NIHRDataInsights/HRCSData huggingface dataset:
Title: ASH Wales: Tackling the illicit tobacco market in Wales
Funder: Cancer Research UK

Abstract: The availability of illicit tobacco undermines many of the most important measures undertaken in tobacco control policy, such as tax increases, point of sale display bans and restrictions on age of sale. To date, no steps have been taken in Wales to evaluate the scale of the problem or to introduce a campaign equivalent to those that have taken place in the English regions. However recent press reports of seizures of illicit tobacco from all across Wales (Wrexham, Aberystwyth and Cardiff/Newport) indicate that the market is present across the whole of Wales. This project therefore aims to collect the data required in order to effectively tackle this major issue which is currently not a priority on the political agenda for tobacco control in Wales. Without a project of this kind, it will not be possible to raise the political profile of the problems created by illicit tobacco in terms of its impact on individuals and communities and the continuation of health inequalities. The project therefore aims to undertake two complementary pieces of work to act as a basis for a concerted campaign to be taken forward by the ASH Wales Press and Campaigns Manager (currently funded by CRUK): - A survey, based on those already conducted in the English regions, to determine levels of supply and demand, availability, purchasing behaviour and attitudes towards illicit tobacco on the part of both smokers and non-smokers; - A ‘problem profile’ to be generated in collaboration with the relevant enforcement agencies through commissioning a trained intelligence analyst to systematically collate existing data and map hotspots of the illicit market in order to allow the campaign to be targeted effectively. The data collected will be used as the basis for a pan-Wales campaign encompassing three interconnected elements: - Lobbying the Welsh Government to take concrete action beyond their Tobacco Control Action Plan’s commitment to lobby the UK Government to prioritise tackling the illicit tobacco trade (Action 1.3) - Promoting effective multi-agency working to tackle supply and demand - Raising awareness among the general population of the risks associated with illicit tobacco, focusing not just on personal health but also the broader community impact. The results will thus be used to influence political opinion, encourage greater coordination to facilitate enforcement action and reduce the number of purchases of illicit tobacco being made in Wales, especially by young people.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION)
Health categories: CANCER AND NEOPLASMS
Title: Planning for the Endgame: Sustaining the momentum of tobacco control in a new era: reflecting on progress since the publication of Beyond Smoking Kills and defining a new national tobacco control agenda for 2015-2020
Funder: Cancer Research UK

Abstract: In 2015 the current Tobacco Control Plan for England will have run its course and a new government will be elected. This will be a critical moment to influence the shape of national policy on tobacco control to 2020 and maintain the momentum of the national effort to reduce the prevalence of smoking. The aim of the project is to provide the tobacco control community with an advocacy tool to help shape government policy from 2015 to 2020. Planning for the Endgame will review progress in tobacco control since the publication of Beyond Smoking Kills, assess the impact of the current government’s Tobacco Control Plan for England, and provide a new, evidence-based agenda for action to inform government strategy following the 2015 election. The report will include international comparisons with other legislatures with advanced tobacco control policies; an evaluation of the impact of current policy; a description of the new policy environment for public health and tobacco control; an inquiry into the economics of the tobacco industry and the economic effects of tobacco on individuals, families and communities; and a detailed, evidence-based analysis of the scope for improving outcomes through further action across all areas of tobacco control. The report will present a case for a new policy agenda that could deliver radical reductions in smoking prevalence. The preparation of the report will be overseen by an editorial committee with a membership of key opinion leaders in tobacco. This group will ensure that the report has the necessary scope, ambition and rigour to be effective in shaping government policy. The report will be used to advocate for an ambitious new government tobacco control strategy for 2015-2020.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE;3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION)
Health categories: CANCER AND NEOPLASMS
Title: Identification of Phosphatase Specific Inhibitors of the DNA Damage Repair Enzyme Polynucleotide Kinase 3´ Phosphatase (PNKP) via a Dual Fragment and Virtual Screening Approach
Funder: Cancer Research UK

Abstract: Identification of Phosphatase Specific Inhibitors of the DNA Damage Repair Enzyme Polynucleotide Kinase 3´ Phosphatase (PNKP) via a Dual Fragment and Virtual Screening Approach Background Pharmacological inhibition of DNA damage repair pathways as an approach for the potentiation of chemo- and radio-therapeutic cancer treatments has attracted great interest in recent years. Inhibitors of several enzymes involved in the repair of DNA strand breaks are currently at various stages of development. Polynucleotide Kinase 3´ Phosphatase (PNKP), a bifunctional DNA damage repair enzyme that possesses both 3´-phosphatase and 5´-kinase activities, plays an important role in the repair of both single strand breaks (SSB) and double strand breaks (DSB) and as a result, RNAi-mediated knockdown of PNKP sensitizes cells to a range of DNA-damaging agents. Inhibition of PNKP has the potential for both greater efficacy and improved safety compared to inhibitors of DNA damage repair mechanisms currently under clinical evaluation. There exists therefore an urgent need to identify potent, selective, drug-like PNKP inhibitors to test this potential. Aims The aim of this project is to identify potent, selective ‘lead like’ molecules with the potential to become drug candidates, and for use as research tools to further explore the potential of PNKP inhibition in preclinical assays. Methods Key to the success of this work at the University of Sussex is collaboration within the School of Life Sciences between the Translational Drug Discovery Group with experience and expertise in drug discovery, and the world leading Genome Damage and Stability Centre with complementary capabilities in DNA damage repair assays and protein crystallography. We plan to identify inhibitors through the parallel execution of fragment and virtual screens. A full screening cascade is already in place, comprising enzymatic and biophysical assays together with cellular assays of DNA damage repair. We have performed preliminary studies which give increased confidence in a successful outcome, including a detailed study of the enzyme active site which has identified a number of locations where drug molecules have a high chance of binding. Future Use of the Results From This Work Based on the existing target validation there is a great need for drug like compounds to fully explore this potential both pre-clinically and clinically. High quality hit compounds arising from this work would therefore attract significant funding for continuation of this project. In parallel we propose rapid publication of suitable compounds so that the research community can use these as chemical probes.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Development of a novel immunotherapeutic for CLL
Funder: Cancer Research UK

Abstract: We plan to develop a novel immunotherapeutic for CLL with this grant. Antibodies will be generated to the target of interest, which is expressed on NK cells. Multiple formats will be tested including monoclonal antibodies, bi-specific T-cell engagers and chimeric antigen receptors. We will select the most promising strategy and test in a simple in vivo model. In parallel, we will explore possible on-target off-tumour effects by screening normal tissue arrays for target protein expression and targeting in mice.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: A comparative qualitative study of patients’ experiences of cancer diagnosis in England, Denmark and Sweden: can comparative analysis of patients’ narratives help us identify how to improve cancer services?
Funder: Cancer Research UK

Abstract: Background Survival rates for those with cancer in England are still poorer than in many European countries, including Sweden. Surveys suggest that this may be due to differences in how people recognise suspicious symptoms, report them to their doctors and how the doctors respond, and that these difference could lead to later diagnosis and a risk of later stage disease developing. This qualitative study will gather, explore and compare experiences of patients with lung and colorectal cancer within and across three European countries (England, Denmark and Sweden). Aims 1. Describe experiences of the main routes to diagnosis of lung and colorectal cancer patients. 2. Use patients’ accounts to extend understanding of potentially modifiable factors known to influence long-term cancer survival, including late presentation, delayed diagnosis and referral into specialist care. 3. Compare patients’ accounts – within and between countries – to identify when and why important variations occur. 4. Compare patient perspectives between countries to highlight opportunities for pathway and service redesign and promote early identification and diagnosis. Methods This 24 months study will start with a literature review and in-depth qualitative interviews with 60 patients in each country (half with lung cancer and half with colorectal cancer), who have been diagnosed within six months. These interviews, from a maximum variation sample, will be audio recorded, transcribed and analysed. Following initial country specific analyses of the full sets of interviews, collaborators from all three countries will meet for a four day “analysis retreat”. The findings from the three countries will be compared to explore why pathways to diagnosis may differ. Cancer Patients’ Voice will advise us throughout to help us maximise the utility and impact of the findings for patient benefit. How the results of this research will be used The study will provide new, in-depth insights into early stages of the care pathway from the patient’s perspective and help explain differences observed in the International Cancer Benchmarking Partnership (ICBP) and other quantitative studies Qualitative studies can illuminate sequences, linkages, circumstances and factors preceding events and experiences, as well as their consequent effects. Such information is particularly important for service improvement, since problems are more likely to be addressed effectively if we understand why they happen. In each country we shall prepare a ‘toolkit’ for those who commission and provide cancer services, identifying opportunities for pathway redesign and a guide to using patient narratives for local service improvement.


Research activity codes: 4.3 INFLUENCES AND IMPACT
Health categories: CANCER AND NEOPLASMS
Title: CRUK/12/045: European Study Group for Pancreatic Cancer Trial 5F prospective sample collection - ESPAC-5FT
Funder: Cancer Research UK

Abstract: Background: The ESPAC-1 trial demonstrated that adjuvant treatment with 5-fluorouracil offers significant survival benefit to patients with pancreatic cancer. ESPAC-3v2 demonstrated no significant survival difference between adjuvant 5-FU/FA versus gemcitabine. ESPAC-4 is an adjuvant trial comparing capecitabine plus gemcitabine versus gemcitabine alone in pancreatic cancer. The CR-UK funded collection of samples from these trials is ongoing and has become the largest collection of pancreatic samples from adjuvant therapy RCTs. ESPAC-5F is a four arm, prospective, multicentre, randomised Phase II trial of immediate surgery compared with neoadjuvant chemotherapies and neoadjuvant chemoradiotherapy in patients with borderline resectable pancreatic cancer. The aim is to evaluate the feasibility of this approach and if successful will inform a follow-on Phase III trial of neoadjuvant therapy. The trial offers a unique opportunity to take samples longitudinally during therapy. Tissue and blood will be available for biomarker analysis that may (i) predict response; (ii) change with response and (iii) predict the progress of patients before and after surgery with different neoadjuvant therapies. Aims: (i) To evaluate the feasibility of collecting samples from patients in the ESPAC-5F trial before and after neoadjuvant therapy and surgery; (ii) To explore markers of response to neoadjuvant therapy. Methods: Samples will be collected according to good clinical practice by a facility expert in standardisation of collection, processing and storage. Serum, plasma and cells will be collected from blood before, during and after neoadjuvant therapy and following surgery. Frozen tumour tissue will be obtained by EUS biopsy prior to neoadjuvant therapy and following neoadjuvant therapy by intra-operative transduodenal tru-cut biopsy. Tissue will be obtained following pathological examination both as fresh frozen and formalin fixed samples. The samples will be available for biomarker analysis by our group and others. Data will be returned and linked to clinical outcomes. How the results of this research will be used: If the aims of obtaining and storing the range of samples described in ESPAC-5FT are achieved then the study will have been successful. This groundwork will provide the basis for sample collection in the anticipated Phase III follow on trial. All samples will be transferred to the ESPAC tissue bank and an independent committee will allocate samples to high quality projects to identify or to test markers.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: Development and pilot evaluation of the Tenovus health check: a targeted cancer awareness intervention for people from deprived communities
Funder: Cancer Research UK

Abstract: Background: Evidence suggests that delayed help-seeking and poorer cancer survival may be linked to low cancer awareness and attitudes reflecting fear, denial and fatalism in deprived populations. To date, interventions designed to increase cancer awareness and encourage help-seeking have not been targeted at communities with high levels of social deprivation. The health check is an innovative intervention developed for this purpose by the cancer charity Tenovus, and is a tablet-based interactive questionnaire delivered face-to-face by a trained lay advisor in disadvantaged communities (http://live.ohc.precedenthost.co.uk/). Aims: ABACus (Awareness and Beliefs About Cancer intervention study) will be undertaken in partnership with Tenovus and other key local stakeholder groups to develop the evidence base for the health check. Methods: In accordance with the MRC framework, the research will be conducted in two phases of development and evaluation, targeting adults aged 50+ living in deprived areas of Wales. Phase 1 development: a) 6 focus groups to understand local community stakeholder views (2 groups with lay representatives and 4 groups with potential providers) regarding the location, format and delivery of the health check; b) field testing the health check with a purposive sample of 20 potential users to assess its acceptability, with intervention modifications as required. At the end of Phase 1, a report will be provided to the NAEDI Committee. We will proceed with Phase 2 on the basis of demonstrated acceptability of the intervention to potential users and providers, and successful modelling of intervention setting and delivery. Phase 2 evaluation: a) prospective, non-randomised evaluation of the adapted intervention to test the feasibility of recruitment in different community settings, and to pilot the quantitative measurement of outcomes including symptom recognition (primary outcome), awareness of risk factors, attitudes, beliefs and help-seeking intentions/behaviours (secondary outcomes) in 95 participants assessed at baseline and 1 month follow-up; b) process evaluation including 20 observations of health check usage and qualitative interviews with 30 health check users to understand how the intervention works and whether it is being used in the way that it was designed to be used. How these results will be used: This multidisciplinary research will build on the foundation of the International Cancer Benchmarking Partnership, with the potential to benefit disadvantaged communities in and beyond Wales. Should the intervention demonstrate acceptability and the potential to improve outcomes relating to symptom awareness and early presentation, the research will form the basis for a future trial of effectiveness.


Research activity codes: 4.3 INFLUENCES AND IMPACT;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: CRUK/09/014: GROMITS+: Genetic Regulation Of Myeloma In Tissue Samples Plus
Funder: Cancer Research UK

Abstract: Background Myeloma XI is a randomised phase III clinical trial exploring the role of two new drugs, lenalidomide, bortezomib, vorinostat and carfilzomib for the treatment of newly diagnosed multiple myeloma. Aims The aim of this project is to establish a sample bank linked to the clinical trial which will allow for the identification and validation of biological prognostic markers. Methods Following informed consent the excess tissue from diagnostic peripheral blood (PB) and bone marrow (BM) aspirate samples will be obtained from myeloma patients entered into the myeloma XI clinical study at presentation. Using established protocols and SOPs CD138+ plasma cells will be obtained by magnetic bead selection from BM and DNA and RNA stored. Somatic DNA and serum will be stored from PB. How the results of this research will be used Future studies will aim to validate prognostic markers identified by gene expression profiling and mapping techniques in the previous study, Myeloma IX, and define new classification and outcome predictors related to lenalidomide, bortezomib, vorinostat and carfilzomib therapy. Additionally, the mutational spectrum of myeloma will be addressed and related to response to therapy and patient outcome.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: CRUKD/14/004 ComPAKT A Phase I multi-centre trial of the combination of AZD5363 (AKT inhibitor) and olaparib (PARP inhibitor) in patients with advanced solid tumours
Funder: Cancer Research UK

Abstract: Background Despite impressive response rates observed in advanced BRCA1/2 mutant cancers, the remissions achieved with poly(ADP-ribose) polymerase (PARP) inhibitor monotherapy have not been durable, and benefit in sporadic cancers that may harbour homologous recombination (HR) defects, such as triple negative breast cancer (TNBC) remains unclear. There has also been modest clinical activity reported with single agent phosphatidylinositol-3-kinase (PI3K)-AKT pathway inhibitors in early phase studies, supporting the use of these agents in combination regimens. The rationale for the combined inhibition of PARP and the PI3K-AKT pathway as an anticancer strategy is supported by recent preclinical studies demonstrating synergistic antitumour effects in BRCA mutant tumours (Juvekar et al, Cancer Discovery 2012). Also, PI3K-AKT pathway inhibition was demonstrated to impair BRCA1/2 expression, with subsequent sensitisation to PARP inhibition in TNBC without BRCA mutations (Ibrahim et al, Cancer Discovery 2012). Aims The primary aim is to determine the safety and tolerability of the PARP inhibitor olaparib in combination with the AKT inhibitor AZD5363, and to establish a maximum tolerated dose (MTD) in patients with advanced solid tumours, including BRCA1/2-mutant cancers and sporadic tumours. The secondary aims are to assess the pharmacokinetic-pharmacodynamic (PK-PD) profile, and preliminary antitumour activity of the combination. Methods A phase I trial will be conducted in 2 parts. (A) Dose escalation phase: AZD5363 will be given twice-daily in two parallel intermittent schedules (4-days-on, 3-days-off; 2-days-on, 5-days-off) with continuous olaparib (300mg bd). Intrapatient dose escalation of AZD5363 will be pursued through 3 dose levels up to the MTD. (B) Once the MTD is reached for both arms, the schedule with the optimum safety and PK/PD profile will be selected for the dose expansion phase, which will comprise 2 arms: (1) Patients with advanced BRCA1/2 mutant cancers; (2) Patients with advanced sporadic cancers not known to harbour germline BRCA1/2 mutations, but which may harbour HR defects, e.g. advanced TNBC, castration-resistant prostate cancer and high-grade serous ovarian cancer, and cancers with somatic mutations or other aberrations known to result in PI3K-AKT pathway hyperactivation. How the results of this research will be used This phase I trial will establish the MTD of the combination of olaparib and AZD5363. Subsequent tumour-specific phase II studies will be conducted depending on findings from this study. If successful, the intrapatient dose escalation trial design may be employed for the conduct of other phase I combination studies.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Protein Structure and Function Laboratory - Studentship
Funder: Cancer Research UK

Abstract: Post-translational modification of proteins by ubiquitin is involved in virtually every cellular process, from cell-cycle control to the wound response in plants. As well as being a signal for proteasomal destruction of target proteins, ubiquitin signaling plays a key role in the DNA damage response. There is a range of different ubiquitin signals that can be produced. A substrate can be monoubiquitinated, or multiply-monoubiquitinated, where a single ubiquitin is conjugated to one or more specific residues. Alternatively, a substrate may be modified by a chain of ubiquitins conjugated to themselves through one of 7 lysine (K) residues and the N-terminal methionine. In addition to homotypic chains, branched chains of ubiquitins conjugated to different lysines can be formed. Much of our research centres on understanding the molecular mechanisms underlying the choice of modification, the recognition of substrates by the ubiquitination machinery, and the regulation of the key enzymes involved. We employ disease-related models to address these questions, using a combination of X-ray crystallography and biochemical techniques.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS