), partnerships with GOS (Dr Jack Bartram) and a UK-wide consortium (UCL/Sanger centre/Newcastle/Barts) studying genomics of adult ALL as well as recent published findings.
King’s College London
Imaging therapies and cancer
My lab contributes to the development of new and the improvement of existing therapeutics in oncology and immunology by employing diverse imaging approaches ranging from whole-body to microscopic levels. Our main research focus is in vivo tracking of cancer progression and spread to unravel underlying molecular mechanisms, and to provide quantitative in vivo platforms for therapy development. Another focus is exploiting imaging for the development and clinical translation of cell-based therapies that are intended to treat cancers and are emerging players in solid organ transplantation and tissue regeneration.
Investigating the interacting effect of immunotherapy and other standard treatments, including radiotherapy, in head and neck and breast cancers and development of new clinical trials
Radiotherapy is one of the most important treatment modalities in many cancers and many studies have demonstrated a critical role for immune cells in mediating response to radiotherapy. However, there is uncertainty of how to combine anti-PD-1/PD-L1 antibody with radiotherapy in terms of dose fractionation as well as treatment schedule. In addition, there may be also other radio-sensitizing agents that could be combined with radiotherapy to enhance its effectiveness. We aim to investigate the combination of radiotherapy with immunotherapy and/or other radio-sensitizing agents using a multidisciplinary approach using patients? samples, animal models and patient-derived organoids, with an aim to translate the research findings to clinical trials.
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Theranostics for ultrasound triggered cancer drug delivery
In pancreatic ductal adenocarcinoma (PDAC), the extracellular matrix forms a barrier that limits the penetration of biological drugs. This project aims to combine novel nanomaterials and mathematical modelling to develop non-invasive, ultrasound change-phase nanodroplets as cavitation agents. These will apply ultrasound caused cavitation forces in the tumour matrix and will ?drill-open? the way for drug penetration. The supervisors? initial data on both modelling and nanodroplets indicate that these sonic drills could improve antibodies penetration in PDAC.
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Behavioural science in cancer prevention and early diagnosis
My group‘s work focuses on understanding behaviours related to cancer prevention and early diagnosis, with a particular emphasis on screening participation. We also investigate acceptability of new innovations including medical devices (cytosponge, HPV self-sampling, GRAIL Galleri blood test) and screening approaches (risk stratification, longer screening intervals), and evaluate the psychological impact of participation in cancer screening. We work closely with Public Health England and our work informs communication materials used in the NHS screening programmes.