NIHRDataInsights/HRCSData huggingface dataset:
Title: Anticipatory medicine: Can we identify, predict, and target mechanisms of disease relapse in childhood medulloblastoma?
Funder: Medical Research Council

Abstract: Medulloblastoma is the most common malignant childhood brain tumour. Despite multimodal upfront therapy, relapse occurs in 30%, and is fatal in the majority. Pioneering studies by myself and others, have indicated that the molecular characteristics of relapse disease evolve over time, raising the hypothesis that the mechanism of relapse is predictable and targetable therapeutically. However, comprehensive characterisation of the molecular landscape of relapsed medulloblastoma has never been undertaken; consequently, the mechanisms driving relapse are not understood. I have undertaken multi-omic profiling of >100 relapsed medulloblastomas and their paired diagnostic counterparts. Individual and integrative analyses of these datasets will identify candidate driver events enriched at relapse and supported by multiple strands of evidence. These will be taken forward for functional assessment. Focused in vitro and in vivo RNAi screens will be performed in established, disease-matched transgenic and novel patient-derived models, to assess candidates' roles in pathogenesis. Competitive co-culture and transplantation approaches in patient-derived models will be utilised to validate prime candidates. This proposal will deliver key translational advances by identifying, prioritising and characterising targets associated with relapse, and by developing a repertoire of patient-derived models for target interrogation and developmental therapeutics. Targets will be pursued pre-clinically though repurposing approaches in these models where established target-drug combinations exist, and in collaboration with the Newcastle Drug Discovery Unit for novel targets. These approaches will provide the essential evidence required to support early-phase trials. Furthermore, these discoveries will uncover the potential to change upfront-treatment, whereby we can anticipate and target the drivers of relapse at diagnosis, aimed at preventing relapse and improving disease outcomes.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: MICA: Upregulation of innate immunity in the tumour microenvironment of oesophageal cancer using oncolytic virus therapy with immunotherapy
Funder: Medical Research Council

Abstract: Oesophageal cancer, of which adenocarcinoma (OAC) is the predominant subtype in the UK, ranks sixth among all cancers for mortality, with survival rates of ~15%. This provides a strong rationale for pursuing a combination of immunotherapeutic approaches that aim to activate those cell types integral for generating an immune response within the OAC tumour microenvironment (TME). Our hypothesis is that intra-tumoural use of oncolytic herpes simplex virus-1 (HSV-1) will increase levels of Natural Killer (NK) cells that will control the levels of stimulatory Dendritic Cells in the TME, leading to recruitment of CD8+ effector T cells. Combining this treatment with a novel IL-15 superagonist/IL-15 receptor alpha fusion complex (N-803) will enhance the number and function of both NK cells and effector T-cells leading to increased responsiveness to immune checkpoint blockade. Using samples collected at surgery, we will evaluate the immune cell types found within the OAC TME using our expertise in state-of-the-art multispectral immunohistochemistry. The frequency of these different cell types will be correlated to other factors related to the TME by RNA immune profiling. Alongside this we will use an ex-vivo oesophageal tumour slice culture system to assess HSV-1 infectivity of the human OAC using direct immunofluorescence. The next stage of the project will utilise a transgenic mouse model of OAC. Initially, we will examine the effect that HSV-1 infection has on a mouse tumour organoid model. Then we will use a triple combination immunotherapy of: HSV-1, N-803 and anti-PD-1 antibody to induce tumour regression in the OAC mouse model. Data analysis will focus on quantitating immune cell types in treated versus untreated tumours, defining their anatomical locations and interactions. All the agents used in this study have been safely used in patients previously and so this combination intratumoural immunotherapy could be translated to a clinical trial in the future.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: A novel imaging biomarker for detecting treatment response in high-grade glioma
Funder: Medical Research Council

Abstract: Aim Detecting changes in tumour metabolism can give an earlier indication of treatment response when compared to conventional imaging. This project will explore deuterium magnetic resonance spectroscopic imaging (MRSI) as a novel, non-invasive imaging modality to detect and quantify treatment response in glioblastoma multiforme (GBM). Objectives 1. We will investigate the potential of dynamic 2H MRSI for measuring tumour glycolytic and oxidative fluxes following administration of [6,6'-2H2] glucose to rats with orthotopically implanted xenografts derived from GBM patients. 2. We will use dynamic 2H MRSI measurements of glycolytic and oxidative fluxes to detect response to conventional chemoradiotherapy, as well as treatment with a novel blood brain barrier penetrating phosphatidylinositol 3-kinase (PI3K) inhibitor. Methodology GBM cells taken from patients will be cultured then implanted intracranially into athymic rats and tumour growth will be monitored using 1H MRI. [6,6'-2H2] glucose will be administered and dynamic 2H MRSI used to measure the time-dependent levels of 2H-labelled glucose, lactate, and glutamate/glutamine. Measurements will be made before and after treatment. Mass spectrometric imaging, histopathology and immunohistochemistry will provide gold-standard comparators for treatment response. Scientific opportunities Professor Brindle is a world leader in the field of metabolic imaging in cancer and has a multidisciplinary team with a wealth of experience in translational research. The CRUK Cambridge Institute has excellent facilities for histopathology, flow cytometry, genomics, microscopy, transgenic rodent and specialised imaging facilities. Prof. Brindle has an excellent track record of supervising clinical research fellows. Medical opportunities Honorary contracts at Addenbrooke's Hospital will be arranged to attend neuro-oncology multi-disciplinary meetings and outpatient clinics.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.4 POPULATION SCREENING;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Multi-Modal analysis of composition and spatial architecture in human premalignant pancreatic lesions to enhance early detection.
Funder: Medical Research Council

Abstract: Pancreatic cancer (PC) has a 5-yr survival of <5% and will soon be 2nd leading cause of cancer-death. Often these cancers develop from pancreatic cysts. Aims We aim to better understand transcriptomic changes occurring in pre-cancerous cysts and determine the immune surveillance failures that enable malignant progression. Our central hypothesis is that spatial transcriptomic analysis of progressive dysplastic cyst epithelium and associated immune microenvironment will reveal pathways essential for pancreatic cancer promotion. Objectives To test our hypothesis, we will: 1)Perform spatial transcriptomics assessment of human premalignant pancreatic cystic lesions, adjacent normal and PC. 2)Undertake high-dimensional spatial characterisation of the immune landscape associated with IPMN evolution to malignancy and according to IPMN subtypes, including integration with transcriptome and genomic profile using a systems biology approach. 3)Commence development of a pancreatic premalignant patient derived organoid (PDO) platform and modulate them to gain insight into IPMN progression. Methodology This innovative proposal employs novel spatial transcriptomics and scRNA-sequencing in combination with high-dimensional immune profiling and systems biology tools to identify pathways underlying IPMN progression. We will validate identified candidate genes in PDOs, modulating them 1) via CRISPR-Cas9 approaches 2) with pancreatic duct implantation into immunodeficient mice. Scientific and medical opportunities The proposed research is significant as it facilitates: A)Generation of a unique biobank of PDO PC precursor lesions, a strategy not previously systematically investigated. Unique medical opportunities include: B)Discovery of novel biomarkers that could refine risk prediction for PC development by distinguishing low- from high-risk IPMNs C)Facilitate identification of potential immunodulatory chemopreventation strategies to inhibit IPMN progression.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Biomarker Development in Cancer- Bridging the Translational Gap
Funder: Medical Research Council

Abstract: The field of oncology is transitioning from a 'one-size-fits-all' approach to more personalised treatments. To facilitate this move to precision oncology, robust cancer biomarker tests are needed to guide treatment decisions. Thousands of potential biomarkers have been proposed but few have been implemented in routine clinical practice. Often this is due to inadequate validation, insufficient investment or inappropriate technology platforms. The 'translational gap' between the academic discovery of a cancer biomarker and its implementation and commercialisation is wide. It is clear that a new collaborative approach is required. The vision of this proposal is to bring together academia, industry and healthcare stakeholders to create alignment of academic insight and industrial capability in the field of oncology. As an oncologist, biomarker expert and clinical triallist, Dr Turkington is ideally placed to perform this role. Through secondment at Almac Diagnostic Services (ADS) he will gain experience in delivering biomarkers in a high-level commercial and regulatory environment. This proposal will equip Dr Turkington with the skills necessary to translate biomarkers from academic discoveries, through development as assays, to application in biomarker-led trials. By retaining his academic position at QUB the cultural impact will be disseminated to his wider research network. Northern Ireland is developing a world-class diagnostic and healthcare environment and critical to its success will be individuals with the skill set to work seamlessly across academia, industry and healthcare. The challenge of this proposal is to grow the skills and expertise necessary to ensure that biomarkers move from bench to business to bedside more rapidly. In conclusion, this proposal will enable Dr Turkington to work at the intersection of academia and industry with wider benefits to cancer patients and the economy through driving innovation in precision oncology.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Cancer drug discovery targeting the interaction of RAS oncogenic proteins with phosphoinositide 3-kinase
Funder: Medical Research Council

Abstract: The RAS family of proteins are activated by mutation in some 20% of human cancers. Constitutively activated mutant RAS proteins stimulate downstream proliferative signalling pathways through effector enzymes such as PI3K and RAF kinases, thereby contributing to the genesis of several types of cancer. RAS proteins remain challenging drug targets, despite the development of inhibitors that target one specific RAS mutation, G12C in KRAS, which represents 14% of total RAS oncogenic mutations. Previous work in the Downward laboratory at the Crick has established that blocking the interaction of RAS proteins with the effector enzyme p110a, a member of the PI3K lipid kinase family, inhibits tumour growth driven by RAS oncogenes in mice with minimal toxicity. In collaboration with AstraZeneca, we have previously developed a cell free assay to measure the interaction of KRAS with p110a (NanoBiT Biochemical Assay - NBBA). This has been optimised for high throughput screening. In this proposal, we wish to second Dr Mohamed Ismail from the Crick to AstraZeneca for two years. During this time he will 1) use the NBBA for high throughput screening of AstraZeneca compound libraries for inhibitors of KRAS/p110a interaction. 2) We will counter screen these hits against RAS interaction with other isoforms of PI3K, such as p110g and p110d. 3) Promising compounds will be followed up by secondary screening for direct interaction with purified RAS or p110a, using nano-format Differential Scanning Fluorimetry. 4) Hits of interest will initially be mapped onto the p110a or RAS protein crystal structure computationally and confirmed by site directed mutagenesis. Further structural follow up may involve co-crystallization of compounds with RAS/p110a. Any promising compounds will be checked for effects on RAS and PI3K signaling in cell lines. Subsequent medicinal chemistry to improve the chemical characteristics of compounds of interest may be initiated at the end of the granting period.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Augmentation of Volatile Biomarkers of Oesophageal Adenocarcinoma from the Tumour Lipidome
Funder: Medical Research Council

Abstract: Introduction: Early detection of oesophageal adenocarcinoma (OAC) is essential to reduce the burden of this disease. The breath of OAC patients is enriched with diagnostic volatile carbonyls (VC) that have an 80% sensitivity and 81% specificity of detecting OAC when measured in a breath test. The diagnostic accuracy may be further improved with an exogenous stimulant that selectively amplifies the production of OAC specific VCs. Comparison of intra- subject breath (pre and post stimulant) and fold change quantification of VCs can be used to detect cancer. This novel approach is known as augmentation and will improve test sensitivity, reliability and early detection of OAC. To augment OAC VCs, it is necessary to target the mechanistic drivers behind their production. Background: The OAC lipidome is reprogrammed with unsaturated phospholipids that are vulnerable to lipid peroxidation, which is a principal mechanism for endogenous carbonyl production. Prokaryotic lipids in the OAC microbiome are also vulnerable to this and putative drivers of lipid peroxidation are higher in the tumour environment. This suggests OAC lipids and/ or OAC associated prokaryotic lipids may generate diagnostic VCs through peroxidation. Aim: to augment the production of OAC VCs to improve the diagnostic accuracy of the breath test. Proposal: Three interconnected objectives will generate data to inform the subsequent step: 1) a lipidomics study of the onco- microbial lipidome using bespoke mass spectrometry with phenotyping of the corresponding carbonyls will identify input lipids that generate VCs, 2) stable isotope experiments based on the degradation kinetics of input lipids to VCs will inform augmentation strategies in vivo and 3) the science will be translated to clinic with a study of the augmented breath test in OAC patients. The innovative proposal will produce a second- generation breath test with improved diagnostic accuracy to achieve better clinical outcomes from OAC


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: The role of Nrf2 in the tumour microenvironment of IDH wild-type glioma
Funder: Medical Research Council

Abstract: High-grade, IDH wild-type gliomas are devastating brain tumours with survival times of ~14 months. Macrophages and microglia promote glioma growth, however how they achieve their tumour-promoting activity is unclear. Nuclear factor erythroid 2-related factor 2 (Nrf2) is activated in macrophages upon upregulation of inducible immunoresponsive gene 1 (IRG1) and inhibits production of pro-inflammatory cytokines. Recent data suggest increased levels of IRG1 and the Nrf2-target gene NQO1 in microglia from human gliomas. This project will test the hypothesis that association with tumour cells upregulates IRG1 in tumour-associated macrophages/microglia, which in turn activates Nrf2, creating immunosuppressive microenvironment. To test this hypothesis, we will combine analysis of human glioma tumours with cell culture and in vivo zebrafish glioma models. We will perform multiplex immunofluorescence of human IDH wild-type gliomas and quantify the levels of IRG1, Nrf2 and target genes in macrophages/microglia. Nrf2 will be manipulated genetically or pharmacologically in primary macrophages/microglial cells grown in glioma-conditioned medium. We will quantify the expression of IRG1, pro- and anti-inflammatory genes and investigate the potential involvement of the IRG1 product, itaconate. A co-culture system will be used to assess glioma cell proliferation, migration and invasion. Using zebrafish glioma models, combined with live imaging, we will analyse glioma initiation and determine the effect of Nrf2 (activation or suppression) on the interactions between macrophages/microglia and pre-neoplastic cells, and on proliferation of oncogenic cells. Detailed understanding of the role of Nrf2 will open possibilities to inhibit the pro-tumoural activity of macrophages/microglia and design effective anticancer treatments. The availability of compounds that inhibit the transcriptional activity of Nrf2 provides unique opportunity to test their effect on glioma development.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Preventing Acute Myeloid Leukaemia Relapse following Allogeneic Stem Cell Transplantation
Funder: Medical Research Council

Abstract: Allogeneic haematopoietic stem cell transplantation is the only curative therapy for many patients with acute myeloid leukaemia (AML). Relapse remains the most common cause of death and is due to failure of donor T cells to eliminate residual disease. Donor T cells are frequently exhausted at relapse, and AML often exhibits reduced immunogenicity. Determining the major drivers of T-cell exhaustion and leukaemic immunogenicity is critical to inform strategies that re-establish anti-leukaemic T-cell responses and prevent relapse. Objective 1: Single-cell RNA and ATAC sequencing will be applied to T cells from post-transplant relapse bone marrow to map enhancer activity and transcription factor binding at exhaustion-associated genes. Using patient samples to dissect the regulation of exhaustion will identify the drivers most relevant to post-transplant relapse, these can then be targeted to prevent disease recurrence. Objective 2: Reduced leukaemic MHC class II (MHCII) expression is common at post-transplant relapse and AML lacking MHCII elicits weaker donor T-cell responses. Our analysis suggests that leukaemic MHCII expression reflects differentiation towards a monocyte-macrophage lineage. Using primary AML and donor T cells in functional co-culture experiments we will determine the immunological consequences of leukaemic differentiation. We will also investigate the ability of differentiation-inducing compounds to augment T-cell activation and promote successful disease clearance. Objective 3: Before novel therapies can be applied, an at-risk population must be identified. Plasma proteomics (SWATH-MS) and mass cytometry will be applied to serial blood samples from multiple transplant patients to identify signatures of immune dysfunction that predict relapse. The development of predictive biomarkers would represent a significant advance, allowing therapeutic targeting of at-risk individuals, for example using donor T-cell administration.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS;5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Investigating cell-matrix networks as determinants of tumour immune response in oropharyngeal squamous cell carcinoma
Funder: Medical Research Council

Abstract: Background Head and neck squamous cell carcinoma (HNSCC) is increasing in incidence and has poor outcomes with high morbidity for survivors. It is a highly heterogeneous disease, and this translates to unpredictable treatment responses. Differences in tumour immune response, demonstrated in HPV positive and negative SCC, appear to correlate with clinical outcomes but are mechanistically unexplained. Heterogeneity also exists in stromal cells and the extra-cellular matrix (ECM). These non-malignant tumour compartments are increasingly understood to interact to play a significant role in tumour behaviour and progression, but are not well studied in HNSCC. Aims and objectives This project aims to establish the role of stromal cell-matrix networks in determining the tumour immune response in HNSCC. Methods Single-cell RNA sequencing to determine cell phenotypes and transcriptome in HPV+ve and HPV-ve OPSCC and non-cancerous oropharyngeal mucosa. Bioinformatic analysis will investigate potential pathogenic interactions between non-malignant compartments, and these will be validated using multiplex immunofluorescence. Manipulation of patient-derived explants will be used for functional validation of markers. Scientific and medical opportunities This project links surgery, bioinformatics, and lab science. An understanding of how the non-malignant tumour compartment acts to modulate tumour immune response will provide urgently needed insights into immunological differences that appear to determine outcome. In the long term, findings may open new avenues for the treatment of HNSCC by guiding the use of existing immunotherapies, and the development of new treatments.


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