NIHRDataInsights/HRCSData huggingface dataset:
Title: 2019 Doctoral Fellowship: Clinical, genetic and molecular correlations in aggressive pituitary adenomas
Funder: Public Health Agency, NI

Abstract: Background - Symptomatic pituitary adenomas (PA) are common1,2 and cause severe morbidity due to hormone secretion and local mass-effects. More aggressive PAs tend to recur and can be resistant to conventional treatments. Some patients have a family history of PA3,4 associated with a germline AIP (aryl hydrocarbon receptor-interacting protein) mutation5,6 leading to acromegalic-gigantism. A new classification for PAs was introduced the by World Health Organisation (WHO) in 20177,8. Study aims 1. Analyse a Northern Ireland (NI) PA population cohort to create a prognostic tool for aggressive PAs; by integrative analysis of traditional clinico-pathological parameters and novel biomarkers, including markers of the tumour microenvironment, using standard and multiplex immunohistochemistry (IHC) and digital image analysis. 2. Investigate the role of friend leukaemia integration-1 transcription factor (FLI-1) and the innate immune-STING pathway in increased chemokine ligand 5 (CCL5) and programmed death ligand-1 (PD-L1) expression in AIPpos PAs using in vitro models. Plan of Investigation - Evaluate clinical-pathological features including gender, age at onset, age at surgery, presence of extrasellar extension on neuroimaging, pathological evidence of invasion into bone or dura, tumour size, response to therapy, hormonal status and cell type of adenoma. Create pituitary tissue microarrays (TMA) to evaluate related biomarkers using molecular digital pathology and bioinformatics tools to identify markers of aggressiveness and to predict response to treatment. Examine potential mechanistic pathways activated in pituitary tumorigenesis using GH3-Aip-KD cell lines and analysis of tissue from pituitary specific Aip--/- mice. Conclusion - Large invasive PAs require multimodal approaches. Understanding molecular pathways underpinning aggressive PA development could facilitate the future introduction of novel targeted therapies; possibly eliminating existing debilitating treatment approaches.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: NI Experimental Cancer Medicine Centre
Funder: Public Health Agency, NI

Abstract: Overall Aims: To link aspects of our laboratory and clinical research programme. To build the necessary clinical infrastructure to facilitate the expansion of our facility in early phase clinical trials. To further develop biomarker studies in patients for prediction of response and toxicity. To apply functional imaging technologies in the monitoring of response to novel therapeutic agents. Outline Plan to which proposal relates. Our current programme of translational research is focused on studies that are applied to the development of improved diagnostic predictive markers and the development of novel therapeutic targets as potential new cancer treatments. The infrastructure already provided by NICC and the CCRCB, facilitates hypothesis-driven translational research and early phase clinical trials. As a result of this, we intend to focus on increasing the number of laboratory studies as part of mechanistic Phase I and early Phase II clinical trials; enhanced predictive marker development as part of clinical therapeutic studies; increasing the number of patients entering into early Phase I and II clinical trials; and increasing the overall number of Phase I and Phase II studies. Our goal is to double accrual to early clinical trials over the course of the next 3 years. Therefore, the overall aim of this proposal is to further develop the necessary infrastructure that will allow effective translational research in areas of experimental medicine such as clinical pharmacology and Phase I/II clinical trials, biomarkers for prediction of response and toxicity, and the application of functional imaging technologies in the monitoring of response to novel therapeutic agents.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: CANCER AND NEOPLASMS
Title: Investigating indoleamine 2,3-dioxygenase (IDO) immune status in head and neck cancer
Funder: Oracle Cancer Trust

Abstract: Existing treatments for head and neck cancer (HNC) have lasting effects on patients’ quality of life. The head and neck region is a site of intense immune cell interactions. Understanding the changes in these cellular signals throughout treatment provides a basis for modifying existing treatments (e.g. radiotherapy treatment dosage) and personalising future therapies (e.g. combining immune-based cancer therapies). Indoleamine 2,3-dioxygenase (IDO) is an important enzyme which allows tumours to evade elimination by the body’s own immune system. The activity of IDO can be measured locally at the tumour and peripherally in blood. We aim to study IDO activity at baseline and mapped throughout HNC treatment to establish IDO as an indicator (biomarker) of the function of the patient’s immune system (immune status). This will be achieved by testing the IDO activity in existing collected and stored blood and tissue specimen from a preliminary study and collecting further specimen to support our initial findings that IDO activity varies significantly during therapy. This work to establish IDO as a biomarker for HNC will support a more personalised, stratified approach to treating this condition in the future and aim to improve outcomes for the patients affected.

Lay abstract: IDO expression is a negative prognostic indicator in melanoma3, ovarian4, colorectal5, and lung cancer6,7. Early studies using immunohistochemistry (IHC) also suggested IDO may correlate with adverse outcomes in HNC (at sites including the oral cavity8, tongue9, and larynx10). These cross-sectional, retrospective expression studies did not, however, inform on IDO activity longitudinally throughout treatment (Table 1). Data from my systematic review on IDO in HNC supports its integral role in TME immunity and that IDO activation is regulated by the Stimulator of Interferon Genes (STING) pathway11. Furthermore IDO expression correlates with expression of the immune checkpoint programmed death-ligand 1 (PD-L1)12,13 and is present along with human papillomavirus (HPV) positive status14. Preliminary data obtained from The Cancer Genome Atlas (TCGA) comparing HNCs with high versus low immune checkpoint expression and overall survival for each group (Figure 1) shows that high IDO and PD-1 expression are both significantly associated with better survival15. However, the relevance of these observations requires further exploration.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Mitochondrial Reprogramming in Cancer
Funder: Cancer Research UK

Abstract: Remarkable cancer cell metabolic flexibility and plasticity enable tumours to grow and combat chemotherapy. Mitochondria are essential organelles that support tumour adaptation to altered metabolic demands and environmental challenges. Accordingly, mitochondrial form and function are dynamically reprogrammed during tumorigenesis. For instance, the levels of key mitochondrial inner membrane proteins, including metabolite transporters, are fine tuned in response to nutrient and oxygen availability to support cancer cell proliferation and survival. Metabolite transporter proteins are required to exchange small molecules including amino acids and nucleotides between the mitochondria and the rest of the cell. The tightly regulated coupling of cytosolic and mitochondrial metabolic reactions across the inner mitochondrial membrane represents an essential but poorly understood facet of tumour metabolism. Our goal is to identify mitochondrial metabolite transporters that control cancer progression using genetic screening approaches in 3D tumour models combined with genetically engineered mouse models. We will also investigate how regulated mitochondrial nucleotide transport and metabolism contribute to tumorigenesis and cancer cell responses to nucleotide-analogue chemotherapy. These studies will improve our basic understanding of mitochondrial reprogramming in tumours and may identify novel therapeutic targets for cancers that depend on metabolic flexibility and plasticity, including pancreatic cancer.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Deep Phenotyping of Solid Tumours
Funder: Cancer Research UK

Abstract: The Le Quesne group combine classical molecular and quantitative microscopic imaging methods to ask questions about solid tumour biology. What can we directly observe in fully contextualised tumour tissue, the natural environment of the malignant cell? How do malignant cells interact with the microenvironment of the tumour? What naturally selected strategies can we identify at cellular scale in human and mouse tumour tissues? Our main interests lie in three areas: The dysregulation of mRNA translation in tumour cells and stroma, and how this reprogramming of the genome facilitates the malignant programme at the cellular level The refinement and development of highly multiplexed microscopic imaging methods to reveal additional levels of single-cellular detail in spatial context (e.g. quantity and subcellular localisation of multiple gene products at mRNA and protein levels) The improvement of biomarkers for the prediction of personalised treatment efficacy and patient prognostication. We study common solid tumour types, but we have a particular emphasis on lung cancer and mesothelioma, and we have developed large focused collections of these tissues for study. In this area, we are engaged in study of how molecular and epigenetic events interact with tumour morphology in early stages of tumour development, and how morphology encodes specific survival strategies that drive tumour virulence and metastasis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Molecular Imaging and Radiotherapy Working Group Workshop at EMIM2022
Funder: Cancer Research UK

Abstract: EMIM2022 is the annual flagship conference for the European Society for Molecular Imaging (ESMI) and attracts hundreds of scientists working in the preclinical imaging field, including image guided therapies, monitoring of tumour response, imaging metabolism in models and image segmentation and quantification. We have secured a workshop session for the CRUK RadNet Molecular Imaging and Radiotherapy Working Group. This is an excellent opportunity to extend the reach of CRUK RadNet to our European colleagues and increase visibility for the Working Group, with the aim to invite and encourage European teams to collaborate with the Working Group on future projects.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: CANCER AND NEOPLASMS
Title: Tomorrow's Leaders Workshop 2020
Funder: Cancer Research UK

Abstract: Background: Tomorrow’s Leaders is a 2-day Workshop aimed at senior trainees in surgical oncology. Cancer care is largely delivered in teams led by consultants in clinical, medical and surgical oncology. The role of surgeons in delivering cancer research has increased in recently years, both in clinical trials that investigate surgical interventions and also in the wider role of surgeons in multi-disciplinary, methodological and translational oncology research. Aims: The aims of the Tommorow’s Leaders workshop are to educate and inspire senior surgical trainees in: Surgical & oncology trial design Trial recruitment Trial funding Accessing research support The workshop will also focus specialty-specific breakouts, fostering a detailed knowledge of their current trial portfolio, the opportunity for a ‘dragons den’, and valuable networking. Methods: Two day workshop, co funded by NIHR, CRUK & Royal College of Surgeons of England. Emphasis on small group sessions and learning through doing, interactive style Outcomes: Educating and equipping the next generation of surgical oncologists for a trials-focused practice.


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: CANCER AND NEOPLASMS
Title: Are we ready for CRISPR in radiation research?
Funder: Cancer Research UK

Abstract: This Workshop will leverage the insights and momentum gained through ongoing RadNet-funded collaborative research, developing state-of-the-art CRISPR-based screens investigating drivers of radiation resistance. Focusing specifically on opportunities and challenges unique to CRISPR-based radiation research, we will enable academic and industry partners to come together to develop strong and meaningful collaborations. The insights gained from this one-day event will inform a consensus paper which we will publish in a peer-reviewed journal. We anticipate that this will be the first of a series of annual CRISPR-based radiation research Workshops over, at least, the next 3 years, to drive collaboration and maintain momentum.


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: CANCER AND NEOPLASMS
Title: RadNet Student/Postdoc Annual Symposium
Funder: Cancer Research UK

Abstract: We propose to hold an annual RadNet PhD/postdoc symposium focused on the efforts of our early career scientists and clinicians in radiation-biology research. This unique meeting will nurture future leaders of the RadNet initiative and provide an ideal setting to develop new collaborations across the network. A Symposium organising committee with representation from all RadNet centres/units will select talks from submitted abstracts from across the network and a poster session will be held in the evening networking session and during the breaks to maximise researcher interactions.


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: CANCER AND NEOPLASMS
Title: Translational Radiotherapy Research in HNSCC Workshop
Funder: Cancer Research UK

Abstract: Radiotherapy is the mainstay of advanced head and neck cancer (HNC) treatment. Translational research efforts center around genetic characterisation of tumours, biomarkers for prognosis, outcome prediction or clinical trial support, novel treatment options and healthy tissue injuries. To address the pressing gaps in a joint effort, the organising committee aims to create a UK alliance that identifies research opportunities, and promotes networking and UK-wide collaborations. This Workshop will gather all stakeholders in the UK HNC arena with a view to a large network grant application, prospective specimen and data collection and standardisation of procedures to support translational HNC radiotherapy research.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: CANCER AND NEOPLASMS
Title: Yorkshire Specialist Register of Cancer in Children and Young People
Funder: Children's Cancer and Leukaemia Group

Abstract: The Yorkshire Specialist Register of Cancer in Children and Young People provides the foundation for an internationally recognised programme of epidemiological research. The Register comprises a unique population-base dataset on 10,700 individuals aged under 30 years and diagnosed since 1974 whilst resident in Yorkshire. Data items includes the diagnosis, treatment, any recurrence and linked health and social outcomes (approximately 125,000 records) to provide a level of quality and depth equal to and in specific areas beyond that held within the National Cancer Registration and Analysis Service or any of the other UK specialist tumour registers. Over the next three years we aim to maintain core funding of the YSRCCYP to continue to gather the most detailed dataset on cancer in young people and to carry out an ambitious research plan focusing on cancer outcomes. The objectives are to expand the programme of research into areas to improve understanding of social and psychological morbidity, by capturing additional contextual information through innovative electronic data linkage with data on mental health hospital episodes, education and unemployment data, and primary care data. Statistical modelling of mortality data will quantify the improvement in the risk of death from cancer in young people since 2000 and assess whether the fall in mortality rates has occurred equally in all socioeconomic and ethnic groups. We will also expand integration of patient and public involvement in the research programme by establishing a Register focus group of young people and their families, who will provide advice on infographic materials, grant applications and study documentation. Their first task will be to guide a full refresh of the Register website to make it more accessible for patients and survivors of cancer (https://medicinehealth.leeds.ac.uk/leeds-institute-cardiovascular-metabolicmedicine/doc/yorkshire- specialist-register-cancer-children-young-people/). Finally, the Register will continue to support other national and international academic and clinical colleagues working in the field of epidemiology and late effects research, by providing access to anonymised data, subject to appropriate ethical approval and data sharing agreements


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: CANCER AND NEOPLASMS
Title: Understanding the role of Kindlin-1 loss in the development of squamous cell carcinoma
Funder: DEBRA

Abstract: Kindler syndrome (KS) is characterised by loss-of-function mutations in FERMT1 which encodes Kindlin-1. KS patients have an increased propensity to develop squamous cell carcinoma (SCC). However, little is known about the aetiology of SCC in KS patients or the impact of Kindlin-1 loss on SCC behaviour.

Lay abstract: We will use a mouse model of solar-simulated UV radiation to address the effects of genetic deletion of Kindlin-1 on UVinduced oxidative and inflammatory stress pathway activation, DNA damage and cutaneous SCC development. In addition, we will take a proteomics approach to identify Kindlin-1 binding partners that contribute to SCC progression.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Development and characterisation of a DNMT3A mutant cell line model of clonal haematopoiesis
Funder: Cancer Research UK

Abstract: Background DNMT3AR882H/C is a common mutation of the de novo DNA methyltransferase in clonal haematopoiesis of indeterminate potential (CHIP) and increases risk of progression to Acute Myeloid Leukaemia (AML). This mutation increases the self-renewal capacity of haematopoietic stem and progenitor cells (HSPCs), conferring a survival advantage. The mechanism for this is incompletely understood. Mutated DNMT3A causes focal hypomethylation at specific genomic regions, particularly CpG shores and enhancers. We hypothesise that the proportion of wild-type and mutant DNMT3A within its functional tetramer unit may result in variable genomic localisation, DNA-binding and methylation efficiency. This focal differential methylation may alter expression of genes that support self-renewal and differentiation, possibly by modulating transcription factor binding at critical regulatory regions. The Mansour lab developed a murine model of CHIP with a Dnmt3aR878C mutation (the murine equivalent of R882C) to study this further. Aims The first aim of this project is to characterise the 416B-Dnmt3aR878C cell line, molecularly and functionally. Once validated, single-allele Dnmt3a epitope-tagged (wild-type and R878C) clones will be developed, to investigate DNA-binding and localisation of wild-type and mutant DNMT3A. Methods This new DNMT3A CHIP model employs 416B cells, a Friend Murine Leukaemia Virus (FLV)-immortalized, diploid, murine haematopoietic progenitor cell line. Using Crispr/Cas9-mediated homologous recombination repair, Dnmt3aR878C was knocked-in to 416B cells. Isogenic 416B-Dnmt3aWT cells were cultured in tandem. First, integration mapping will be used to determine sites of FLV-integration. Next generation RNA-sequencing will be used to determine the expression profile of 416B-Dnmt3aR878C vs 416B-Dnmt3aWT. Differential methylation patterns between to isogenic lines will be determined using whole genome bisulfite sequencing (WGBS). Self-renewal and differentiation in vitro assays will determine functional capacity of these cells. Next, single-allele Dnmt3a epitope-tagged clones in 416B cells will be produced. A plasmid containing 1Kb of Dnmt3aR878C or Dnmt3aWT with a 3xTy1-tag immediately prior to the stop codon will be cloned into a vector containing multiple selection markers and delivered into 416B cells. Two isogenic clones will be made: 416B-Dnmt3aR878C-3xTy1/WT; 416B-Dnmt3aR878C/WT-3xty1. ChIP-sequencing will be performed to determine variable DNA-binding and localisation of the DNMT3A isoforms. The generation of Dnmt3a epitope-tagged clones will provide a powerful model from which to ask questions about DNMT3A CHIP. In particular we will explore the mechanism by which variable differential methylation takes place across the genome and the impact that has on transcription factor binding, higher order chromatin and gene expression. This preliminary data will be used to develop a PhD fellowship proposal.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Immune Cells and Metastasis
Funder: Cancer Research UK

Abstract: Understanding how cancer spreads from its primary site of origin to distant organs is one of the major challenges in cancer research. What has become evident in recent years is that mutations in cancer cells are not sufficient to drive metastasis formation – cancer cells need assistance from surrounding healthy cells. Among these various healthy cells, immune cells have emerged as powerful instigators of metastasis formation but, at the same time, immune cells can also prevent cancer cells from spreading. Our lab focuses on these dichotomous roles of immune cells and how tumours control immune cell behaviour. We study these concepts in the context of breast and ovarian cancer. We are particularly interested in ?? T cells, a rare population of T cells with properties that are distinct from conventional CD4 and CD8 T cells, as ?? T cells can be both pro-tumourigenic and anti-tumourigenic. Our ultimate goal is to understand how ?? T cells and other immune cells participate in the metastatic process and to develop new immunotherapies that counteract metastatic lesions.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS