NIHRDataInsights/HRCSData huggingface dataset:
Title: Systematic development of the anti-avß6 imaging peptide A20FMDV2 for use as an anti-cancer therapeutic.
Funder: Cancer Research UK

Abstract: Background:Integrins are on the surface of almost all cells in the body. they connect the inside of the cell with the outside and thus act both as sensors of the environment and and transmitters (of behaviour) for cells. The integrin avß6 is expressed only by epithelial cells, and then only during processes that involve tissue remodeling, including cancer. In fact we calculate that over 100,000 new cancers are diagnosed each year in the UK alone that express moderate or high levels of avß6, making this integrin a potentially important new cancer-selective therapeutic target. Data from this lab and others show clearly that avß6 is likely to promote cancer growth and spread as it promotes growth signaling, survival signaling, secretion of matrix metalloproteinases, migration and invasion. Clinical data show that high expression of avß6 correlates with very poor prognosis for patients with cancer of the colon, cervix and lung. Since avß6 is upregulated on many different types of carcinoma where it promotes cancer, and is surface-expressed, it represents an important therapeutically accessible target for anti-cancer treatment. This lab (Barts Cancer Institute, London) has developed the 20 amino-acid long peptide, A20FMDV2, which is 1000-fold more selective for avß6 over other integrins (there are 23 others), has a very high affinity for the integrin, can block the ability of avß6 to bind ligand and has been proven to locate selectively to avß6-positive human xenografts after intravenous injection. A20FMDV2 is rapidly internalized by cells upon binding to avß6 and a recent collaboration with a biotech company showed that A20FMDV2 could deliver a cytotoxin selectively to avß6-positive cells (200-fold selectivity) in vitro. Thus A20FMDV2 could function as a therapeutic targeting agent in humans, able to selectively deliver cytotoxic drugs and chemicals. The problem is that A20FMDV2 is highly susceptible to serum proteases and rapid excretion. Aims and Methods: colleagues from the University of Auckland, who have a distinguished record of using medicinal chemistry to generate peptides for clinical use, will utilise medicinal chemistry to systematically improve A20FMDV2 in order that it may be used as a therapeutic delivery system. Each batch of novel chemically modified A20FMDV2 peptides will be screened in biological assays by this lab. Goals: Thus this proposal seeks to improve the pharmacokinetics of A20FMDV2 in order to make it a useful avß6-specific drug-delivery agent.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Screening, prevention and diagnosis of colorectal cancer. Supported by the Bobby Moore Fund for CRUK
Funder: Cancer Research UK

Abstract: Background: The CSPRG is a multidisciplinary team undertaking research projects focusing on screening and prevention of colorectal cancer (CRC). Aims: Our aim is to reduce CRC incidence and mortality. Over the next funding period, we will: - Answer outstanding questions relating to flexible sigmoidoscopy (FS) screening. - Identify the optimum method of surveillance for people with large or multiple adenomas. - Investigate the risk factors for proximal CRC. - Determine whether colonoscopy surveillance can be replaced with annual home-testing by FIT. - Find ways to help GPs determine which patients need investigation for CRC. Methods: We will continue to analyse the data collected in the UK FS screening trial (UKFSST), to investigate how long the effect of a single FS lasts, how to ensure that FS is performed to a high standard, and how performance of FS affects future risk of CRC. We have followed up 200,000 people who had colonoscopy, and collected and coded data from their exams We will use this data to identify the optimum surveillance interval between colonoscopies. The data will also be used to determine risk factors for proximal cancer. We will explore the genetics and histology of proximal lesions. We will complete the FIT for Follow-Up study, to determine whether annual FIT testing is a feasible alternative to colonoscopy surveillance. We are also initiating a new study to assess whether FIT is sensitive and specific enough to identify which patients presenting to their GP with low-risk symptoms should be referred for further investigation. How the results of this research will be used: As a result of the UKFSST, FS screening is now being offered to everyone in England at age 55 and is expected to prevent 5,000 cases and 3,000 deaths from CRC each year. Our ongoing research will provide information on the longer-term benefits of FS screening. Determining optimal surveillance intervals will reduce the number of CRCs occurring between surveillance colonoscopies, and ensure that patients do not have to undergo colonoscopy unnecessarily. Understanding risk factors for proximal CRC should help in reducing incidence rates, since at present colonoscopy is far less effective in preventing proximal than distal cancer. If FIT testing can be used to replace colonoscopy surveillance, this would be cheaper and more convenient for patients. Using FIT in primary care would give GPs a more accurate means of assessing risk, and would allow many patients to avoid referral to hospital.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Role of ER stress and REDD1 induction in aspirin-induced mTOR inhibition
Funder: Cancer Research UK

Abstract: Background:<br/><br/>Colorectal cancer (CRC) is the second most common cancer to cause death after lung cancer in the UK. Aspirin prevents CRC, but the molecular mechanisms are unknown and the increased risk of bleeding potentially offsets this reported benefit overall. <br/><br/>One candidate molecular pathway involves mammalian target of rapamycin (mTOR), which is ordinarily an important regulator of cell growth and survival, but is overexpressed in CRC and inhibited by aspirin.<br/><br/>Hypoxia and endoplasmic reticulum stress is an important feature in most tumours including CRC, caused by inadequate vasculature within the tumour to meet its oxygen demand. Malignant cells can survive these conditions by adapting its molecular responses, including the unfoled protein response (UPR). <br/><br/>Regulated in development and DNA damage responses (REDD1) is a crucial element in the stress response as it is induced by DNA damage and hypoxia. REDD1’s induction by UPR is dependent on ATF4. REDD1 in turn has been shown to inhibit the activity of mTOR in hypoxic conditions via the activation of the tumour suppressor complex (TSC 1/2), inducing cellular autophagy. In the setting of malignancy, REDD1 has been shown to be down-regulated in breast cancer, which could allow it to ‘escape’ cellular death that would normally be induced by mTOR. <br/><br/><br/>Aim:<br/><br/>To test the hypothesis that aspirin induced ER stress and REDD1 activation lead to mTOR inhibition in CRC<br/><br/><br/>Methods:<br/>1.Determine whether aspirin up-regulates UPR, REDD1 and TSC1/TSC2, and down regulates mTOR in CRC cell lines, under normal and hypoxic conditions by using immunoblotting. <br/>2. Establish whether blocking ER-stress using inhibitors (4-phenylbutyric acid, salubrinal) inhibits aspirin-induced REDD1 expression, mTOR inhibition and autophagy.<br/>3. Use small interfering RNA and using mice embryonic fibroblasts to establish whether AT4, REDD1 and TSC1/TSC2 mediates and is necessary for the inhibition of mTOR by aspirin in CRC cell lines.<br/>4. Establish whether aspirin up-regulates UPR, REDD1, TSC1/TSC2 and down-regulates mTOR in vivo in humans (n=5).<br/><br/><br/>How the results of this research will be used:<br/><br/>By understanding the molecular mechanisms underlying the chemo-preventive nature of aspirin against CRC, new agents that are more effective can be developed. The same findings could be applied for other cancers that are inhibited by aspirin (oesophageal, pancreatic, lung and breast).


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: CANCER AND NEOPLASMS
Title: Exposure to nicotine and tobacco-related toxicants in long-term users of nicotine-containing products
Funder: Cancer Research UK

Abstract: Background: There is good evidence that the provision of Nicotine Replacement Therapy (NRT) to smokers who cut down their cigarette consumption results in more sustained decreases in cigarette consumption and improves their chances to stop smoking completely. For this reason, NRT in the UK is licensed for smoking reduction, i.e. dual use, and available to smokers who cannot or are unwilling to stop smoking completely as a long-term harm reduction measure. There is also evidence for an increase in use of electronic cigarettes (e-cigarette) both for purposes of harm reduction and smoking cessation. However, surprisingly little data exist on the impact of long-term NRT use on of health outcomes and even less is known about the effects of e-cigarette use. In light of forthcoming NICE guidance on harm reduction and likely MHRA regulation on e-cigarettes, knowledge in this area and further data are urgently needed to inform policy makers from both the UK and elsewhere in the world about the suitability of this approach by providing estimates of the likely impact of long-term use on health outcomes and safety. Aims: This pragmatic study seeks to provide preliminary evidence to inform further definitive studies by comparing a)levels of tobacco-related metabolites in long-term ex-smokers who are long-term users (1 year or more) of either e-cigarettes or NRT and b)metabolite levels of long-term smokers with or without concurrent long-term use of nicotine-containing products. Methods: Four naturally occurring groups - ex-smokers with 1)long-term NRT use or 2)long-term e-cigarette use; current smokers with 3)long-term NRT or e-cigarette use (dual users) or 4) no use of either product - will be recruited from multiple sources to maximise representativeness of the sample. Participants will visit the laboratory once to complete a questionnaire and to provide breath, saliva and urine samples. Samples will be analysed for a general health biomarker(CRP) and, to estimate exposure, for metabolites of nicotine (cotinine, hydroxycotinine), acrolein (3-HPMA) and known tobacco-related toxins (CO, NNAL). Forty-five participants per group will provide sufficient power to detect meaningful differences (f=0.25, medium effect size) between groups. Analysis will use general linear models and propensity score matching to address potential confounders. Use of results: Findings will be disseminated through research papers and conference presentations and through close links of study collaborators with the Department of Health, NICE, MHRA and other national as well as international organisations fed back to inform policy and implementation of guidelines.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: CANCER AND NEOPLASMS
Title: Children’s exposure to second-hand tobacco smoke: An analysis of newspaper coverage 2002-2012. Does it tell us about the direction future policy should be going?
Funder: Cancer Research UK

Abstract: Background: The introduction of smoke-free legislation in enclosed public spaces in the UK has produced substantial reductions in population level exposure to second-hand smoke (SHS). The legislation was targeted at the workplace and adult social space (bars and restaurants) and, as a result, one group that have not experienced the same exposure reduction benefits as others are children who live with smoking parents. The public health approach to tackling children’s SHS exposure has tended to centre on the education of parents to understand the benefits of creating smoke-free homes (Wilson et al., 2012; DH, A Smoke-free future, 2010). While further legislation is likely to be difficult in terms of people's homes there is debate about introducing restrictions on smoking in cars when children are present. The role of media coverage about the harms of SHS in the lead up to the smokefree legislation in 2006/7 is likely to have been important in influencing public attitudes and behaviours, and producing the eventual high level of public compliance after implementation (Gorini et al., 2011). The recent focus on the debate around reducing children’s exposure to the harms of SHS has led to increased media interest, and understanding how media presentations of children’s exposure to SHS may be changing will be key to informing future tobacco control policy development in Scotland, the UK and internationally. Aim: This project proposes to analyse UK newspaper coverage of children’s exposure to SHS over a ten year period to determine what changes have occurred in framing and content. Method: Content analysis will be conducted on nine newspapers (four quality, two mid-market, three tabloid. These newspapers have been selected with a range of readership profile and high circulation figures. Our search period will be from 1st January 2003 to 31st December 2012. How the results of this research will be used: To provide policy makers, academics and those involved in tobacco-control education with an insight to current media representations of the issues around children's exposure to SHS. These findings will be disseminated and used to inform health advocacy strategies and shape media communications, with the aim of framing future communications and engagement to educate smokers regarding the effects of tobacco smoke and the impacts of SHS exposure on children. As part of our dissemination strategy we will write two high quality papers for peer review journals and present the findings from this work at national conferences.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: CANCER AND NEOPLASMS
Title: Innovative packaging measures to communicate health risk/cessation messages to smokers
Funder: Cancer Research UK

Abstract: Packaging has been a vital communications tool for tobacco companies for over a century. For smokers the pack is their personal choice, a statement of their identity and a constant companion which they will look at countless times every day. The packaging turns a generic product into a bespoke marque. For non-smokers, tobacco packs are also a familiar feature of life, whether at the point-of-sale, as litter or in the hands of their smoking friends and relatives. It is unsurprising, then, that tobacco companies have and continue to be very creative in their use of all elements of the pack – colour, shape and design, the cellophane wrapper, the cigarette tube and inserts – to communicate the positive qualities of the product and especially the brand. The response to this threat has been to impose on-pack health warnings, the success of which partly reflects their capacity to counteract and constrain the industry’s on-pack marketing. The possibility now exists to complement this reactive control with the proactive exploitation of the pack to promote cessation and prevention. Having wrested the pack from the hands of the tobacco marketer it can now become a legitimate platform for health promotion and the creative energies the tobacco industry has used over the last century to promote tobacco use could be harnessed to push it in the opposite direction. Supposing, for example, each cigarette had a health message on it? Or the pack spoke its warning when it was opened? Or a Quick Response barcode on the pack could direct smartphone users to a stop-smoking service, or similar innovations using barcodes, like Blippar, could direct the user to social networking campaigns. The options are many and varied. This project has two objectives: i) to explore the nature and range of possible health-promoting packaging innovations; ii) to examine adult smokers’ response to these. The first will involve depth interviews with marketing professionals asking them to consider how, given a free hand, they would use the pack to promote tobacco control. These innovative ideas, alongside other innovative measures that we have already developed, will then be presented to adult smokers in focus groups and their cognitive, conative and behavioural responses examined. Findings will be disseminated via publications, presentations and to interested parties.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: CANCER AND NEOPLASMS
Title: Cambridge Research Institute: post-doctoral research support
Funder: Cancer Research UK

Abstract: The fundamental principle for research at the CRUK Cambridge Institute is to link the laboratory to the clinic, thus driving the development of new approaches to screening, prevention and treatment. Our research is built around four themes: 1.Basic research into the molecular and cellular biology of cancer, for example: ■the biology of normal epithelial tissues and the early stages of cancer development; ■the stem cells of epithelia; ■the interactions between emerging cancer cells and normal cells; ■the mechanisms of gene control and their disruption in cancer. 2.Research in molecular imaging, genomics, bioinformatics and biomolecular modelling. 3.Research focussed on specific cancer sites, which form a bridge between laboratory and clinic. 4.Clinical investigations including experimental medicine based clinical studies and clinical trials, leading to population-based studies in screening and prevention in the longer term. These clinical and basic research themes, supported by the core facilities, intersect and tap into readily accessible clinical resources provided through Addenbrooke's Hospital. The research at the CI thrives on collaboration, and our researchers carry out their work with colleagues at the University, Addenbrooke’s Hospital, and other institutes in Cambridge and further afield.


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: Imperial Cancer Research UK Centre (Bridging funding)
Funder: Cancer Research UK

Abstract: Researchers at the Imperial Centre (link is external) specialise in breast, bowel and prostate cancer. They are developing innovative new imaging techniques to help diagnose cancer earlier and track response to treatment. The Cancer Research UK Imperial Centre is a partnership between Cancer Research UK, Imperial College London and the Imperial College Healthcare NHS Trust. The Centre brings together scientists, doctors, nurses and educators to enhance multi-disciplinary collaboration to get research to patients faster. At the Imperial Centre, research focuses on breast, ovarian and colorectal cancers and is divided into Themes along the Patient’s Journey: 1.Prevention and Early Detection 2.Imaging, Physics and Radiation Therapy 3.Surgical Technology and Cancer Intervention 4.New Target Identification and Chemical Biology 5.Systems Oncology and Stratified Medicine http://www1.imperial.ac.uk/crukcentre/


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: CRUK/09/010: IDEAL-CRT: A phase I/II trial of concurrent chemoradiation with dose-escalated radiotherapy in patients with stage II or stage III Non-Small Cell Lung Cancer
Funder: Cancer Research UK

Abstract: Intensification of radiotherapy treatment has been shown to improve the effectiveness of lung cancer treatment. In both the CHART study and in studies comparing sequential with concurrent chemoradiation, improved overall survival was seen with no increase in RT dose but rather with an increase in intensity. With CHART this was via acceleration and with concurrent chemoradiation through the simultaneous use of cytotoxic agents. RT dose escalation is another form of dose intensification. The IDEAL CRT trial was set up to evaluate the safety and early efficacy of a novel dose escalation schedule that was to be isotoxic for radiation pneumonitis and fixed in overall treatment time to six weeks. The first recruitment of IDEAL CRT successfully treated 84 patients with stage II & III NSCLC with concurrent chemoradiation, using standard cisplatin plus vinorelbine chemotherapy and radiotherapy to a dose of 63-73Gy in 30 fractions. The dose was selected for each individual according to a formula based on their radiation dose distribution that predicted a 10% risk of grade 3+ radiation pneumonitis (Arm 1). At the doses per fraction used there was no existing safety data for oesophageal toxicity so a conventional dose escalation design was used for patients in whom the maximum dose to 1cc of oesophagus was above 63Gy (Arm 2). The dose levels used were 65Gy, 68Gy, 71Gy and 73Gy. It was found that 73Gy to 1cc of oesophagus was rarely required to achieve even the maximum tumour dose of 73Gy and so no patients were recruited in to this cohort. The maximum tolerated dose was not reached. In view of the lack of excess toxicity a second recruitment is planned. The same dose calculations will be used but the treatment will be accelerated from 6 weeks overall time to 5 weeks. This is achieved by chemotherapy being delivered on 1,2,4 and 5 instead of weeks 1,2,5 & 6 and by giving radiotherapy twice a day, one day a week. The oesophagus dose cohorts will recruit again from 65Gy through to 71Gy as the most likely increase in toxicity resulting from acceleration is likely to be oesophagitis. The increased intensity could result in as much as 10% higher local control rates, which could improve overall survival. IMRT was introduced during the first recruitment and we expect a far higher proportion of patients to be treated with IMRT during the second recruitment.


Research activity codes: 6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS