NIHRDataInsights/HRCSData huggingface dataset:
Title: A novel high-throughput approach to stratify patients based on chemotherapeutic response.
Funder: Health and Care Research Wales (Welsh Government)

Abstract: Cancer is a devastating disease and is more prevalent in Wales than other countries of the UK (CR-UK figures). The mainstay cancer treatment, chemotherapy is effective in only some patients. Indeed, some patients undergoing chemotherapy find that their cancer actually spreads. This form of resistance to therapy is complex and is governed by a myriad of genetic interactions that are unique to each tumour/patient. At present it is not feasible (due to high costs) to dissect these detailed genetic factors and plan tailored therapy for all patients. However, we urgently need to better understand the effectiveness of chemotherapy early enough so that patients and clinicians can make informed decisions about whether to switch treatment regimens (if it is not working) or in some cases to cease treatment if there is no benefit. Until now, the mixed response to chemotherapy in different patients has only been apparent after the treatment ends and once scans show either shrinkage of the tumour, or no change in tumour size. We have developed a “low-cost” blood test that sensitively measures circulating DNA mutations in blood cells induced by chemotherapy. We have trialled this in oesophageal cancer patients and have shown some patient’s blood cells respond to the chemotherapy and many mutations are induced, however others show minimal response with very few mutations induced. This test may then act as a surrogate for the “response” of the tumour to therapy and may identify the responders and the non-responders to chemotherapy –actually during the treatment phase. Hence, it may be possible to intervene early using this technology in cases where patients are not responding and switch treatments between cycles. This studentship will create further pilot data, building on the preliminary investigations carried out to date and provide evidence as to whether this approach can be clinically useful.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: CANCER AND NEOPLASMS
Title: Therapeutic exosomes as novel treatment for ovarian cancer.
Funder: Health and Care Research Wales (Welsh Government)

Abstract: Ovarian cancer is the fifth most common cause of cancer death in women and accounts for more UK deaths than all of the other gynaecological cancers put together. Over 7,000 women are diagnosed with ovarian cancer every year in the UK and 4,200 will die. Symptoms of ovarian cancer are often vague early on and many women are not diagnosed until after the cancer has grown and spread to other parts of the body. Less than half of women with ovarian cancer survive five years from diagnosis with many not respond to current treatments. Platinum-based drugs (such as cisplatin and carbonplatin) are the most widely used chemotherapy drugs in ovarian carcinoma (85% patients will receive this treatment), but their efficacy is not satisfactory. Recent studies have demonstrated that a subpopulation of adult stem cells expel chemotherapeutic drugs in extracellular compartments using specialised transporters system called “exosome”. These exosome vessels have been found to provoke the cell death of liver, breast and tumour blood vessel cells. Studies in animals have also reported similar results in reducing tumour growth and stimulate cancer cell death. This proposal aims to investigate whether therapeutic exosomes may influence the growth of ovarian cancer cells in vitro. In addition, these novel drugs will also be assessed in combination with current treatments including cisplatin to determine their potential benefit for combination therapy. If therapeutic exosomes are found to be effective at killing ovarian cancer cells, they could be a new treatment option for patients with ovarian cancer. This may improve survival when current treatments have stopped working.. To achieve these goals, a collaborative effort will be necessary and thus, this proposal will unite teams in Swansea University specialized in ovarian cancer research and the Torino Molecular Biotechnology Centre, Torinio University (Italy) that discovered these therapeutic exosomes.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Novel CD38 Targeting Cancer Immunotherapy
Funder: Innovate UK

Abstract: Tusk Therapeutics is a UK biotechnology company with a focus on harnessing the power of the immune system to fight cancer through the development of novel immune modulating therapeutics. The company has established a diversified pipeline of antibodies against both novel and validated targets that play an important role in the body’s immune response to cancer. The company is actively pursuing three preclinical programmes, including TSK011010, a novel fully human anti-CD38 antibody. The funding sought in this application will further accelerate the development of TSK011010, enabling the company to bring it to market more quickly, benefitting cancer patients worldwide.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Novel c-Met Protein Targeted Molecular Imaging of Cancer with the SurgVision Endoscope Explorer
Funder: Innovate UK

Abstract: To deliver a revolutionary optical cancer screening solution that combines a unique biomarker with a novel imaging device, addressing a significant gap associated with current screening methods (high cancer miss rates, poor visualisation). Project outputs will determine which of a number of possible indications to take forward to full stage clinical trials and provide data to support regulatory submission and help to obtain "an indication and diagnostic" label.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Characterisation of Chromatin Landscapes of Pre-leukaemic and Leukaemic Stem Cells in Core Binding Factor AML and their Response to Epigenetic Therapy
Funder: Leuka

Abstract: Acute Myeloid Leukaemia (AML) is a clonal disorder of the myeloid lineage. Whilst up to 80% of patients treated with intensive chemotherapy can achieve a clinical remission, most will eventually relapse and die. One type of AML, caused by mutations in the genes encoding the haemopoietic master regulator RUNX1 or its binding partner CBFB, is defined by the generation of RUNX1-ETO (in t(8;21) AML) or CBFB-MYH11 (in Inv(16) AML) fusion genes as a result of genomic translocations. There are also mutations in the RUNX1 gene itself. Monitoring translocation patients during remission shows that those with detectable fusion transcripts by RT-PCR are more likely to relapse. We hypothesise that these transcripts originate from pre-leukaemic or leukaemic stem cells (LSCs) that are insensitive to chemotherapy. We will purify LSCs from the bone marrow cells from AML patients at diagnosis and characterise their epigenome using ATAC-Seq and RNA-Seq. Single cell RNA-Seq will examine cellular heterogeneity. We will use this information as well as data from pre-leukaemic cell line models to examine enriched cells from patients in remission to identify additional markers for the presence of minimal residual disease. We also know from the literature and from our preliminary data that the transcription factor WT1 is upregulated in CBF leukaemia and that such patients relapse earlier. To gain an understanding how RUNX1-ETO and WT cooperate, we will map global WT1 binding sites, knock it down or overexpress it to assess how WT1 contributes to the RUNX1-ETO specific transcriptional deregulation. Finally, at Birmingham, the phase II RAvVA trial led by my supervisor Prof Craddock, looks at the efficacy of the epigenetic drugs Azacitidine and Vorinostat in patients with AML. By profiling the chromatin landscape of serial marrow from patients with RUNX1 mutations recruited to the trial, we will gain a unique insight into disease evolution and the emergence of resistance to therapy.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Molecular and Cellular Basis of Clonal Dominance in Myeloid Malignancy
Funder: Leuka

Abstract: Recently it has been shown that clonal haematopoiesis associated with somatic mutations is common in elderly individuals. The majority of mutations occur in genes encoding three epigenetic regulators, DNMT3A, TET2 and ASXL1, and notably mutations in the same genes are initiating events in the development of acute myeloid leukaemia (AML). Acquisition of one of these mutations in a haematopoietic stem or progenitor cell leads to clonal expansion and increases the risk of haematological cancer, though blood cell production is not impaired. This project aims to determine the molecular and cellular mechanisms that lead to clonal advantage in the development of myeloid malignancies. To identify the cell type which propagates this state, we will characterise primary human bone marrow samples from elderly adults with clonal haematopoiesis, and from patients with AML in disease remission. In parallel, a mouse model with an inducible Dnmt3a-R882H allele will be developed, that will allow mutant haematopoietic cells to be fate-mapped in situ. We will determine the phenotypic consequences of mutations in purified haematopoietic stem and progenitor cells - this will involve assays of proliferation, self-renewal, differentiation and lineage potential - and study how the epigenetic and transcriptional profile is altered in order to identify genes that are dysregulated in mutant cells. Comparing results from human and murine cells will allow common pathways in equivalent cell types to be identified. A shRNA dropout screen will be developed to test which of these pathways are critical to driving clonal advantage. This study will shed light on how myeloid malignancies develop, and provide general insights into cancer development and stem cell ageing. By elucidating the mechanisms underlying clonal advantage, we hope to identify a therapeutic target that would allow eradication of dominant preleukaemic clones prior to the development of fully transformed leukaemia.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Lebedev PhD studentship: Researching Young People with Cancer on the Internet: Development of Ethical Guidance and Suggestions for Research Regulation using the Views of RECs and Young People
Funder: Marie Curie

Abstract: The ethics of research using the Internet and the particular challenges of doing so with children and young people remains under-developed. The first part of this study will involve reviewing the current literature and practice on research with children and young people using the Internet with a view to assessing how the Internet could be used as a platform for researching populations of children and young people with cancer or indeed how to provide care through online platforms for young people (13-25 years) with palliative care needs in a safe and secure fashion. A systematic review will explore the types of Internet-mediated research that has been conducted with young people with cancer (13-25 years), in addition to the ethical issues and the efficacy of using Internet-mediated research methods with this population. A document analysis will be conducted on decision letters from UK Research Ethics Committees to explore the types of ethical conflicts that can arise within the context of Internet-mediated clinical research with young people (13-25 years) with life-limiting or life-threatening conditions. Following the collation of the results of the first part further studies will be developed to ascertain the opinions of young people with cancer, their parents and clinicians on research using the internet and internet mediated technologies.


Research activity codes: 7.2 END OF LIFE CARE
Health categories: CANCER AND NEOPLASMS
Title: Sonographic and Biological Indicators of Malignant Pleural Effusion Efficacy (SIMPLE) - a randomised trial
Funder: Marie Curie

Abstract: Background Malignant pleural effusion (MPE) is a common and increasing problem. Pleurodesis using sterile talc is the standard of care for MPE, and is successful in 70-80%. The procedure requires a catheter to be placed in the chest, full drainage of the chest and subsequent pleurodesis, but there is no robust evidence addressing the time course of pleurodesis occurrence, nor the optimal timing of drain withdrawal. Thoracic ultrasound is increasingly used at the bedside, and pilot data suggest it may be useful in the diagnosis of pleural adhesion soon after talc administration. Aims 1. Establish if a novel radiological investigation (thoracic ultrasound) can improve quality and efficacy of care for MPE patients undergoing talc pleurodesis. 2. Establish a biobank of prospectively collected biological samples and radiology in patients undergoing talc pleurodesis, linked to robust outcome data, to investigate factors associated with pleurodesis success and redefine the current understanding in a patient centred model. Methods 1. Conduct a randomised multicentre controlled trial of the use of thoracic ultrasound during the first 24-72 hours post talc administration in patients with MPE, to assess if this accurately identifies pleural adherence early in treatment, permitting shorter hospital stay without reducing pleurodesis success. 2. Assess potential health economic impacts of this new treatment paradigm. 3. Collect robust outcomes and sequential biological samples, and statistically model parameters against clinically important outcomes (pleurodesis success, relief of breathlessness, improvement in quality of life) to establish predictors of clinical success in talc pleurodesis, to redefine the role of interventions in a patient centred model, and permit individualisation of care. How the results of this research will be used If thoracic ultrasound is able to identify patients with a high likelihood of pleurodesis success early after talc administration, this will change the current treatment paradigm for thousands of patients / year. This may permit earlier discharge from hospital and promote improvements in quality of life and substantial healthcare cost reductions. Identification of potential predictors of outcome success in talc pleurodesis will revolutionise the use of pleurodesis, with the potential to individualise patient treatment. This will permit rational selection of potentially dangerous interventions, and targeting of these interventions to those who would benefit most. Focus on outcomes important to patients (breathlessness, chest pain, quality of life) and clinicians (hospital stay, healthcare costs) ensures any results are translatable to real patient and healthcare system benefits.


Research activity codes: 7.2 END OF LIFE CARE;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Double-blind randomised parallel group trial of paracetamol versus placebo in conjunction with strong opioids for cancer related pain.
Funder: Marie Curie

Abstract: National guidelines advocate the use of paracetamol in conjunction with strong opioids for cancer pain, despite a lack of evidence for its efficacy. A systematic review by our group highlighted very limited evidence for this practice (1). Furthermore, eight tablets a day of paracetamol contributes significantly to the tablet burden of large numbers of patients with cancer. Work is needed to examine the analgesic benefit of paracetamol in this large patient group we propose a definitive study to examine this important issue. Aim: To establish if paracetamol in combination with strong opioids provides superior analgesia for cancer related pain than strong opioids alone. Methods: Patients with incurable cancer and cancer-related pain currently taking regular strong opioids and regular paracetamol are the target group for study. This is a 17 day study with a three day baseline assessment, during which time patients will continue to take their usual regular paracetamol and strong opioids. On completion of this phase patients will be randomised to receive either placebo/paracetamol in the ensuing intervention phase. On day one of intervention phase patients will no longer be taking their own supply of paracetamol and will instead receive either paracetamol or placebo, which they will take for the next 14 days. Brief daily pain assessments will be completed. Pain scores from day 14 of the intervention will be compared to scores from day one of the baseline assessments for each participant. The primary outcome is the proportion of patients in the placebo group who have a clinically meaningful (30%) increase in their BPI score between baseline assessment day minus 3 and intervention assessments day 14 compared with those randomised to paracetamol. 140 participants will be recruited to each arm. Results: Results will be presented at appropriate scientific conferences and published in peer reviewed journals. The results have the potential to impact on national and international guidelines and to alter the prescribing habits of specialists and generalists treating patients with cancer pain.


Research activity codes: 7.2 END OF LIFE CARE;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: An exploratory study to develop and evaluate a simple bedside tool for community use to identify who is most likely to benefit from palliative radiotherapy for cancer induced bone pain: Thermal testing in Bone Pain (TiBoP)
Funder: Marie Curie

Abstract: Cancer induced bone pain (CIBP) (pain from cancer deposits in bone) is a major clinical challenge. It often causes significant distress and suffering for patients, with patients needing to attend hospital for radiotherapy (XRT). Although XRT is the best available treatment for CIBP, only ~40% of patients will get good analgesia taking up to 6 weeks to work, with XRT toxicity affecting up to 60% of patients (1). For patients, the burden of XRT is justified if it provides pain relief, but not if it is ineffective and/or delays consideration of other potentially effective strategies. There is an urgent need to improve our understanding of who is most likely to benefit from XRT for CIBP using a community-based tool. This would allow XRT to be directed appropriately, whilst protecting others from hospital visits and ineffective treatment. Pilot work by our group assessed a wide range of clinical biomarkers in patients with CIBP undergoing XRT, in the hospital setting. Our findings suggest that altered sensitivity to warm and cool stimuli on the skin overlying the site of CIBP, may predict those patients likely to respond to XRT. We are now able to refine these clinical biomarkers to a simple bedside tool and assess the feasibility of its use in the community. Aims: To develop and evaluate the feasibility of using a simple bedside tool (measuring thermal sensitivity) in the community to identify patients most likely to benefit from palliative radiotherapy for CIBP; To measure the strength of the association between altered thermal sensitivity (assessed using this bedside tool) with XRT analgesic outcome when used in the community setting. Methods: After ethics approval and written informed consent, patients with CIBP, due to undergo XRT at the regional cancer centre, will be assessed in the community and at 2, 4, 8 and 12 weeks. Assessments of thermal sensitivity, validated self-report measures of CIBP and its impact, plus basic demographic measures, as well as the burden imposed on patients by XRT, and satisfaction with use of the tool will be recorded. Use of results: This exploratory study will inform the design of future randomised controlled trials to assess clinical utility and predictive value of this simple bedside tool. The proposed study is the next logical step from our promising pilot study in the development process of a simple aid to direct management and reduce unnecessary treatment and attendance at a specialist cancer centre.


Research activity codes: 7.2 END OF LIFE CARE
Health categories: CANCER AND NEOPLASMS
Title: Developing and Evaluating an educational intervention for the management of constipation: a feasibility intervention study (DEMCoN)
Funder: Marie Curie

Abstract: Background The WHO advocates that palliative care should seek to improve the quality of life of patients and their families through early identification and treatment of symptoms. Constipation is one of the most frequently encountered symptoms in the palliative care population causing considerable suffering, either as a direct consequence of physical symptoms or due to related social and psychological complications. Previous research indicates that variations in the assessment, diagnosis and management of constipation in palliative care settings exist, despite best practice guidelines. Education of health care professionals (HCP) is essential to overcome barriers to implementing evidence in practice and to equip HCPs to provide good quality care for patients and their families. Aims To develop and test the feasibility and acceptability of a novel educational intervention for health care professionals to help them manage constipation experienced by people in the hospice setting. Methods The study will involve four phases. The first phase will include a systematic review of educational interventions for HCPs for the management of constipation, a retrospective purposive review of patient charts (n=150) in three Marie Curie hospice sites in the UK, qualitative interviews with patients/carers (n=15) and 3 focus groups (n=30) with HCPs to identify potential barriers and facilitators of effective management of constipation within specialist palliative care settings. These findings combined with a key stakeholder workshop will lead to the development of an educational intervention. The third phase of the study involves the implementation of the novel educational intervention with a sample of HCPs (nurses, medics and pharmacists n=approx. 30 HCPs) within one Marie Curie hospice site in the UK. This will involve the use of a ‘Train the Trainer’ model, identification of key champion and innovative technological support derived from Project ECHO (Extension for Community Healthcare Outcomes). The final phase will seek to evaluate the primary feasibility outcomes: usability and acceptability of the intervention from the perspective of HCAs and patients in an inpatient hospice setting. To gain HCP feedback questionnaires focusing on knowledge and competency will be collected. Evaluation with patients’ outcomes will be assessed using tools defined and refined in Phases 1&2 and guided by recommendations of a consensus paper on the selection/use of outcome measures in palliative care research. Cost implications of the intervention will be assessed from the NHS, hospice and patients/families perspectives.


Research activity codes: 7.2 END OF LIFE CARE
Health categories: CANCER AND NEOPLASMS