CRUK CoL Centre MBPhD supervisors 2022

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.

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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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

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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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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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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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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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.

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.

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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