NIHRDataInsights/HRCSData huggingface dataset:
Title: A facility for in-house X-ray data collection and analysis of crystals with large unit cells
Funder: Cancer Research UK

Abstract: Background Crystallisation of large protein complexes results in crystals with large unit cell dimensions. The diffraction pattern from large unit cells results in a pattern in which the spots are close together. Resolution of these spots requires a small, highly focussed X-ray beam. Although such a beam is available at synchrotrons, access to beamlines is limited and not as frequent as we might like. A dedicated x-ray source in-house will allow us to analyse crystals and make best use of synchrotron time when it is available. Aims To collect and analyse X-ray diffraction data from crystals of large protein complexes in large unit cells. We will then use these data to determine the molecular structure of the complexes to allow us to understand how they work. Methods X-ray diffraction is a technique to determine high resolution structural information about molecules. How the results of this research will be used This information is required to be able to understand biological functions at the molecular level. Furthermore, understanding molecular structure of target proteins is a prerequisite for designing drugs to inhibit them.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: CANCER AND NEOPLASMS
Title: Immune targeting of a novel tumour endothelial marker CLEC14A
Funder: Cancer Research UK

Abstract: Background Compared to normal tissue, angiogenesis in tumours is deregulated and/or aberrant, resulting in a structurally and functionally abnormal vasculature. Targeting unique features of the tumour vasculature to compromise blood flow in tumour tissue should therefore provide therapeutic benefit. We have recently identified a novel tumour endothelial marker, CLEC14A (Mura et al, Oncogene 2011). This C-type lectin is highly expressed on the surface of endothelial cells lining the vasculature of many common human cancers (including breast, prostate, bladder, ovarian) but in the vasculature of healthy tissue, expression is low/undetectable. Aims As part of our recent work, Cancer Research Technology generated five mouse monoclonal antibodies against mouse CLEC14A that also recognise the human protein (67% protein sequence homology). Our proposal uses in vitro assays and animal models to explore the therapeutic potential of these antibodies expressed as chimeric antigen receptors (CARs) on T-cells. CARs combine the specificity of antibodies with the potent cytotoxic and immunomodulatory functions of self-replicating T-cells, thereby potentially augmenting the anti-cancer effects of antibodies. Methods In vitro studies will further characterise the binding of these CLEC14A-specific antibodies using CLEC14A deletion mutants and tissue arrays. CARs generated from these antibodies will be tested for expression and function in T-cells using assays of cytotoxicity, cytokine production and proliferation. We shall then explore the anti-tumour effects of these agents. How the results of this research will be used Given favourable results including evidence of anti-tumour effects, we shall proceed with a clinical trial using these CARs expressed on autologous T-cells. The pharmaceutical industry has already expressed interest in licensing CLEC14A. The CRUK Clinical trials unit (Birmingham) have also expressed an interest to work with us to develop the project to early clinical trials.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Molecular mechanisms of mammalian autophagy
Funder: Cancer Research UK

Abstract: The focus of my laboratory’s research is mammalian macroautophagy, an intracellular degradative pathway mediated by lysosomes. Macroautophagy, which is universally called autophagy, is fundamentally a sequestration process during which cytosolic solutes, proteins, and organelles are engulfed and sequestered into autophagosomes, followed by fusion of the autophagosomes with lysosomes and degradation of the sequestered material. The function of autophagy is to maintain intracellular homeostasis (through removal of damaged cytosolic components) under normal conditions, and to enable survival under stress (through replenishment of amino acids and metabolites). Many of the proteins required for autophagy, first identified in yeast and called Atg (autophagy related) proteins, have now been identified in mammals. However, their molecular function remains largely unknown and it is their molecular function we aim to understand. Importantly, autophagy has been shown to play a role in human diseases including cancer. My laboratory aims to understand the process of autophagosome formation and maturation at a molecular level building upon our identification of three essential mammalian Atg proteins, ULK1, Atg9 and WIPI2, and new regulatory or accessory molecules that my lab has recently identified. Specifically, our studies involve a molecular dissection of 1) the earliest event, autophagosome formation and 2) regulatory mechanisms controlling expansion, and maturation of autophagosomes. Our first aim will focus on ULK1, and the multi-spanning membrane protein Atg9 which responds to activation of ULK1/2. WIPI2 is the main effector of the lipid Phosphatidylinositol 3-Phosphate produced by the class III PtdIns 3-kinase, while WIPI1 appears to be upregulated in melanoma. We are studying the subcellular localization, and interdependence of these Atg proteins. We are also seeking to identify post-translational modifications that activate and allow recruitment of these proteins upon induction of autophagy, including phosphorylation, fatty acid modifications, and ubiquitination. These experiments provide a platform for our second aim, to identify and understand regulatory, or accessory, proteins required for autophagy. We speculate that these molecules regulate the process of autophagy from formation to degradation of content. Candidates have been obtained through our proteomic analysis of proteins interacting with ULK1, Atg9 and WIPI1 and 2, and other candidates have been obtained from a siGenome screen for novel regulatory proteins involved in starvation-induced autophagy and a screen targeting Rab proteins (small GTPases involved in vesicle formation and targeting). Our candidates include ER and Golgi resident proteins, RabGAP TBC proteins, Rab proteins and their associated effectors, and previously uncharacterized proteins.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS
Title: Understanding the causes and mechanisms of cancer invasion and metastasis
Funder: Cancer Research UK

Abstract: The majority of cancer deaths are caused by metastasis; therefore, any therapeutic strategies that reduce or prevent metastasis are likely to have a significant impact on the lives of people with cancer. Our research programme focuses on some of the key steps in the metastatic process. Firstly, we investigate the invasion of cancer cells into surrounding tissue, which is an early step in the metastatic process. This work on cell migration seeks to understand the critical principles of both single and collective cancer cell migration in different matrix geometries, both empirically and theoretically. Intravital imaging is used to study of the causes of cancer cell invasion, including heterogenous cell signalling and interactions with cancer-associated fibroblasts (CAFs). We investigate how CAFs are generated and how they remodel the tumour matrix and thereby promote invasion. We are also expanding our research programme to study later stages in metastasis: our analysis of the cortical actomyosin network suggests that it is critical for effective extravasation and we will devote significant effort into understanding the co-option and function of cancer-associated fibroblasts at secondary sites.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Cell Motility Group
Funder: Cancer Research UK

Abstract: Intracellular pathogens have co-evolved with their hosts to develop multiple mechanisms to hijack many cellular pathways of their unwilling host to facilitate their entry, replication, survival and cell-to-cell spread. Understanding how pathogens take advantage of their host offers the promise of obtaining fundamental insights into basic cellular processes that are frequently deregulated during tumour development. To this end, we are using a variety of quantitative imaging and biochemical approaches to study Vaccinia virus as a model system to understand signalling networks, cytoplasmic transport, cytoskeletal dynamics and cell migration. We are also investigating a number of other topics including the cellular function of Tes, a tumour suppressor that regulates Mena-dependent cell migration as well as mechanisms regulating the formation and function of invadopodia.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Understanding axonal transport and signal integration in health and disease
Funder: Cancer Research UK

Abstract: The future research programme of the MNP Laboratory is based on key results obtained over the past five years. These will be used as a starting point for novel investigations integrating the molecular and cellular analysis of axonal transport and somatic sorting with the study of these processes in vivo. This programme is articulated via the following two fully-integrated parts: 1. Understanding axonal transport and somatic sorting in health and disease. The main goal of this component is to assemble a functional map of the organelles responsible for the axonal transport and sorting of neurotrophin receptor complexes and other physiological cargoes. We aim to determine how the composition of these organelles change during their progression along the axonal transport route and whether their composition varies in neurons with similar topological features but affected by different diseases, such as motor and sensory neurons. We plan to achieve this goal by building on technologies developed in the last five years, such as high-throughput siRNA, differentiation of neurons obtained from mouse embryonic stem cells, human neural stem cells and human induced pluripotent stem cells in 2D and 3D cultures, together with implementation of assays testing somatic sorting and transcytosis using microfluidic devices. 2. Signal integration of multiple growth factor receptor pathways. The main aims of this component is to define the role of Kidins220/ARMS in the localisation of neurotrophin, ephrin and VEGF receptors in neurons and uncover the mechanisms responsible for the integration of these different signalling pathways. We would like to use Kidins220/ARMS as a paradigm for the analysis of the signalling originating from these three classes of growth factor receptors and understand the degree of crosstalk between these signalling streams in neurons and other cell types. Results will be verified in mice lacking Kidins220/ARMS in the CNS and brain vascular system. Furthermore, we aim to clarify the role of Kidins220/ARMS in neurogenesis in both the embryonic and adult brain. The strongest feature of the MNP laboratory is the integration of basic science with disease models providing direct translational potential for human medicine. We believe that only by understanding the basic principles of membrane trafficking and signalling will we be able to uncover the pathological changes responsible for many human disorders, including cancer. These might then be exploited to provide an earlier and more accurate diagnosis, translating into improved pharmacological treatments and more favourable prognosis.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS
Title: CRUKD/12/016: A CR-UK Phase I study of PI3K inhibitor BKM120 in patients with non-small cell lung cancer receiving thoracic radiotherapy
Funder: Cancer Research UK

Abstract: Lung cancer is the most common malignancy in industrialised countries. Non-small cell lung cancer (NSCLC) represents more than 80% of all lung tumours, with approximately 35% of patients presenting with locally advanced disease. Despite the significant gains achieved with combination chemo-radiotherapy treatment, local tumour failure rates remain as high as 69%. Improving the efficacy of both radiotherapy and chemotherapy treatment is an important goal in improving the outcomes for these patients. We have previously demonstrated that altering oncogenic signalling (such as the PI3K pathway) can render tumour cells more sensitive to radiation without altering the sensitivity of normal tissue cells. In addition to altering intrinsic radiosensitivity we have recently found that treatment with BKM120 (a PI3K inhibitor) causes a reduction in tumour hypoxia, an increase in tumour perfusion, and normalisation of the tumour vasculature. If BKM120 was able to induce these changes in the tumour microenvironment in human tumours, it is likely that it would significantly increase the effectiveness of treatments such as radiotherapy and chemotherapy. We therefore propose to conduct a phase I study of BKM120 in patients with NSCLC receiving thoracic radiotherapy. The study will be a single-centre, open-label,3+3 cohort, dose escalation phase I study of BKM120 in combination with radiotherapy in patients receiving palliative thoracic radiotherapy. In addition to assessing safety and identifying the maximum tolerated dose (MTD), we will also assess changes in tumour perfusion and hypoxia by performing perfusion CT and F-MISO PET scans respectively. This imaging will be used to assess whether BKM120 induces the same changes in the microenvironment of human tumours as it does in in vivo models.


Research activity codes: 6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Cancer Research UK Centre for Tobacco Control Research (CTCR)
Funder: Cancer Research UK

Abstract: BACKGROUND Established in 1999, the Cancer Research UK Centre for Tobacco Control Research (CTCR) is the first academic research unit in Europe dedicated to tobacco control. CTCR has carried out a combination of Core Research and Additionally Funded projects. The Core Research Projects comprise two complementary projects: the Youth Tobacco Policy Survey (YTPS) and an Audit of Tobacco Marketing Activities. They use different research methodologies, but both are concerned with the longitudinal surveillance of the tobacco industry’s marketing. The YTPS is a quantitative tracking study of young people, using a repeat cross-sectional survey design, selecting a new sample of 11 to 16 year olds across the UK at each survey wave. The Audit is a smaller scale exercise, monitoring the trade press and conducting observations within retail outlets, to uncover new industry marketing activities. AIMS The YTPS aims to monitor young people’s awareness and involvement with tobacco marketing, alongside their smoking knowledge, attitudes and behaviour before, during and after implementation of tobacco control policies. The Audit aims to monitor and record marketing activities undertaken, by the tobacco industry, during and after the implementation of new tobacco control policies. METHOD The YTPS, from 1999 to 2011, has taken detailed measures on response to tobacco marketing across a time period of considerable change. We propose a further wave of the YTPS in 2014 to provide longer term monitoring of existing policies and enable us to monitor short term response to the first phase of the PoS regulation whereby tobacco products in large stores will be put out of sight from April 2012. It is proposed that the Audit continues over the next 3 years, focussing on remaining areas of marketing, namely PoS and packaging. HOW THE RESULTS WILL BE USED The Centre has made important contributions to public policy, particularly in relation to plain packaging and Point of Sale. Recent and forthcoming developments in both tobacco marketing (such as packaging innovation and PoS displays) and public policy (such as pictorial warnings and the forthcoming PoS display ban) mean that the YTPS and Audit, for at least the next five years, will continue to be instrumental in what remains a vital policy arena and they will continue to inform public policy.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: CANCER AND NEOPLASMS
Title: Improving the detection of localised prostate cancer by combining longitudinal reference ranges, clinical prediction rules and genetic information
Funder: Cancer Research UK

Abstract: Prostate cancer is an increasingly significant public health issue. Many prostatic tumours remain asymptomatic, are not life-threatening, and there is no definitive method to distinguish ‘high risk’ tumours despite much research. Initial results of on-going randomised controlled trials evaluating the long-term effectiveness of prostate-specific antigen (PSA) based testing for prostate cancer indicate uncertainty over whether the potential benefits outweigh the harms An important limitation of PSA testing in detecting prostate cancer is that it has poor sensitivity and specificity: many cancers are missed whilst other men undergo unnecessary invasive biopsies. This proposal develops optimal PSA thresholds for initial screening, and also recommendations for biopsy in initially PSA test-negative men. It will contribute to risk stratification and individual management of men undergoing PSA testing by: 1. building on existing age-related PSA thresholds to develop a unique method based on longitudinal reference ranges to improve the performance of PSA testing; 2. developing novel prediction rules for use post-PSA or biopsy to predict clinically important prostate cancer in men who are initially given a ‘negative’ test result and hence false reassurance. This is original work as most existing prediction rules are for use prior to PSA testing or biopsy, i.e. to predict biopsy outcome, or to predict tumour characteristics and prognosis, not to predict false negatives as I propose; 3. investigating the impact of the genetic contribution to PSA levels on PSA testing, which we believe to be innovative. Analyses will be informed by a systematic review of risk factors for subsequently developing prostate cancer in men who are initially deemed cancer-free, and a review of methods for adjusting for verification bias caused by incomplete ascertainment of true disease status. Data are from a nested population-based case-control study, within the Prostate Testing for Cancer and Treatment (ProtecT) study, including 25049 men with a PSA result (3109 cases), 2000 men with initially low PSA (140 of whom subsequently develop prostate cancer), 1130 men with raised PSA and negative biopsy (130 of whom subsequently develop prostate cancer), and 2985 men with genome-wide data (1820 cases). It uses longitudinal reference ranges, PSA velocity, clinical and non-clinical risk factors, and genetic variation in PSA levels as a basis for decision aids to be used at different stages of the diagnostic process. Achieving more accurate detection of clinically significant prostate cancer will reduce the need for unnecessary biopsies and allow targeted follow-up of men with initially negative results.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: The role of the BRCA1 N-terminus in cancer development.
Funder: Cancer Research UK

Abstract: Amino acid changes (missense) are potentially powerful tools to aid the molecular understanding of protein function. In this context the group has a particular interest in BRCA1 missense changes identified in patients’ with a personal or family history of disease. In the past using protein: protein interactions of the BRCA1 N-terminus has suggested BRCA1 activity as a ligase is relevant to tumour predisposition. Now These studies are widening using the AFFECT collection of tumour samples from individuals with BRCA1 gene changes predicted to be represented at the protein level.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: MRI measurement of tumour spatial heterogeneity: pharmacological biomarker discovery and assay development
Funder: Cancer Research UK

Abstract: Background Imaging biomarkers have yet to reach their full potential as tools in anti-cancer drug development, despite growing use and extensive methodological research. One important reason for this is that conventional radiological analyses are often too simplistic. Average parameter values (e.g. of perfusion) are used to describe tumours that have substantial spatial heterogeneity in angiogenesis, hypoxia, cell death and other cancer hallmarks. There is emerging evidence that analysing individual regions within tumours provides far greater insight into therapy response and resistance to therapies (cytotoxics, radiotherapy and targeted agents) given either alone or in combination regimens. However, these analysis techniques are complex and application has been limited by practical and technical considerations. Here, we aim to address these issues. Aims 1. To determine if MRI can prospectively identify tumour regions that show early response or resistance to chemotherapy, radiotherapy and anti-vascular therapy. 2. To characterise the underlying histopathology and vascular geometry of image-defined tumour tissue associated with beneficial and poor response. 3. To apply these methods to clinical data Methods Pre-clinical MRI at 7T will acquire dynamic contrast-enhanced (DCE-MRI), oxygen-enhanced (OE-MRI) and diffusion-weighted (DWI) images along with anatomical data in various subcutaneous and orthotopic models of glioma. Methods will be developed to define sub-regions within tumours that have common signal profiles using data-driven principal components analyses. The volume, the cluster profile based on DCE-MRI, OE-MRI, DWI, T2 and the vascular geometry (measured by fractal analysis) will be determined for each sub-region. This builds on published techniques, developed in-house. Initial experiments will determine assay accuracy and precision using a) spatial correlation of imaging biomarker and histopathology and b) micro-CT measurements of vessel geometry. Next, the relationship between the pharmacodynamic imaging biomarkers and anti-tumour efficacy will be evaluated for following temozolomide, fractionated radiotherapy and anti-VEGF therapy. Relationships between imaging biomarkers and circulating levels of pro-angiogenic growth factors will also be investigated. Finally, the methods will be applied to a two-centre clinical study of high grade glioma. How the results of this research will be used This research will develop methods to define and quantify responding and resistant regions within tumours. It will inform how different therapies induce early pharmacodynamic effects within tumour sub-regions that are temporally and spatially separated from one another. This has potential to improve use of imaging biomarkers in drug development, particularly in studies of combination therapies.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.4 POPULATION SCREENING
Health categories: CANCER AND NEOPLASMS