NIHRDataInsights/HRCSData huggingface dataset:
Title: Edinburgh Cancer Research UK Centre (Clinical Training Account)
Funder: Cancer Research UK

Abstract: Clinical Training at the Edinburgh Cancer Research UK Centre: The Edinburgh Cancer Research UK Centre brings together scientists, doctors and nurses from across the city. It harnesses the breadth of research expertise in Edinburgh, developing new ideas from the laboratory into improvements in treatment that will benefit patients in the city and beyond. The Centre is a partnership between Cancer Research UK, the University of Edinburgh and NHS Lothian, which links state-of-the-art cancer research to the best possible patient care. Researchers at the Edinburgh Cancer Research UK Centre focus on bowel, breast and ovarian cancers, but will also develop new research programs into other common cancers. They study the genetics and biology of cancer, as well as researching and devising new ways to treat the disease. Scientists at the Centre are particularly interested in understanding how cancer spreads and becomes resistant to drugs. They aim to develop new imaging techniques to monitor cancer spread and, crucially, to find ways to slow or stop the process. This research will help to improve treatment for patients with advanced cancer. Researchers in Edinburgh are also uncovering the genetic changes involved in bowel cancer, making it possible to identify those people at greatest risk of the disease and offer them tailored advice, screening and treatment. Scientists and doctors will work in partnership to identify biomarkers that can be used to predict an individual’s cancer risk or determine the best treatment. And unique imaging approaches will underpin efforts to detect cancer earlier and to monitor the effects of treatment.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: Cambridge Cancer Research UK Centre (Clinical Training Account)
Funder: Cancer Research UK

Abstract: Clinical Training at the Cambridge Cancer Centre: The launch of the Cambridge Cancer Centre puts Cambridge at the forefront of cancer research, bringing benefits to patients in the South East. The Centre is a major new research collaboration which exists though a unique partnership between Cancer Research UK, Cambridge University, Cambridge University Hospitals NHS Foundation Trust and Cambridge University Health Partners. The Centre will be funded by Cancer Research UK to the tune of £2 million a year and joins our specialist network of cancer Centres across the UK. Researchers at the Centre will concentrate on understanding the biology of how and why cancers develop, particularly breast, lung, ovarian, pancreatic, oesophageal, blood and prostate cancers. Scientists will also focus on developing new ways to detect cancer though cutting-edge imaging techniques.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: Mothers Learning About Second-hand Smoking (MLASS)- Feasibility Study
Funder: Cancer Research UK

Abstract: Background Exposure to second-hand smoke(SHS) during pregnancy and early infancy leads to low birth weight and childhood illnesses. 50% of all newborns in the UK are exposed to tobacco smoke due to maternal smoking or contact with SHS. The evidence to support specific measures to implement smoking restrictions and reduce SHS exposure at home is limited. Our research team is currently conducting studies evaluating similar interventions in other settings. Objectives In this application, our aim is to adapt 'Smoke Free Homes'(SFH) for antenatal and postnatal healthcare settings and test its feasibility. We will integrate SFH within the broader smoking cessation advice service currently provided to women during pregnancy and after birth. We plan to conduct a before-and-after study of the adapted SFH intervention to i) test its fidelity, appropriateness and acceptability; ii) investigate the key constraints and drivers in delivering SFH iii)optimise parameters (e.g. recruitment, outcomes measurements) to strengthen the design of a future pilot trial. Methods The SFH intervention is essentially designed to help women learn about the hazards of SHS, evaluate their own smoking behaviour, and empower them to negotiate smoking restrictions at home. An expert panel will identify the relevant components of SFH & adaptations needed; and the optimal method(s) for delivering and integrating it within the broader smoking cessation advice given to women during pregnancy and after delivery. We will work with a group of 12 midwifes and health visitors to develop a tailored protocol and to train them to deliver SFH. In a quasi-experimental mixed method study, we will recruit 150 pregnant women (through midwives) and 150 women just after birth (and their newborns) (through health visitors). The intervention will be delivered over six weeks. We will measure salivary cotinine levels to assess the level of exposure to SHS in all women before and after the intervention. An additional urinary cotinine sample will also be collected in the newborns. A structured questionnaire will be used to assess the level of smoking restrictions at home. FGD with mothers and health professionals will investigate the key constraints and drivers in the delivery & integration into routine practice for SFH. Output The output from this study will be a standardised acceptable, feasible and appropriate intervention to protect mothers and babies from SHS at home, capable of integration into routine practice; and information that can be used to inform a future evaluation of its effectiveness.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: CANCER AND NEOPLASMS
Title: Cardiff Cancer Research UK Centre (Clinical Training Account)
Funder: Cancer Research UK

Abstract: Clinical training associated with: The launch of the Cardiff Cancer Research UK Centre will help set the pace for progress in genetics and cancer biomarkers. Part of Cancer Research UK's national network of virtual cancer research centres, the Cardiff Centre aims to be a world leader in developing treatments tailored to individual cancer patients based on understanding the biology of the disease and how it varies among patients. Researchers at the Centre will focus on the biology and treatment of bowel, breast and urological cancers as well as leukaemia. Working with the Wales Office of Research and Development for Health and Social Care (WORD), they will also work on better understanding how to prevent cancer and detect the disease earlier. Cancer Research UK is looking to increase its contribution to research in Cardiff by spending an extra ú2 million over three years - this boost will enable Cardiff to continue leading the way on cancer research in Wales. The Centre will also continue Cardiff's excellent record of training the next generation of clinical and non-clinical researchers - aiming to expand the existing four-year PhD programme together with Cardiff University. The Cardiff Centre is a partnership between Velindre NHS Trust, Cardiff and Vale NHS Trust, Cardiff University and Cancer Research UK. Grants support a variety of training projects - where available coding is done on the basis of these individual pieces of research.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: Mechanistic studies of angiogenesis
Funder: Cancer Research UK

Abstract: BACKGROUND TO THE PROPOSAL:&lt;br/&gt;The growth of new blood vessels or angiogenesis is a complex process involving the interplay of many genes of which we have identified several new ones. The genes are roundabout4 (Robo4), endothelial cell specific chemotaxis regulator (ECSCR), C-type Lectin 14A (CLEC14A) and rhomboid family member 2 (RHBDF2). This proposal aims to further characterise the role of these genes in angiogenesis and vascular development.&lt;br/&gt;&lt;br/&gt;RELEVANCE TO CANCER:&lt;br/&gt;Disruption of the existing or developing tumour vasculature offers exciting opportunities for therapeutic intervention in cancer. The approach has been shown to be widely applicable to all solid tumours. The complexity of angiogenesis provides promising opportunities for cancer therapy in view of the numerous molecular targets that can be used to disrupt the process. Our interest lies in understanding the molecular basis of tumour angiogenesis that can lead to new therapeutic approaches involving the vasculature. &lt;br/&gt;&lt;br/&gt;SPECIFIC AIMS OF THE RESEARCH:&lt;br/&gt;We hypothesise that the novel genes we have identified play a functional role in angiogenesis and vascular development. The aim of the programme is to provide a wide functional characterisation for these genes. We will also identify the signalling pathways used by these genes and identify the conditions under which they are activated.&lt;br/&gt;&lt;br/&gt;OUTLINE PLAN OF RESEARCH:&lt;br/&gt;The proposed research aims to characterise the role of the listed new genes in angiogenesis. This will be carried out by a combination of in vitro molecular cell biology and in vivo studies in zebrafish and mouse models. &lt;br/&gt;&lt;br/&gt;To define the function of a new gene, we will either increase or decrease expression and document the effect in in vitro and in vivo models pertinent to angiogenesis. In vivo studies will employ assays of cell behaviour such as filopodia formation, migration and tube formation. In vivo studies will employ morpholino knockdown in zebrafish and complete and conditional knockout in mice. &lt;br/&gt;&lt;br/&gt;Concomitant with delineation of function, we will characterise downstream signalling pathways for the new genes and their activation. This will involve standard molecular biology approaches including yeast 2-hybrid and pull down assays combined with domain and point mutagenesis. Interactions will be confirmed using techniques such as directed yeast 2-hybrid and microscopy using live imaging and FRET.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Role of distinct macrophage subpopulations in tumour responses to, and recovery after, conventional anti-cancer therapies
Funder: Cancer Research UK

Abstract: Tumour-associated macrophages (TAMs) have been shown in various transgenic murine tumour models to drive tumour angiogenesis and metastasis. Moreover, two particular subsets of TAMs have now been identified that are thought to be particularly aggressive in tumours – those that experience hypoxia within the tumour microenvironment (and upregulate the transcription factors, HIFs 1 and 2, along with a host of HIF-driven, tumour-promoting factors) and another that expresses the angiopoietin receptor, Tie2. Evidence has emerged recently for these cells being recruited into tumours after their treatment with such conventional anti-cancer therapies as chemotherapy, irradiation and the vascular damaging agent, combretastatin –A-4-P (CA4P). Our data show that these cells are then exposed to various signals that activate their potent, tumour-promoting, reparative functions - and that this then aids tumour revascularisation and post-therapy recovery. However, a conclusive study of their role in tumour responses to, and recovery from, therapy has yet to be conducted. Here we propose to use a number of powerful, highly informative model systems to investigate the role of these macrophage subsets in the regrowth/recurrence of tumours following their treatment with the anti-cancer treatments listed above. First, we will genetically knockdown HIF and Tie2-expressing TAMs prior to treatment of tumours with these forms of therapy. This will outline their exact role in both the initial responses of tumours to these treatments and their regrowth/recurrence afterwards. We will then investigate the mechanisms recruiting these cells to treated tumours and those that activate their reparative, tumour-promoting functions in these sites. Finally, we will identify ways of targeting/inactivating these cells so that their antagonising effect on therapeutic outcome can be removed and the efficacy of these treatment regimens markedly improved.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Understanding the control of cellular DNA damage responses and how defects in these pathways contribute to human disease
Funder: Cancer Research UK

Abstract: Background_x000D_ Cellular pathways that maintain genome stability are collectively termed the DNA damage response (Ddr) and comprise those that regulate DNA damage detection, cell cycle checkpoint activation, DNA repair and apoptosis. Whilst much is known about how phosphorylation mediated by the ATM/ATR protein kinases functions to coordinate cellular signals from the DNA damage to effector proteins that mediate activation of checkpoints and repair of the damaged DNA, the role of ubiquitylation in this regulation is only just becoming clear. Although it has been demonstrated the ubiquitin-dependent Ddr (Ub-Ddr) is involved in recruiting repair proteins to the sites of damage through its ability to modulate chromatin structure, the underlying mechanisms remain elusive._x000D_ _x000D_ Relevance to Cancer_x000D_ Deficient repair of DNA damage is the most frequent underlying cause of genetic instability and probably represents the most important event that contributes to, and in some cases initiates the development of cancer. It is therefore important to understand both the normal cellular response to genotoxic stress and how this is subverted in cancer cells._x000D_ _x000D_ Aims of Research_x000D_ The outlined research aims to investigate the mechanisms by which the Ub-Ddr regulates the cellular response to genotoxic damage and how defects in the Ddr contribute to human disease associated with a cancer predisposition._x000D_ _x000D_ Plan of Research_x000D_ This proposal aims to dissect the role of the ubiquitin system in regulation DNA repair by:_x000D_ _x000D_ - Determining the role of deubiquitylating enzymes in regulating Rad18-dependent DNA repair processes._x000D_ - Investigating how a novel MDC1-associated E3 ubiquitin ligase regulates DNA damage-induced checkpoint activation and mitotic exit._x000D_ - Understanding the selective involvement of ubiquitylation/SUMOylation in the regulation of RNF168-dependent recruitment of BRCA1 to sites of DNA damage._x000D_ - Identifying novel DNA repair genes mutated in human genome instability syndromes associated with tumour predisposition by total genome sequencing._x000D_


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Inflammatory Cytokines and Oncolytic Adenoviruses in Ovarian Cancer
Funder: Cancer Research UK

Abstract: Background:_x000D_ Ovarian cancer kills nearly 5000 women each year in the UK. Standard treatment is surgery and chemotherapy but most patients develop treatment resistance and long-term survival remains poor. New treatments are urgently needed. Oncolytic adenoviral gene therapy has repeatedly demonstrated potential in preclinical cancer models, hundreds of patients have received a variety of agents in early phase clinical trials and one virus has been licensed in China. A consistent feature of adenoviral gene therapy trials has been cytokine release causing systemic toxicity, including one highly publicised patient death. This toxicity has prevented further clinical investigation of many promising agents. Despite this, the mechanisms by which viruses activate innate immunity remain poorly understood, although ß3 integrins are thought to play a role. Understanding, and ultimately manipulating, this inflammatory response is essential for further clinical development of these promising agents. _x000D_ Ovarian cancer produces ascites rich in macrophages and tumour-promoting cytokines. We have shown that inhibition of the cytokine TNF-a improves adenoviral efficacy, but how intraperitoneal (IP) adenoviruses behave in the inflammatory ascites of ovarian cancer is largely unknown. This project will investigate adenovirus-induced acute inflammation in ovarian cancer. Understanding this will enable me to devise and test novel therapeutic combinations of gene therapy and cytokine manipulation, which should facilitate the safe delivery of maximally effective oncolytic adenoviruses to patients. _x000D_ Aims: _x000D_ 1. To clarify the role of peritoneal macrophages and ß3 integrins in the inflammatory response to IP adenovirus. _x000D_ 2. To evaluate the influence of peritoneal tumour-macrophage interactions in the cytokine response._x000D_ 3. To test combinations of oncolytic adenoviruses with cytokine and integrin inhibition._x000D_ Methods:_x000D_ 1: Adenoviral activity and cytokine release will be characterised in ß3-/- and ß3+/+ tissue-specific macrophages in the peritoneum, liver and spleen. _x000D_ 2: Virus-induced cytokine release will be evaluated in co-cultured primary peritoneal macrophages and ascitic tumour cells from our patients. _x000D_ 3: RNAi and cytokine/integrin antagonists will be tested in combination with adenovirus in the primary ovarian cancer co-cultures developed in aim 2. Oncolysis, cytokine release and toxicity will be determined._x000D_ Scientific and Medical Opportunities:_x000D_ Attempts to improve ovarian cancer treatment using new chemotherapy regimes and targeted agents have made little impact, whilst promising adenoviral therapies have been limited by inflammatory side effects. This proposal aims to unravel the inflammatory response to IP adenoviruses and test combined adenoviral and cytokine manipulation strategies as a prelude to clinical trials in ovarian cancer.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Characterising long range interactions between breast cancer risk loci and their target genes
Funder: Cancer Research UK

Abstract: _x000D_ Eighteen breast cancer susceptibility loci have recently been identified through genome-wide association (GWA) studies. For six of these the most strongly associated tagging SNP maps to a linkage disequilibrium (LD) block lacking identifiable genes or predicted transcripts. We hypothesise that these LD blocks contain long-range regulatory elements that target genes associated with breast cancer risk. Chromosome conformation capture (3C) is a powerful method for assessing whether a region of interest (the constant fragment) interacts with pre-specified target genomic fragments but only interactions considered a priori will be detected. HiC allows the unbiased detection of long-range interactions. To date, however, the resolution (1Mb) has prohibited the characterisation of specific interactions ._x000D_ _x000D_ To combine the unbiased coverage of HiC with an additional sequence capture step to provide high resolution coverage of breast cancer risk loci mapping to “gene deserts”. By combining these data with conventional fine-mapping, in silico prediction of regulatory function and functional assays we aim, specifically, to determine the mechanism underlying recently identified breast cancer susceptibility loci that map to 1p11.2, 2q35, 9q31.2, 10q223 and 11q13.3._x000D_ _x000D_ Fine-mapping of breast cancer risk loci is currently underway as part of the Collaborative Oncological Gene-environment Study (COGS). We will subject 4.1 Mb comprising the fine mapping regions for five “gene deserts” to HiC followed by sequence capture. A positive control region comprising 1,551 kb mapping to 8q24.21 for which interactions between a constant fragment (annotated by rs13281615) and MYC have previously been demonstrated using 3C will also be included as a positive control. HiC libraries will be made from four cell lines (two breast cancer cell lines, a non tumourigenic breast epithelial line and a lung fibroblast cell line), ditags mapping to any of the target regions will be captured and sequenced using next generation sequencing. Validation and quantitation will be by enhanced ChIP 4C and/or 3C, regions of interaction will be prioritised for functional assays and the characterisation of novel pathways._x000D_ _x000D_ GWA studies have been extremely successful in identifying new breast cancer risk loci. The underlying causal variants and the mechanisms by which they affect breast cancer risk, however, remain largely unknown. Understanding these mechanisms will provide insight into breast cancer aetiology and may identify new therapeutic targets. By adapting current methodologies we will determine the targets of five loci mapping to gene poor regions of the genome. _x000D_ _x000D_


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Tumour suppression and ageing - obligate counterparts or discrete and separable p53 functions?
Funder: Cancer Research UK

Abstract: p53 plays a critical role in vertebrate tumour suppression as is evident from its functional disruption in most human cancers. p53 is also implicated in ageing through the gradual erosion of stem and progenitor cells, and plays a pivotal role in the pathological response to acute DNA damage, for example that induced by chemo- and radiotherapy. Life without destructive p53 may therefore, in principle, confer many benefits to vertebrates, including enhanced tissue regenerative capacity, increased life-span and radio-resistance. However, such benefits would be more than offset by the high susceptibility to cancer development that p53 loss engenders, precluding any geriatric benefit._x000D_ _x000D_ By uncoupling the destructive effects of p53 in normal tissue from the beneficial effects of p53 in incipient and established tumours it may be possible to improve on our tumour-suppressor legacy. We aim to achieve this in mice by placing total p53 expression under control of the exquisitely oncogene-sensitive ARF promoter that limits downstream-gene expression to incipient tumour cells. By redirecting p53 expression away from normal cells to incipient tumour cells it may be possible to eliminate the destructive and pro-ageing activities of p53 whilst maintaining all of the tumour protection. In Aim 1 we will determine the susceptibility of p53-/-;ARF+/p53 mice to spontaneous and radiation-induced tumours, as well as investigate their resistance to tumour development when crossed to tumour-prone Myc transgenic mice. Notably, p53-/-;ARF+/p53 mice are heterozygous for the transgene and possess a single copy each of ARF and p53; they are therefore unlikely to survive tumour-free long enough to ascertain the potential geriatric benefits of redirecting p53 expression from normal to tumour cells. Thus, in Aim 2 it will be necessary to increase the dosage of both ARF and p53 in the mice, so that at the very least they contain two copies of each gene. We will then determine the impact of such genetic engineering on organismal longevity and vitality._x000D_ _x000D_ In summary, we will challenge the generally held tenet that the damaging effects of p53 in our normal tissues are the unfortunate but inescapable consequence of the pivotal role of p53 in tumour suppression. This research is critical to our fundamental understanding of how one of the most eminent of tumour suppressors exerts its activity both in preventing cancer and influencing ageing. Discovering the key to a longer and healthier life is an ongoing enterprise to which this research will undoubtedly contribute.


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