NIHRDataInsights/HRCSData huggingface dataset:
Title: Functional characterisation of candidate causal variants at the 9p21 breast cancer susceptibility locus
Funder: Cancer Research UK

Abstract: Genome-wide association studies (GWAS) have identified 72 new loci associated with breast cancer. We recently identified a single nucleotide polymorphism (SNP) using this strategy at 9q21 associated with breast cancer risk (marker SNP rs1011970; OR = 1.20; 95% CI 1.11–1.30; p=2.5x10-8). SNP rs1011970 tags a ~180 kb region with three cancer candidate genes nearby - CDKN2B-AS1, CDKN2B and CDKN2A. The aim of this project is to identify the likely causal SNP(s) at the 9p21 locus, the defective molecular mechanisms and the target gene(s). We have carried out initial fine-scale mapping by using a custom genotyping array (iCOGS) to genotype 715 SNPs in 89,050 subjects of European ancestry from 41 case-control studies in the Breast Cancer Association Consortium (BCAC). After imputation of an additional 1,028 SNPs we identified two independent association signals, one confined to estrogen receptor positive disease and the other confined to estrogen receptor negative disease. The set of highly correlated SNPs with the strongest evidence for association within these two signals will be considered for functional follow-up. Using bio-informatic data such as the encyclopedia of DNA elements (ENCODE), I will first localise the likely functional SNPs by identifying those that lie in regulatory elements in the region. This subset of SNPs will be investigated for possible functional effects. As the functional SNP is likely to affect nearby gene expression I will conduct an expression quantitative trait locus (eQTL) analysis in 123 normal breast tissue and 254 breast tumours from the Norwegian Breast Cancer Study to look for correlation between SNPs genotypes and expression levels of neighbouring genes. I will then perform chromatin conformation capture (3C) experiments in normal mammary epithelial and breast cancer cell lines. This will examine if the effect on expression is mediated via physical interaction between the regulatory element that contain the risk-associated SNP and the promoter of the target gene. Allele-specific 3C will also be performed to determine the presence or absence of chromatin loops between the SNP and the target-gene promoter. Finally, the regulatory element with and without the risk allele of the SNP will be cloned into a luciferase reporter vector upstream of the promoter of the target gene so that I can assess the effect of the SNP on the regulation activity of the regulatory element. Results emerging from this project will help our understanding of the molecular mechanisms behind breast cancer susceptibility at the 9p21 locus.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Poison or prevention: do cognitive representations of breast cancer chemoprevention affect adherence
Funder: Cancer Research UK

Abstract: Background: Breast cancer is the second leading cause of cancer death in women. Incidence is increasing, which is raising interest in primary prevention, particularly among high-risk groups. In July, 2013 the National Institute of Clinical Excellence (NICE) recommended that women at high risk of breast cancer should be offered Selective Oestrogen-Receptor Modulators (SERMs) as a means to reduce their risk. Low levels of adherence in terms of initiation, implementation and persistence have been noted in clinical trials and in countries where chemoprevention is already offered. Poor adherence has been shown to increase all-cause mortality and healthcare costs. The psychological and social factors associated with adherence behaviours have rarely been explored. Aims: This proposal aims to test the effectiveness of a behavioural science theory (Self-Regulation Theory [SRT]) as a predictive model of breast cancer chemoprevention adherence behaviours. Secondary aims are to: i) investigate the importance of socio-cognitive factors (e.g. fear of medications) that have proven efficacy for predicting adherence in other clinical contexts; ii) identify the prevalence of low adherence and document observable inequalities; iii) develop a cost-effective and novel technique for assessing adherence objectively; and iv) refine SRT for use in a cancer preventive setting. Methods: We propose to use a prospective longitudinal design to follow-up women who have been offered chemoprevention medication at either a clinical genetics service or family history clinic. Questionnaire-based socio-cognitive data will be used to test the utility of SRT in predicting adherence behaviours at baseline, 1-month and 1-year post-appointment. Socio-demographic and clinical data will also be recorded and used to investigate secondary aims A protocol for recording adherence behaviours by telephone will be established during a collaboration/networking visit that is proposed in the application. Semi-structured individual interviews analysed using thematic analysis will help to refine SRT for use with women considering chemoprevention. How the results of this research will be used: This plan of work will contribute to the design of future interventions aiming to support adherence behaviours. The findings will also help to explain why previous attempts to improve adherence have not been successful, enabling modifications to be made to their design and content. The development of a low-cost and valid assessment of adherence will enable it to be used in a number of different health contexts. More broadly, investigating representations of cancer among a high risk group will further our understanding of how the public make cancer-related decisions.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;3.4 VACCINES
Health categories: CANCER AND NEOPLASMS
Title: Developing and testing targeted invitation materials to increase uptake of lung cancer screening in communities at high risk of lung cancer
Funder: Cancer Research UK

Abstract: Background: Lung cancer is consistently diagnosed late, with close to 70% of patients presenting with advanced disease, and ~40% as emergency cases. The results from the National Lung Screening Trial in the US showed that screening high-risk individuals with low-dose computed tomography (CT) reduced lung cancer mortality by 20%. This highlights the scope to cut the toll of lung cancer deaths through population-based screening if the target population can be engaged. Smoking is the dominant risk factor, and smoking rates are highest in lower SES groups. However, recruiting to lung cancer screening trials has been challenging and the profile of volunteers is skewed away from smokers and lower SES groups. Novel approaches to recruiting hard-to-reach groups are needed both for formative research and for effective screening programmes. Aims: This study aims to: i) identify attitudes and barriers to lung CT screening in population sub-groups at high risk of lung cancer; ii) develop screening invitation/information materials that meet requirements for informed decision-making and are acceptable to the target population; and iii) demonstrate the efficacy of the new invitation materials in achieving enhanced CT screening uptake in a local-area pilot screening programme. Methods: The work will be carried out in four stages with a mixed-methods design. Stage 1 will build ‘community-academic partnerships’ to make contact with socioeconomically deprived communities where smoking rates are high. Stage 2 will use qualitative methods to explore attitudes and perceived barriers to lung cancer screening in high-risk smokers and ex-smokers (30 pack-years). Stage 3 will develop screening invitation/information materials based on the findings of the exploratory work and state-of-the-art techniques from behavioural economics. Stage 4 will use a randomised controlled trial design to compare screening attendance with the new invitations vs. standard-type invitations in 2000 high-risk former and current smokers identified through primary care. How the results of the research will be used: The invitation materials produced will be translatable for a national lung cancer screening programme, enable the target population to make an informed screening decision, and ultimately reduce lung cancer deaths in the most health-disadvantaged group in the UK.


Research activity codes: 4.3 INFLUENCES AND IMPACT;8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: CANCER AND NEOPLASMS
Title: CRUK Glasgow (West of Scotland) Centre - Non Clinical Training Account
Funder: Cancer Research UK

Abstract: Non-clinical training associated with the Glasgow Centre: Researchers at the Cancer Research UK West of Scotland Cancer Centre are particularly focusing on bowel cancer and leukaemia, although their work will touch on many other cancer types. Scientists at the Centre also have considerable expertise in studying how cancer cells break away from a tumour and spread through the body - their work is paving the way for new treatments to halt this process. The Centre builds on Glasgow's excellent track record in developing new drugs for cancer. Scientists, doctors and nurses are working together to understand the molecular faults that lie at the heart of cancer, and find new drugs to target them. Researchers at the Centre also have the expertise to take exciting new treatments out of the lab and into the clinic, testing them in early-stage clinical trials with patients. To ensure that Glasgow continues to be a focus for cancer research for years to come, the Centre will play an important role in recruiting and training the next generation of cancer researchers. The staff at the Centre will reach out to the local community, highlighting the importance of a healthy lifestyle in cutting the chances of cancer, and how to spot the early signs of the disease (http://aboutus.cancerresearchuk.org/what-we-do/research/research-near-you/glasgow/science-research/)


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: CANCER AND NEOPLASMS
Title: Optimising x-ray and proton radiotherapy treatment plans for thoracic or abdominal tumours: trade-offs in plan quality and plan robustness and possibilities for dose escalation and normal tissue sparing
Funder: Cancer Research UK

Abstract: Radiotherapy treatment techniques, such as intensity-modulated radiotherapy (IMRT), which use multiple high-energy x-ray beams to deliver a highly optimised dose to the tumour, are now widely used in the UK. However, for thoracic or abdominal tumour sites (e.g. oesophagus) local tumour control may be difficult to achieve, as dose is limited by the highly radio-sensitive organs which surround the tumour, and further enhancements in dose distribution may be required to improve treatment outcomes for these patients. A solution to this problem could potentially be provided by proton therapy, which can generate exquisitely conformal dose distributions with a small number of beams, whose energy and intensity may be tuned to deposit dose at the tumour site, whilst sparing the normal tissues traversed by each beam. However, patient movement (e.g. respiration) during proton beam delivery may alter the planned dose distribution, unless a sufficiently robust treatment plan has been designed to mitigate these effects. In addition, capacity for proton treatments in the UK centres currently being planned is likely to be limited, so that identifying patients who would benefit most from proton therapy, and using these facilities efficiently, will be of paramount importance. In this project we will compare proton and x-ray radiotherapy plans, investigating in particular the capacity of each technique to maintain an acceptable level of toxicity in surrounding normal tissues whilst increasing tumour dose. Mixed modality treatments (partial treatment using both x-rays and protons) will also be explored in order to identify the optimal use of proton therapy facilities. Plan quality will be examined using standard dose metrics to analyse the conformation of the physical dose distribution to the target volume and surrounding organs at risk. An important factor will be the robustness of these dose-metrics for both x-ray and proton plans in the presence of respiratory movement, since proton dose distributions can be highly sensitive to small changes in patient anatomy. In addition, radiobiological modelling will be used to link the physical dose distribution in each organ to predicted clinical outcome (such as radiation pneumonitis in lung). This may be applicable in assessing the possible trade-offs in local tumour control and toxicity when prescribed dose is increased. This information will be used to explore the limits of each technique, and the optimal degree of mixed modality treatment which would represent a real improvement in patient quality of life.


Research activity codes: 5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Conference grant to help us host the 8th International Conference on Oncolytic Virus Therapeutics
Funder: Cancer Research UK

Abstract: Background: Oncolytic viruses are now causing considerable interest in cancer medicine, with three different agents mediating improved survival of cancer patients and the first products soon expected to achieve licensure in the West. Reinforcing this strong clinical position is a lively scientific community, pioneering a whole raft of innovative technologies ripe for clinical translation. Aims: Against this exciting scientific and medical backdrop we will host a major international Conference on Oncolytic Virus Therapeutics – the 8th in a well-established worldwide series – in Oxford, April 10-13th 2014. Methods: The Conference will bring together worldwide leaders in the field, working at the interface of virology and translational cancer biology. Our goal is to deliver an intellectual focus that enables improved communication and collaboration throughout the field, and accelerates translation of sound science into the clinic. The programme combines scientific and clinical presentations from world experts, providing an excellent forum for robust scientific discussion and an outstanding training opportunity for those new to the field. The Conference will be held at the historic Examination Schools in central Oxford, with accommodation focussed around the 15th century Lincoln College with its historic underground bar. The draft Conference website is here: http://oncolyticvirusmeeting.weebly.com/index.html The meeting will be accredited for CPD Points by both the European Society for Medical Oncology (ESMO) and the Royal College of Physicians. How results of this work will be used: The Conference is designed to allow specialist cancer science to be presented and discussed in detail, alongside sessions focussed on supporting technologies (such as Imaging and Vector Systems). Overall we aim to fertilise high quality scientific innovation by encouraging new insights and providing networking opportunities. We prioritise the involvement of younger scientists and provide subsidised registration for PhD students. That is one of the central reasons why Cancer Research UK support is vitally important to us. In addition your support will make an essential contribution towards accelerating scientific progress in the field of cancer virotherapy and improving comprehensive science-led and ethical evaluation of new technologies in the clinic.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: CANCER AND NEOPLASMS
Title: Association for Radiation Research Meeting (ARR2014)
Funder: Cancer Research UK

Abstract: The Annual meeting of UK’s Association for Radiation Research in 2014 (ARR2014) will be held at the University of Sussex. We aim to attract 120-200 delegates. The ARR aims to promote radiation research within the UK and interfaces with European and the US Radiation Research Societies. The scope of ARR covers all aspects of basic radiation biology, a strength in the UK, applied aspects such as radiotherapy, radiation protection and understanding how radiation causes cancer. Radiotherapy remains a front-line cancer treatment, with 50 % of all cancer patients receiving radiotherapy. Optimising radiotherapy regimes and care of patients receiving radiotherapy is central to the ARR. Evaluating whether diagnostic exposure to X-rays/CT scans represents a cancer risk are further important aspects. The radiation field is cross disciplinary involving radiation chemistry, physics, mathematical modelling and biology. Delegates at the meeting will include clinical, basic and applied scientists, with representatives from these displicplines. The aim of the meeting is to disseminate knowledge on radiation research and to provide a forum to promote interactions and collaborations. Facilitating interactions between workers in distinct disciplines is an important goal in this cross disciplinary area of science. Another important goal is to promote the training of future radiation scientists, who we call scientists in training (SIT) (which encompass MSc, PhD and young post-doctoral scientists). We have a SIT representative on the ARR committee and a SIT session at the meeting, specifically to encourage presentations from younger members. We particularly like to offer bursaries for SIT attendees. Thus, all aspects and sessions of the meeting have a connection to cancer research.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: CANCER AND NEOPLASMS
Title: Characterization of chromatin-binding properties of kinesins using Fluorescence Correlation Spectroscopy
Funder: Cancer Research UK

Abstract: Kinesins are attractive as potential target for cancer therapy. They have been reported to contribute to tumorigenesis and confer resistance to microtubule poisons. Thus, to validate kinesins as viable cancer drug target, it is essential to fully understand their functions. Kinesins are motor proteins functioning in intracellular transport and mitosis, by walking on microtubule tracks. I observed that kinesins co-purified with chromatin in a cell cycle dependent manner. These results were unexpected because the nucleus is a microtubule-free environment. To understand potential nuclear functions of kinesins, I aim to study the biophysical parameters of the interaction between chromatin and kinesins. I will use a single molecule approach, Fluorescence Cross Correlation Spectroscopy (FCCS). This advanced technology will allow me to visualize the mobility of kinesins and chromatin and to determine if they move together as a complex. I will be able to investigate the chromatin-binding properties of kinesins in different contexts (e.g. different cell cycle phases). This project will clarify how kinesins interact with chromatin and further studies will allow to determine the molecular basis of this interaction using different kinesin mutant constructs. Finally, this assay will be a valuable tool to measure the chromatin-binding properties of any protein of interest.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS
Title: Personalised genomics and prevention
Funder: Cancer Research UK

Abstract: Background Personalized genomic analysis is increasingly in the public eye. Reductions in genotyping costs have resulted in genome sequencing being used across the medical spectrum from diagnosis to treatment, and direct-to-consumer genetic testing is available over the internet. At all levels, understanding people’s responses to genomic information is crucial; not only to support informed decision-making but also to ensure that genetic test results achieve maximum patient/public benefit. Aims The aim of this symposium is to share new research findings and discuss the issues surrounding the applicability of risk communication using personalised genetic test feedback for disease prevention, with a view to informing and improving practical applications of the use of personalised genomic information. Methods The three speakers in this symposium will address the use of genetic information to enhance health promotion and disease prevention. Professor Colleen McBride (NIHGRI) will discuss how genomic risk information can be best used to add value to interventions, Dr Nora Pashayan (University College London) will discuss the use of genomic information to stratify cancer screening schedules, and Susanne Meisel (University College London) will discuss emotional and motivational responses to genetic test feedback for obesity risk. I plan to invite a science journalist to take the Discussant role to represent the constituency of those who ultimately shape public understanding. How the results of this research will be used This research aims to enhance health professionals’ and the public’s understanding of the potential of personal genetic test feedback to influence risk appraisal and behaviour, and inform them about recent applications of personalised genetic feedback in the context of disease prevention. The discussion will focus on potential benefits and barriers to realising the potential of personalised genetic testing and developing a future research agenda.


Research activity codes: 3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: Cancer Research UK Barts Centre
Funder: Cancer Research UK

Abstract: Scientists at the Barts Centre are focusing on blood cancers, such as leukaemia and lymphoma, as well as hard-to-treat cancers, like pancreatic cancer. They are also researching how cancers such as ovarian tumours grow and interact with healthy cells in the body, to find new targets for drug treatment. Barts Cancer Institute has a long tradition of pioneering research and innovation. Many surgical procedures were first discovered here as well as the use of radiotherapy to treat cancer. By investing in and undertaking world-class research, we aim to prevent cancer and develop better diagnostic techniques and treatments. This will ultimately increase patient survival and enhance the quality of life for those with long-term disease. A wide range of research is currently underway and includes: •Therapeutic and diagnostic target identification and validation in both haematological and solid malignancies •Clinical trials exploring new therapies •The development of novel molecular approaches for diagnosis •Classification and treatment of human cancers •Investigations into the regulation of tumour spread and host anti-tumour responses (http://www.bci.qmul.ac.uk/research)


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS