NIHRDataInsights/HRCSData huggingface dataset:
Title: Lymphocyte Interaction Laboratory
Funder: Cancer Research UK

Abstract: Previous and current research The fate of developing and mature B cells is determined by antigen binding to the antigen receptor (BCR) on the B cell surface. At the immature stage, encounter with high-affinity antigen leads to cell death (a way of preventing the production of autoreactive cells). In contrast, at the mature B cell stage, the immune system specifically selects for B cells that recognise the antigen with high affinity, as production of high affinity antibodies is essential for protective immunity to viruses and other foreign antigens. Future projects We will use our experimental model together with the latest imaging techniques to understand the cellular and molecular mechanisms leading to B cell activation. We will explore how the kinetics of synapse formation and receptor compartmentalisation will be affected by the density, affinity and the context in which antigen is seen. We will also focus our attention on the cellular mechanisms behind the different compartmentalisation of the receptor. This work in combination with in vivo studies will provide a better understanding how the fate of a B cell is determined and how it can be regulated. Goal We want to understand the cellular and molecular mechanisms by which B cell activation and fate are controlled.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS
Title: Mechanisms Regulating Human Normal and Leukaemic Stem Cells.
Funder: Cancer Research UK

Abstract: A fundamental problem in cancer research is the identification of the cell type capable of initiating and sustaining the growth of the neoplastic clone in vivo. The key to solving this problem lies on the observation made over 40 years ago that tumours are heterogeneous and thus might be maintained only by a rare subset of cells called “cancer stem cells” (CSCs). However, the proof of this principle was only possible after the development of modern research tools for investigating the behaviour of defined cell populations in vivo. The blood-related cancer leukaemia was the first disease where human leukaemic initiating cells (LICs), were isolated. The development of quantitative xenotransplantation assays using immune-deficient mouse recipients to detect primitive human HSCs with in vivo repopulating ability and the adaptation of this model to leukaemia has been instrumental. Leukaemia can now be viewed as aberrant haematopoietic processes initiated by rare LICs that have maintained or reacquired the capacity for indefinite proliferation through accumulated mutations and/or epigenetic changes. Yet, despite their critical importance, much remains to be learned about the developmental origin of LIC and the mechanisms responsible for their emergence in the course of the disease. Over the years our laboratory has been involved in better defining human normal HSCs and LICs compartments. During the last 6 years, we have identified new heterogeneity in both normal and LICs compartment. We have established new tools to study LICs ex vivo, to examine the interaction of LICs and HSCs with their niche and to monitor the development of leukaemia in vivo using whole body imaging. We have also deciphered the role of beta catenin in the maintenance of LICs as well as the role of CEBPa mutations in normal HSC development. We have prospectively isolated and identified a population of murine mesenchymal stem cells and contributed to the understanding of the ageing of murine and human HSCs.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Cell Cycle Laboratory
Funder: Cancer Research UK

Abstract: Work from the laboratory investigates the cell cycle, cell growth and the generation of cell form, processes fundamental to all living organisms and important for the understanding of cancer. During the cell cycle the genome is accurately replicated and segregated to the newly formed daughter cells, ensuring faithful transmission of genetic information from one generation to the next. Also during the cell cycle, the cell needs to grow sufficiently and to reproduce itself in space to generate viable daughter cells. For studies of these processes we have used the single celled eukaryote, the fission yeast Schizosaccharomyces pombe, which has powerful genetic, genomic, biochemical and cell biological methodologies and resources available for its study. It has a well-characterized, typically eukaryotic cell cycle, a regular cylindrical cell shape, and maintains a constant cell size at division from one generation to the next. These features make it ideal for studies of the cell cycle, cell form and overall cell growth.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS
Title: CRUK/12/035: Isotoxic Intensity Modulated Radiotherapy (IMRT) in non small cell lung cancer (NSCLC)
Funder: Cancer Research UK

Abstract: Background_x000D_ ~12,000 patients are diagnosed with stage III NSCLC in the UK each year and their survival is ~15% at 5 years. As the majority of patients are not suitable for the gold standard treatment (concurrent chemo-radiotherapy (CTRT)), novel strategies integrating radiotherapy (RT) technological advances and radiobiological knowledge need to be evaluated in patients treated with the alternative treatment option, sequential CTRT._x000D_ There is solid evidence that improving local control in lung cancer leads to increased survival. Strategies to improve local control in stage III NSCLC include dose escalation and individualisation which are limited by the dose delivered to surrounding tissue. We hypothesise that this will be facilitated by the use of intensity modulated radiotherapy (IMRT)._x000D_ _x000D_ Aims _x000D_ To demonstrate the feasibility of delivering isotoxic RT using IMRT and hyperfractionated accelerated RT in stage III NSCLC patients who are not suitable for concurrent CTRT._x000D_ Primary endpoint: Delivery of isotoxic IMRT to dose 60 Gy EQD2 (total biologically equivalent in 2 Gy fraction)._x000D_ Secondary endpoints: Estimation of the suitability for lung isotoxic IMRT, estimation of proportion of patients with acute grade 3+ non haematological toxicity, estimation of local control/overall survival and development of a robust QA process for lung IMRT._x000D_ _x000D_ Methods _x000D_ Patients with stage III NSCLC, PS 0-2, not suitable for concurrent CTRT, will be treated with individualised doses of radiation based on pre-specified normal tissue doses. Radiotherapy will be delivered twice-daily over 4 weeks using IMRT and the dose of radiation will be increased until one or more of the organs at risk tolerance or the maximum dose of 79.2 Gy is reached._x000D_ 35 patients will be recruited in this prospective multicentre feasibility study. Stopping rules are in place to ensure the safety of patients. We estimate that this regimen would be of added value to a national randomised phase II trial if 80 % of the patients can be planned to a dose 60 Gy EQD2._x000D_ _x000D_ How the results of this research will be used_x000D_ If this IMRT isotoxic regimen proves feasible it will then be incorporated into a planned national randomised phase II “pick-the-winner” type study incorporating 3 other novel RT regimens that are currently under assessment in the UK. This is part of a national strategy endorsed by the NCRI Lung CSG. Furthermore the QA programme for this study will allow the standardisation of lung IMRT in the UK by providing a framework for implementation of this technique.


Research activity codes: 6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Redirected Immunotherapy
Funder: Cancer Research UK

Abstract: Therapeutic antibodies have emerged as an important class of biological targeted agents with considerable application in the management of patients with cancer. However, to date these agents do not typically offer cancer patients curative treatment options and frequently offer only modest benefit in survival. This Discovery Committee proposal seeks to develop on a novel discovery that enables T-cells to engage with targeted agents such as therapeutic antibodies. This new approach, for the first time, allows antibodies to activate antigen-specific T-cells, redirecting their cytotoxic activity against a cellular target in vivo. The technology consists of virus-derived peptide directly conjugated to an antibody via a linker region containing a specific protease recognition domain. The peptide is delivered to a target cell and, following binding, is cleaved and loaded onto MHC class-I or class-II molecules on the cell surface. This promotes T-cell receptor mediated recognition of the target cell by re-directed virus-specific Cytotoxic T-Lymphocytes (CTL), and subsequent killing. The addition of the protease cleavage site introduces increased specificity toward the tumour tissue allowing larger therapeutic doses to be given. The aim of this proposal is to continue preclinical development of the redirected immunotherapy technology and provide in vivo proof of concept data, with a view towards advancing the project towards the clinic.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Beyond the Tobacco Control Plan for England: Using the Tobacco Control Plan for England as a springboard to advocate more ambitious tobacco control measures including the introduction of plain, standardised packaging.
Funder: Cancer Research UK

Abstract: Background In 2010 CRUK funded ASH for the first two years of a five year advocacy project to sustain tobacco control through the new parliament. This application covers years three and four, taking the project on to June 2014, less than one year before the next election. In 2010 the outgoing Labour Government published “A smokefree future”, its 10 year tobacco control plan. Following the General Election the Coalition Government published its own Tobacco plan, committing to “ambitions” for smoking prevalence, a consultation on plain, standardised packaging for tobacco products and the prohibition of tobacco displays and vending machines. This was a great success for tobacco control and the primary goal of the predecessor to this grant application. However, while the government’s plan sets out ambitions, it gives little direction on how they are to be achieved. Thus the publication of a plan and consultation are not, in themselves sufficient to achieve health gain. Other government health policies include the transfer of public health from the NHS to local government. This presents significant threats, particularly to the continued provision of smoking cessation services. The risk is three fold: 1) money ring-fenced for public health may be spent on existing services which broadly contribute to health but are not currently funded from health budgets; 2) the spend within the public health budget may shift to work other than tobacco control that has less robust evidence of need and effectiveness; 3) funded tobacco control work may shift to interventions which are politically or intuitively effective but for which there is a poor evidence base. Local government and the NHS have very different approaches to what constitutes evidence of need and effectiveness in Public Health. Therefore, it will be essential to continue to make the case for tobacco control clearly and strongly and to advocate evidence based measures for local implementation. The project This grant will fund advocacy of tobacco control measures beyond those set out in the Tobacco Control Plan for England. Deliverables The main priority will be to secure the implementation of plain standardised packaging. In the crucial period running up to a 2015 election, the project will support advocacy for local delivery in addition to the areas set out under the previous grant: harm reduction, smoking in cars, tobacco taxes and smuggling and licensing of retailers.


Research activity codes: 3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION)
Health categories: CANCER AND NEOPLASMS
Title: G1 radiation checkpoint inhibition to improve radiation response in cancers
Funder: Cancer Research UK

Abstract: We propose to seek validation that inhibition of specific cellular enzymes will increase the response of cancers to radiation therapy. We identified these cellular enzymes in our previous work as required for the activation of the G1 cell cycle checkpoint in cultured cancer cells exposed to radiation therapy (http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0031627). G1 checkpoint activation is known to protect actively growing cells from radiation therapy inflicted death and a considerable amount of clinical evidence indicates that loss of this response in cancers is associated with increased therapeutic response of such cancers to genotoxic therapy, including radiotherapy. Hence inhibition of the enzymes that we identified may be a viable therapeutic strategy to improve the clinical response of cancers to radiotherapy, and potentially also chemotherapy. The work proposed seeks to provide sufficiently firm evidence that inhibition of one or several of these enzymes will increase the radio-sensitivity of cancer cells in order to justify the development of therapeutic inhibitors for clinical use in cancer patients.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Experimental Cancer Medicine Centre (ECMC): Cardiff
Funder: Cancer Research UK

Abstract: Publishable Summary The Cardiff ECMC has twin haematological and solid cancer themes. The haematological aim is to support the large NCRI AML trials in three ways: (1) Bank samples collected in the account for future research in Leukaemia. These samples support several research groups in the UK and beyond who are able to obtain their own research awards. Because they are part of a trial they are well characterised and the clinical outcome is known; (2) Using banked samples to conduct lab tests on new agents to make a case for bringing them into national trials – there are a number of examples of this leading to testing in the national trial portfolio; (3) Conduct mutation analysis and biomarker assessment in ‘real time’ for patients in the AML trials – this enables entering a relevant clinical question. Similarly, the solid cancer theme has a strong focus on translational research involving molecular analyses of patient tissue samples for which there is high-quality clinical outcome data. This includes samples held in the Wales Cancer Bank, both from hosted UK NCRI clinical trial collections and from non-trial patients from 7 Welsh hospitals. Specific examples of ECMC-supported projects include: (1) the identification of prognostic and predictive molecular biomarkers from samples from the MRC COIN (colorectal) and NCRI ABC (breast) trials; (2) gene re-arrangements and mutations in non-trial prostate cancers; and (3) mechanisms of endocrine treatment resistance in breast cancers. Future planned strategic developments include the correlation of functional imaging (PET) with molecular biomarkers and an expansion of early phase trials activity for patients with solid tumours. Based on the ECMC work early and late stage trials are sponsored by Cardiff University including the ECMC network. Disease Focus Areas: Breast, Colorectal, Leukaemia, Prostate.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: Platform technology for producing anti-glycolipid monoclonal antibodies: Lead optimisation of anti-Lewis y monoclonal antibody and lead identification of monoclonal antibodies to Fucosyl-GM1 and Gb3.
Funder: Cancer Research UK

Abstract: Glycolipids consist of a glycan (carbohydrate) head and a lipid tail. Monoclonal antibodies (mabs) can specifically recognise these glycans. Glycolipids are ideal targets as they are over-expressed by tumours and are co-accessory molecules for most physiological processes. Mabs can block these processes leading to tumour cell death. Furthermore, as glycolipids are densely clustered, mabs binding to them are excellent mediators of immune effector functions. In the existing project we have identified : Platform: • A patentable method for stimulating mabs targeting both novel and known glycolipids. Products: • Two mabs which target novel glycans expressed on ovarian cancer. • Two mabs targeting Lewis y glycolipid Mabs produced with current funding: Using DC funding we have produced two mabs recognising unique glycans which are currently being identified by the glycome consortium of the National Institute of Health in the USA. We have also identified two identical mabs targeting LewisY, These mabs are very specific as they do not cross react with similar carbohydrate determinants. They have a more restricted normal expression and should be less toxic when compared to other related mabs. We have also shown that the they induce cell death, ADCC and CDC. The first aim of the new funding is to find a human isotype that also promotes direct cell killing, ADCC and CDC and to optimize the Lewisy mab for the clinic. New mabs: Although, we have validated the platform with three mabs, only the Lewisy mabs have so far been conclusively proved to recognize a glycolipid antigen. It is therefore essential if we want broad coverage on the patent, to validate the method with other glycolipids. At the same time it would be cost effective to produce new therapeutic mabs. Our second aim is therefore to further validate our platform by producing human mabs targeting two new glycolipids. The predicted outcome: A validated platform technology for the generation of mabs to tumour associated glycolipids. 3 fully characterised patent-protected therapeutic chimeric mabs for clinical development.


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: The Cancer Research UK Drug Discovery Programme at the Newcastle Cancer Centre, Newcastle University
Funder: Cancer Research UK

Abstract: BACKGROUND Targeted anticancer drugs are an exciting new type of cancer treatment that exploits the underlying molecular and cellular pathology of the disease; activated oncogenes and immortality genes, tumour suppresser gene loss, invasion, angiogenesis and metastasis. AIM The aim of the Cancer Research UK (CR UK) Drug Discovery Programme is to discover small molecule targeted cancer therapeutics, and associated biomarkers, for clinical evaluation by the Clinical and Translational Research and Paediatric Oncology and Haematology Groups at the Newcastle Cancer Centre. The targets exploited by the CR UK Drug Discovery Programme are identified by the Solid Tumour Target Discovery and Paediatric Oncology and Haematology Groups, additional groups in Newcastle and occasionally by external collaboration. METHODS Both high-throughput screening, through collaboration, and structure-based drug design are used to identify hit chemical matter. Hits are validated in primary target assays and appropriate counter-screens, and in mechanism-based in vitro cell line models, prior to hit-to-lead and lead optimisation studies utilising iterative target compound synthesis with in vitro and in vivo pharmacological evaluation using genetically-defined human tumour models. In addition to conventional invasive biomarker approaches, and in conjunction with the Newcastle and Durham CR UK Cancer Imaging Programme, the CR UK Drug Discovery Programme makes extensive use of non-invasive imaging magnetic resonance (MR) and positron emission tomography (PET) biomarkers with the objective of developing predictive, pharmacokinetic, pharmacodynamic (proof-of-mechanism and proof-of-concept) and surrogate response biomarkers for all compounds prior to clinical candidate selection. In the previous quinquennium 9 projects have been completed, 2 progressing to clinical trial, and in the new Programme 6 ongoing and 2 illustrative new projects are proposed. RESEARCH USE The research will generate new drugs and associated biomarkers for early phase trial evaluation in cancer patients.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Pre-clinical efficacy and safety evaluation of MOv18 IgE, a novel class of antibody targeting alpha folate receptor
Funder: Cancer Research UK

Abstract: Background All existing antibody therapies for cancer have relied on one antibody class, namely IgG. Compared with IgG, IgE has a very high affinity for its Fc receptor and readily enters tissues in association with effector cells, which are different to those recruited by IgG. These attributes suggest improved efficacy using IgE for the therapy of solid tumours. We have generated in vivo data supporting this hypothesis by engineering and testing an IgE antibody against the tumour-associated antigen Folate Receptor alpha (FRa). FRa is expressed in a range of human cancers, but levels in normal tissues are extremely low. Two IgG antibodies specific for FRa have demonstrated safety in clinical trials, and our preclinical data indicate that an IgE alternative could provide superior clinical efficacy. Our findings in two murine xenograft models, and early data in a syngeneic rat model of FRa-expressing metastatic carcinoma, support therapeutic superiority of IgE over IgG. Other experiments confirm the risk of anaphylaxis is low. Aims We have proposed a proof-of-concept phase 1 trial of an IgE monoclonal antibody, and are completing the collection of pre-clinical efficacy and safety data to support a regulatory submission for a trial. This trial will mark the first introduction into man of this antibody class as potential therapy for cancer, therefore a cautious translational approach is being be employed. Methods The rat model has been established to test efficacy in an immunocompetent animal, to acquire pre-clinical safety data, and to study biodistribution of labelled antibody using whole-animal imaging. Binding studies of chimeric MOv18 IgE to effector cells from a range of species are being conducted to establish that there is no better model for pre-clinical safety. In the second year of the funding period we will require laboratory support once the clinical trial has opened, to perform ex vivo assays relating to clinical safety and efficacy. How the results of this research will be used The proposed work will complete the pre-clinical package for the regulatory submission, and support the conduct of the trial in two established ECMC Phase 1 Units. This trial will mark the first introduction into man of IgE as potential therapy for cancer. Demonstration of clinical safety for IgE immunotherapy would allow development of IgE variants of many of the already-licensed IgG drugs, with wide-ranging impact in the field of clinical antibody immunotherapy.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES;5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS