NIHRDataInsights/HRCSData huggingface dataset:
Title: A biomarker approach to improving population outcomes for renal tumours of childhood
Funder: Cancer Research UK

Abstract: Background Wilms tumour (WT, nephroblastoma) is the commonest paediatric kidney cancer, affecting 1 in 10,000 children. Whilst most (~85%) can expect to be long term survivors, approximately half of all Wilms tumour patients still receive doxorubicin or more intensive chemotherapy and/or radiotherapy either upfront or at relapse, with a predictable risk of long term health problems that include cardiac failure and second cancers. This project aims to address the challenge of balancing risk of relapse against the risk of permanent harm from front line therapy for Wilms tumour. Aims This project aims to achieve this through testing the addition of molecular biomarkers, (principally gain of chromosome 1q and loss of 1p/16q), into a revised approach to risk stratification of first line therapy for each child. This requires prospective testing in tumours characterised more accurately for other potential risk factors, such as the residual volume of the blastemal component of WT after pre-operative chemotherapy. Methods Samples will be analysed with a custom multiplex ligation dependent probe amplification (MLPA) assay measuring copy number status of 1q, 1p, 16q, TP53, WT1, WTX, MYCN and FBXW7. MLPA will be carried out on multiple spatially distinct samples (typically 3 per case) to allow assessment of spatial intra-tumour heterogeneity as a potential confounding factor (if multiple frozen specimens are not available, DNA from FFPE blocks may be substituted). Each tumour will be profiled with an Illumina CytoSNP array at the UCL Genomics core facility, according to their standard SOPs. Copy number aberrations and allelic imbalances will be detected using OncoSNP (http://www.well.ox.ac.uk/ogc/arrays-analysis-tools). Additionally retrospective anaplastic WT samples sourced from SIOP 2001 collections will be analysed for TP53 mutational status by sequencing and for 17p copy number by MLPA. Finally we will determine the mutation status of the known WT genes WT1, CTNNB1, WTX and TP53 for all the tumours in the study. How the results will be used This project will use the results achieved to determine whether known molecular biomarkers for ‘high risk’ Wilms tumour should be introduced into risk stratification for Wilms tumour treated by pre-operative chemotherapy in future clinical trials of the SIOP Renal Tumours Study Group. The existing translational research programme in our laboratory, incl' methylation, expression profiling, exome sequencing and proteomics will as far as possible use an overlapping sample set with the current study, complementing the analyses described here and adding significant value to this proposal


Research activity codes: 4.4 POPULATION SCREENING
Health categories: CANCER AND NEOPLASMS
Title: Oxford Cancer Research UK Centre (Bridge Funding)
Funder: Cancer Research UK

Abstract: The Oxford Cancer Research Centre builds on the city's long history of groundbreaking scientific research, bringing together world-class scientists, doctors, nurses and radiotherapists to speed progress in beating cancer. The Centre is a partnership between Cancer Research UK, the University of Oxford and the Oxford University Hospitals NHS Trust. Researchers at the Centre are studying many different types of cancer. In particular, they are focusing on breast, skin, gastrointestinal and urological cancers, which covers bladder, prostate, kidney and testicular cancers. Radiotherapy research is a particular strength of the Oxford Centre, spearheaded by scientists at the Gray Institute for Radiation Oncology and Biology - created to be the largest group of doctors and scientists specialising in radiotherapy research in the country. Another key strength is research into the genetic and lifestyle factors that increase the risk of cancer, building on decades of experience in this area. Oxford scientists first showed that smoking causes cancer more than 40 years ago, and researchers in the city have made many more major discoveries in understanding the causes of the disease. Other areas of expertise at the Oxford centre include research into the faulty genes and molecules that lie at the heart of cancer. Researchers will also be investigating ways to improve cancer diagnosis, as well as searching for 'biomarkers' to help doctors predict the effectiveness of cancer treatment. A major aim of the Oxford centre is to bring benefits to cancer patients faster than ever before. To achieve this, the University has established a new Department of Oncology next door to the new Oxford Cancer Centre at the Churchill hospital in the city. This will help to build stronger links between researchers working in the lab and doctors caring for cancer patients, speeding up the creation of new treatments. Finally, the centre is designed to be part of the community in and around Oxford. Working with our Local Engagement and Development team, researchers will engage with local people to raise awareness of cancer and the world-class research on their doorstep.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: CANCER AND NEOPLASMS
Title: Identifying demographic and psychosocial predictors of flexible sigmoidoscopy screening intentions and uptake
Funder: Cancer Research UK

Abstract: Background Flexible Sigmoidoscopy screening has the potential to significantly reduce the mortality and incidence of colorectal cancer. However, there is concern that low uptake will undermine these benefits. Aims The proposed research will be the first to analyse uptake in the new FS screening programme. The first study will examine demographic and social inequalities. The second will compare attenders and non-attenders in terms of attitudes and beliefs and whether there are different sub-groups of non-attenders reporting specific barriers. Lastly, we will explore prospective predictors of attendance with an emphasis on trying to explain the social gradient in uptake. Methods This project will use three approaches to investigating predictors of uptake and mediators of inequalities in uptake. Study 1 will use an area-level analysis to examine demographic predictors of FS uptake and ‘benchmark’ social inequalities in participation. The study will also offer insights into the prevalence and demographic characteristics of various sub-types of non-attenders (e.g. people who do not respond to the invitation vs. people who do not attend a confirmed appointment). Study 2 will be a primary-care based survey of approximately 1200 individuals who have received an invitation for FS screening. We will also conduct an embedded qualitative study which will allocate a sub-sample of non-attenders to a telephone interview. The main objective will be to compare attitudes and beliefs among attenders and non-attenders. Secondly, we will use responses by non-attenders to a combination of attitude and knowledge items to classify them according to a taxonomy of non-attenders. Study 3 will be a prospective survey of psychosocial and socio-cognitive predictors of intentions to participate in FS screening in a sample of 1800 adults who will be followed up to record their actual participation in the FS programme. One of the key objectives will be to explore the role of psychosocial predictors as mediators of demographic differences in intention and uptake. How the results will be used This proposal has been developed with screening centres as part of an on-going collaboration to optimise the FS programme and increase attendance. The continued involvement of screening practitioners will provide an applied background against which to develop theory-based interventions to increase uptake of FS screening.


Research activity codes: 4.3 INFLUENCES AND IMPACT
Health categories: CANCER AND NEOPLASMS
Title: Simulation of next generation cell-level force measurements in angiogenesis
Funder: Cancer Research UK

Abstract: We have reached an exciting time in the field of vascular patterning as a number of previously disparate pieces of the jigsaw are slowly beginning to interlock and shed light on the underlying principles of angiogenesis. Pivotal in this progress has been the ability to rapidly iterate between experiment and simulation to refine predictions and experimental design in order to efficiently isolate and interrogate phenomena of interest. Recent results have elucidated the important role of the physical forces that are present at the cellular and sub-cellular level. As the next generation of experiments to test these phenomena are being designed and are due to come online in the coming months, we plan to develop a complementary computational model as an extension of the previous generation of model (Bentley, K., Gerhardt, H. and Bates, P. A. (2008) Agent-based simulation of notch mediated tip cell selection in angiogenic sprout initialisation. Journal of Theoretical Biology, 250(1):25-36.). The tight integration between the predictive model and experimentation will allow us to rapidly refine and develop our investigative framework. The final computational code will be modular and well-documented, in order to make it as widely applicable as possible, in the Vascular Biology Laboratory and other labs.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: CANCER AND NEOPLASMS
Title: Why are girls from Black and Asian minority ethnic backgrounds less likely to receive the human papillomavirus (HPV) vaccine? Developing and testing a complex psychological intervention to increase informed uptake
Funder: Cancer Research UK

Abstract: Background Since 2008 the HPV vaccine to prevent cervical cancer has been offered to 12-13 year old girls. The 3-dose schedule is delivered almost exclusively in schools. Uptake has been good, but lower among some ethnic minority groups. Research has not examined this disparity. Methods This Fellowship will follow Medical Research Council guidelines to develop a theory- and evidence-informed complex intervention to increase uptake of the HPV vaccine among girls from Black and Asian minority ethnic (BAME) backgrounds and conduct a feasibility study. It comprises three studies: 1) Interviews with parents of daughters from BAME backgrounds who have received the vaccine and parents from BAME and non-BAME backgrounds who have not done so. The interviews will explore parents’ reasons for their daughters’ immunisation status, taking a multifaceted approach to ethnicity. 2) I will use barriers to vaccination identified in Study 1 and existing research to develop a leaflet targeting parents of daughters from BAME backgrounds who are due to be invited to receive the HPV vaccine imminently, with the aim of increasing informed uptake. The leaflet content will be based on relevant theory and will include corresponding efficacious behaviour-change techniques. I will discuss drafts of the leaflet with three stakeholder groups. 3) Where Study 2 will be an application of theory, Study 3 will provide preliminary evidence of the utility of these theories and behaviour-change techniques using a feasibility study to inform the decision to conduct a randomised controlled trial (RCT). This study will allow me to estimate the proportion of the two trial arms to initiate the vaccine series (to calculate the required sample size for a future trial). Response rates, willingness to participate, availability/completeness of the RCT primary outcome (initiation of the vaccination series) will be examined. The feasibility study will provide proof-of-concept evidence for the intervention and mechanisms behind any effect. How the results will be used The aim of the intervention is to reduce inequalities in HPV vaccination uptake, which could reduce inequalities in cancer outcomes. Ultimately, immunisation teams and Cancer Research UK may use the intervention routinely. Results will be presented in peer-reviewed journals and at conferences. This Fellowship signifies a gear change in my career trajectory. I will increase my subject expertise and independently implement skills acquired in post-doctoral positions. I will foster collaborations and gain leadership skills to enable me to support other researchers.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: CANCER AND NEOPLASMS
Title: Stratified medicine: methods for evaluating predictive biomarkers for treatment of cancer
Funder: Cancer Research UK

Abstract: Background Stratified medicine aims to tailor treatment decisions to individual patients typically using molecular information such as genetic mutations, gene expression or protein expression to predict treatment benefit (predictive biomarkers). Research suggests that lack of success in identifying predictive biomarkers for use in clinical practice can be attributed to poor methodology. The potential impact of stratified medicine to benefit patients is considerable but successful implementation into clinical practice is dependent on sound research methodology. Aims The overall aim of this project is to improve stratified medicine research by establishing a methodological framework that maximizes the opportunity to identify genuine predictive biomarkers that will guide optimal treatment for cancer patients and thereby improve their health outcomes. Methods Our overall objective is to identify and evaluate research methodology for assessing predictive biomarkers, considering scientific, statistical and logistical issues, in order to fully understand the strength of claims made in this area of cancer research. Focus will be on (i) the consistency and validity of measurement from the biomarker test being evaluated, (ii) appropriateness of the trial design used in evaluation and (iii) validity, generalisability and relevance of the results for clinical practice. A series of work packages will address our four key objectives as follows: (1) To identify the research methods that are being used in practice to establish predictive biomarkers for stratified medicine. (2) To identify research methodology and frameworks proposed in the methodological literature for the evaluation of predictive biomarkers to enable stratified medicine. (3) To investigate the degree to which the current practice in generating evidence for stratified medicine matches the theoretical methodological standards being espoused by the literature, establish the reasons for any mismatch and understand the implications. (4) To establish a definitive methodological framework that will provide guidance on good practice in the future. How the results of this research will be used This project could have a major impact on the success of future stratified medicine research by providing a better understanding of standards of methodology required. It will provide the clinical, regulatory and research community with guidance on good practice for the future evaluation of predictive biomarkers for stratified medicine and provide tools to enable funders and journals to assess the quality of studies that evaluate candidate predictive biomarkers.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Tumour Endothelial Markers in Hepatocellular Carcinoma
Funder: Cancer Research UK

Abstract: Background Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the third leading cause of cancer mortality. Global incidence is increasing and within the UK HCC incidence has increased by 40% since 1979 and is projected to increase by a further 27% by 2030. Treatment of HCC worldwide yields poor survival rates due to late presentation preventing curative treatments and high post-treatment recurrence rates. Treatment of advanced disease is limited, with only one systemic treatment currently licensed within the UK, which provides only modest survival benefits. Aims The aims of this project are to isolate the endothelium within both healthy hepatic tissue and HCC in order to identify tumour endothelial markers which signify differentially expressed genes in the tumour endothelial transcriptome. Such genes may have a focal role in tumour angiogenesis and therefore provide potential targets for future drug development. Methods Tissue samples of hepatocellular carcinoma and normal liver tissue will be obtained from University Hospitals Birmingham NHS Trust. Magnetic bead isolation techniques, using the lectin Ulex europaeus Agglutinin I, will be used to isolate hepatic endothelium. Confirmation of endothelial isolation will be achieved through quantitative real-time PCR (qPCR) of the endothelial marker CD31. A combination of Agilent 66k whole gene arrays and RNA 2nd generation sequencing will then be used to define the healthy tissue and tumour endothelial transcriptome. Once a core group of differentially expressed tumour endothelial markers are identified, investigation into their expression across a larger number of tumour samples will be carried out. How the results of this research will be used Identification of differentially expressed endothelial genes may lead to the development of targeted therapies in the form of small molecule inhibitors, monoclonal antibodies and vaccine therapy. Targeting of aberrantly expressed genes and inhibition of their function may successfully disrupt tumour angiogenesis. Through the profiling of the tumour transcriptome we may also be able to identify biomarkers which predict response to targeted therapies, thus increasing the efficacy of therapy by population targeting, while preventing unnecessary drug exposure to those with lower chance of response. Focussing treatment with the use of genetic profiles to predict benefit or response is an attractive clinical, ethical and economical approach to treatment which will feature far more in treatment over the coming years.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: The role of cyclooxygenase-2 expression in stage II and stage III colon cancer survival.
Funder: Cancer Research UK

Abstract: Background: Colorectal cancer (CRC) is the third most common cancer in the UK with a 5-year survival of 50-55%. Numerous studies have demonstrated that regular aspirin use is associated with a lower risk of colorectal adenoma or cancer. The anti-neoplastic effects of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) are thought to be through the inhibition of cyclooxgenase 2 (COX-2), the rate-limiting step in the conversion of arachidonic acid to pro-inflammatory prostaglandins. While the association between CRC risk and the use of aspirin or NSAIDs has been extensively investigated, it remains unclear if these medications influence disease progression or mortality among patients diagnosed with CRC. COX-2 is over-expressed in 80-85% of colorectal tumours and is associated with a poorer prognosis in some but not all studies. Clarification of the association between COX-2 expression and CRC progression may assist in the development of targeted cancer treatment strategies. Aim: To analyse the association between COX-2 expression and survival in a population-based cohort of patients with stage II and III CRC. Methods: All stage II and III colon cancer patients diagnosed between 2004 and 2008 (n=1600) will be identified within the NI Cancer Registry (NICR). Patients will be followed up for date and cause of death for at least 5 years from diagnosis. Relevant clinical data will be retrieved from NICR and the Clinical Oncology Information System. Surgically resected formalin fixed paraffin embedded tumour blocks of included cases will be retrieved via the NI Biobank and prepared at the Northern Ireland Molecular Pathology Laboratory. An expert GI pathologist will undertake histological verification. Validated immunohistochemical assessment of COX-2 expression on tissue microarrays will be performed. Cox proportional hazards will be used to generate hazard ratios (HR) and 95% confidence intervals for the association between tumour COX-2 expression, colon cancer specific survival and overall survival. Adjustments will be made for potential confounders, such as treatments and lifestyle related variables How the results of this research will be used: A well designed cohort study analysing the association between COX-2 expression and CRC survival will help to clarify the role of this biomarker. COX-2 activity is readily modifiable therefore this project addresses an important clinical question and may strengthen the justification for tailored randomised clinical trials using aspirin or other NSAIDs in addition to standard adjuvant therapy in CRC.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Identifying small-molecule inhibitors of cancer-related cytoplasmic uridylyltransferase activities controlling tumour-suppressor miRNA biogenesis
Funder: Cancer Research UK

Abstract: Background MicroRNAs (miRNAs) play a determining role in cell fate, by acting as master switches for the coordinated regulation of groups of genes. Among the most important processes they control are the rate of cell growth and division and the differentiation from, or maintenance of, a stem cell state. As a result changes in miRNA expression are known to play a role in cancer at all stages and miRNAs are proving powerful tools for the typing of cancers and the assessment of prognosis. We have been studying the enzymatic process by which the let-7 family of miRNAs are generated, which in 90% of cases involves a critical uridylyltransferase reaction carried out by one of two enzymes in humans, ZCCHC6/TUT7 or ZCCHC11/TUT4. Oligo-uridylylation, promoted by Lin28A, results in pre-miRNA degradation and loss of tumour suppression, but mono-uridylylation results in pre-let-7 maturation. Aims We aim to identify compounds inhibiting ZCCHC6 and/or ZCCHC11 for the development of candidate drug series during a later stage in the drug development process. We have identified squamous non-small-cell lung carcinoma (SNSCLC) as the most significant potential target but treatment of other cancers would be likely to benefit too, including breast cancers and cancer of the large intestine. How the results of this research will be used Identification of compounds which inhibit ZCCHC6/11 with potency in cells will result in our being able to access the Lead ID steps in new drug development, beginning with series design.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS