NIHRDataInsights/HRCSData huggingface dataset:
Title: Clinical trials in brain tumours
Funder: Medical Research Council

Abstract: Approximately 4000 patients are diagnosed with a primary brain tumour every year in the UK. Many are incurable and consequently brain tumours account for 7% of the years of life lost from cancer before the age of 70, despite accounting for only 2% of all primary tumours.|MRC trials have focused mainly on the treatment of adult patients with malignant glioma. The results of our BR12 randomised trial in patients with recurrent glioma are now in press; this compared standard treatment combination chemotherapy with procarbazine, CCNU and vincristine (PCV) - with temozolomide (TMZ), given according to one of two schedules (5 days x 200mg/m2 vs 21 days x 100mg/m2 every 28 days until progression). This is the largest trial ever conducted in recurrent glioma, and while it showed no clear benefit to TMZ over PCV, the novel 21-day TMZ regimen was shown to be inferior to the conventional 5-day schedule, challenging the current rationale for increasing temozolomide dose intensity by prolonged scheduling.|Two prospective, international, randomised trials (BR13 and BR14) conducted in collaboration with the European Organiation for Research and Treament of Cancer (EORTC) are currenty recruiting patients with the MRC coordinating the UK intergroup collaboration. |Patients with low grade gliomas often receive no active treatment until they have symptoms of progressing tumour. At that point, radiotherapy is generally employed although there is increasing interest in using chemotherapy instead, in particular to avoid some of the late effects of radiotherapy on quality of life (QL) including cognitive function. The BR13 trial compares progression-free and overall survival and QL in patients treated with either radiotherapy or chemotherapy (temozolomide). The target accrual of registered patients was met in 2010; randomisation of registered patients will continue to 2011.|In grade IV tumours, an EORTC trial showed that the combination of radiotherapy with concurrent temozolomide, followed by a course of adjuvant temozolomide, significantly improved survival. However, the contributions of each aspect of treatment could not be teased out, and the results may not apply to lower grade tumours. BR14 examines both components in a 2x2 factorial design in patients with grade III gliomas, excluding those with 1p and 19q deletions. The primary outcome measure is survival. This trial is a collaboration between the UK (NCRI Brain Tumour Group and MRC CTU), the EORTC, the NCIC (Canada) and the RTOG and HUB groups in the US, and opened in the UK in 2010.


Research activity codes: 6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Genomic Instability in mature B-cells
Funder: Medical Research Council

Abstract: Several forms of cancer are linked to gross chromosomal abnormalities, which result from a general instability of the genome. Genome instability can be caused by exposure to toxic chemicals or by other genotoxic or epigenetic factors. In the pathogenesis of the malignancies of mature lymphocytes, namely the non-Hodgkin lymphomas and chronic lymphocytic leukaemia, chromosomal translocations involving the immunoglobulin loci are common and we have developed techniques to facilitate their cloning.||In collaboration with several groups worldwide, we continue to clone new chromosomal translocations, since although rare, these allow identification of genes that play a pivotal role in the development of normal and malignant B-cells.||Work in the lab is now establishing how the involved oncogenes transform mature B-cells. However, we are also using whole cell genomic and proteomic approaches to search for additional abnormalities, including the identification of novel tumour suppressor genes.||Since, the pathogenesis of these diseases is not known and many remain incurable with conventional chemotherapy, the molecular dissection of the genetic defects associated with these malignancies should allow rational development of new and effective targeted therapies. Our studies provide new insights in the mechanisms of development of cancer and at the same time provide new targets for the development of safe drugs.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Exploration of factors associated with place of care and place of death in patients with haematological malignancies
Funder: Marie Curie

Abstract: Home is generally considered the preferred place of care and death, however, our systematic review and meta-analysis showed that patients with haematological malignancies are over twice as likely to die in hospital as those with other cancers (Annex 1). They are also less likely to receive palliative and hospice care (Annex 2). This has implications for patients who may not be dying in their preferred place, and health care commissioners who may be funding expensive end-of-life care in inappropriate acute hospital settings. Haematological malignancies are common and have a high case fatality rate compared to many other cancers. Their trajectories are complex and diverse, and whilst some patients die soon after diagnosis, improvements in the treatment of others mean that patients can live long periods with what is essentially chronic disease. Despite these issues there is an absence of empirical evidence about place of care and death in haematological malignancy patients. Aims and objectives We aim to generate evidence about place of care and death in patients with haematological malignancies. Key areas will be identified where practical changes would facilitate care and death in the patient’s preferred place. Methods The study is cross-disciplinary, based on the infrastructure of the Haematological Malignancy Research Network (HMRN, www.hmrn.org) and supported by the Palliative Care and Haematological Malignancy Steering Group and Haematology User Group (Annex 3). Mixed quantitative and qualitative approaches will be used to gather information from multiple sources. Initially, the hospital records of 808 patients with a haematological malignancy, dying within the HMRN area during 2009 will be examined (Annex 4). Events during the last two weeks of life will be recorded using our validated day-by-day calendar approach (Annex 5). This will complement data routinely collected by HMRN for audit on these patients. Semi-structured interviews will also take place with relatives, carers and haematology, palliative care and generalist practitioners in primary and secondary care. These will be transcribed and analysed using Atlas-ti to identify codes and themes. How the results of this research will be used Results will be synthesised alongside existing literature and policy in collaboration with the Steering Group. Findings will be disseminated locally at Network Site Specific meetings and will be used to instigate practitioner-led change. The HMRN area is representative of the UK in terms of both demography and clinical practice, meaning results are highly generalisable. National and international dissemination will occur via publication and conferences.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;7.2 END OF LIFE CARE
Health categories: CANCER AND NEOPLASMS
Title: BRIGHTLIGHT on End of Life care for young adults – what do young adults and their families need and how can it best be delivered?
Funder: Marie Curie

Abstract: Background The impact of incurable cancer on patients and families is strongly influenced by life stage, most easily identified by age. For adults in early to mid-life, very little is known about end of life (EoL) experience or how care is best delivered although acknowledgement of its specific challenges is frequent amongst professionals. This study will define the EoL needs of 16-40 year olds, chosen as those on the borders of paediatric care but who are less often encountered in adult cancer and palliative care services. Aims The study aims to understand a) The core components in the pathways of care in the last year of life for people with cancer aged 16-40 years. b) Any differences between the experiences of people with cancer from the age ranges 16-24 and 25-40 years. c) How young adults and their families can be supported in the last year of life to achieve their preferences for care. d) The challenges that exist for health and social care professionals providing care. Methods A national multiple methods study guided by the MRC framework for complex interventions which uses realistic evaluation, a methodology particularly suited to informing practice and service improvement. The study links to BRIGHTLIGHT (NIHR RP-PG-1209-10013). It intends to explore causal mechanisms and context through five consecutive phases of research: (i) Preparatory phase: detailed synthesis of literature; analysis of care patterns described by national cancer data sets (ii) Interviews with patients, families and professionals. Longitudinal qualitative interviews with 16-24 years olds in the BRIGHTLIGHT study. Case studies of thirty 16-40 year-old cancer patients at EoL, family members, key professionals. Analysis of written communication and documentation in medical notes (iii) Scenarios workshop: nine workshops nationally for interactive discussion and to disclose perspectives, opinions and experience. Three workshops with patients and family, three with professionals and three with mixed participants. (iv) Panel of experts: presentation of findings and iterative analysis to test fit of potential outcomes to mechanisms (v) Development of recommendations for practice and further evaluation. An overarching account of the core components and pathways of EoL care will be developed and shared to incorporate feedback with research participants, policy makers, commissioners and other stakeholders. How the results of this study will be used Definition of national standards, pathways of care and core competencies are A15722 Dr Jeremy Whelan IN CONFIDENCE MC - Project Award - October 2012 13 anticipated. Areas for potential intervention, recommendations for future empirical evaluation and testing of the effect on outcomes will be identified.


Research activity codes: 7.2 END OF LIFE CARE;7.3 MANAGEMENT AND DECISION MAKING
Health categories: CANCER AND NEOPLASMS
Title: Changing patterns of place of cancer deaths in children and young people, 1984-2010
Funder: Marie Curie

Abstract: BACKGROUND Knowledge about place of death in adults has advanced dramatically over the past thirty years. Cancer is one of the leading causes of death. However, limited evidence on place of cancer deaths is available for children and young people. Whether and how the patterns of place of cancer deaths in children and young people have changed over time, has never been evaluated at the national level. AIMS The study aims to provide evidence about how end-of-life cancer care in children and young people has changed over time. The specific objectives: a) to determine pattern changes in place of cancer deaths and the associated factors; b) to provide recommendations for service providers, NHS management and policy makers to improve end-of-life care. METHODS A whole population observational study. The data are extracted from the ONS Death registry database. All cancer related deaths (ICD-9: 140-209; ICD-10: C00-C97) in children and young people (=24 years), which occurred between 1984 and 2010 in England are included. Outcome variable is place of death; explanatory variables include socio-demographic, clinical, geographic and other variables. The analyses are performed for the whole period (1984-2010) and for the defined sub-periods separately. The sub-periods are defined in the context of the national programmes for end-of-life care improvement and the coding changes. The place of cancer deaths are described as count and relative frequency by selected explanatory variables. Modelling analyses are performed at the individual-level and populationlevel. Factors associated with place of cancer death (modelled as binary or nominal variable) are investigated using the generalised linear models (GLM) at the individual-level; the clustering effects within geographical units are adjusted using the generalised estimating equation (GEE) technique. The pattern changes in place of cancer deaths and the associated factors are evaluated using three strategies: 1) population-level modelling: we will fit the data with a series of candidate models (eg. quadratic trend model, joinpoint regression model), the models are tested against the null hypothesis (no change across the defined periods); 2) in-depth exploration of interaction effects between periods and candidate variables; 3) comparing and contrasting individual-level modelling results across the defined periods. HOW THE RESULTS WILL BE USED Research findings about pattern changes in place of cancer deaths and the associated factors will be fed back nationally and regionally to service providers, NHS management and policy-makers through various methods (eg. webpages, scientific publications, conferences, seminars and workshops).


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;7.2 END OF LIFE CARE
Health categories: CANCER AND NEOPLASMS
Title: ACCESSCare: Advanced Cancer Care Equality Strategy for Sexual minorities
Funder: Marie Curie

Abstract: Background Lesbians have a higher lifetime risk of breast, cervical and ovarian cancer than heterosexual women, and gay men have a greater prevalence of cancer compared to heterosexual men. There is a greater risk of breast and prostate cancers for maleto-female transgendered people, and of ovarian, breast and cervical cancers for female-to-male. The UK’s End of Life Care Strategy “Equality Impact Assessment” concluded “sexual orientation and gender identity are perhaps the most likely areas for inequality and discrimination to occur in end-of-life care.” Despite ongoing innovative work to enhance older LGBT care, little attention has been paid to those in the last year of life of all ages. Our recent systematic review of palliative and endof-life needs, preferences and experiences of LGBT people identified 12 original studies, 1 from the UK. The data provided opportunities to improve communication, expectations, environments and practice, and highlighted evidence gaps to be addressed. Aims To develop and disseminate evidence-based mass media resources with the LGBT community to increase the demand for appropriate end-of-life care, and to improve supply of appropriate end of life care through development of training resources for integration within existing end-of-life care curricula for health care professionals. Methods PHASE 1 1. To conduct qualitative interviews with lesbian, gay, bisexual and transgender adults with advanced disease, and their caregivers, to determine their views on the current global evidence and guide the development of patient/carer-centred UK-wide resources. PHASE 2 2. To integrate the evidence of the systematic review and findings from the qualitative study to develop mass media resources for distribution, drawing on our Project Steering Group. 3. To conduct field testing of the patient/carer-centred mass media resource and revise as necessary, and to disseminate widely through LGBT media and other consumer end-of-life care contact points. PHASE 3 4. To develop training resources from the systematic review, qualitative evidence and final patient-centred outputs, for delivery within existing end-of-life courses. 5. To implement a protocol monitoring impact through relevant metrics. How the results of this research will be used Our strategy includes data demand and utilisation activities. 1) Advancement of knowledge: peer review publication of the UK original data. 2) Demand for better care: integration of the existing and new data into relevant mass media resources; dissemination through UK-wide LGBT community resources and points of end-of-life care. 3) Supply of better care: integration of the resources into existing UK end-of-life care training packages.


Research activity codes: 7.2 END OF LIFE CARE;7.3 MANAGEMENT AND DECISION MAKING
Health categories: CANCER AND NEOPLASMS
Title: ASPP2: A molecular switch of cancer initiating cells in Squamous Cell Carcinoma?
Funder: Medical Research Council

Abstract: Around 80% of human cancers are epithelial in origin. Of the different tumour types arising in epithelial tissues, squamous cell carcinoma (SCC) is the most malignant and has the highest metastatic potential. Our preliminary results show that the tumour suppressor ASPP2 is able to repress p63 expression, is highly expressed in keratin 1-positive and keratin 14-negative stratified epithelial cells, and that differentiation induces ASPP2's expression in vitro. Most importantly of all, ASPP2 heterozygous and null mice spontaneously develop SCC of the skin. These observations challenge the current view that SCC is derived from basal cells (p63+, keratin 14+/keratin 1-), as ASPP2 is hardly expressed in this cell population. SCC cells may instead be derived from differentiated keratin 1-positive cells in the suprabasal layer. Due to changes in their epigenetic regulation, differentiated keratin 1-positive squamous epithelial cells may start to re-express keratin 14 and p63 to gain a proliferative potential. To determine the precise origin of SCC, ASPP2 will be deleted in keratin 14-positive basal cells and keratin 1-positive suprabasal cells using keratin 14-Cre or keratin 1-Cre respectively. The ability of these mice to develop spontaneous SCC will be studied. To identify genes that ASPP2 uses to suppress SCC, we will also conduct gene array analysis on SCC samples from ASPP2 exon3-null and heterozygous mice, and compare them with tissue samples from wild type mice. The identified ASPP2-regulated genes will then be analysed further to determine whether or not they are involved in epithelial stratification. In particular, genes involved in epithelial stratification and that are targets of the p63, Notch and Wnt signaling pathways will be examined to determine the molecular mechanisms by which ASPP2 is able to suppress the development of SCC.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: TACC3 as a target in tumour stem cells and brain tumourigenesis
Funder: Medical Research Council

Abstract: Brain tumour growth and recurrence have been attributed to so called brain tumour stem cells (BTSCs) and targeting BTSCs is expected to improve the efficiency of anti-brain cancer therapies. However, this approach is hampered by a poor understanding of the genes and pathways that promote BTSC-driven growth. Recent evidence including our studies and preliminary data suggest that TACC3 is a potential brain tumour-driving factor. We demonstrated thatTACC3 downregulation, either by RNAi or a novel small molecule inhibitor significantly decreases neural stem cell (NSC) self-renewal via NSC differentiation. Accordingly, the important questions arise as to whether TACC3 promotes the BTSC phenotype, whether TACC3 is functionally relevant for brain tumourigenesis (potentially causing malignant transformation of NSCs into BTSCs), and what downstream pathways mediate TACC3 function in BTSCs compared to NSCs. To this end, we will use our established biological tools (including patient-derived BTSCs and adult NSCs) and biological readouts for self-renewal and differentiation in vitro plus xenograft tumour formation in vivo. Our BTSC models in combination with loss-of-function (RNAi or chemical inhibitor) and gain of function (cDNA overexpression) studies will allow us to investigate the link between aberrant TACC3 levels and resulting cellular phenotypes. In addition, we will use gene expression analysis and mass spectrometry-based proteomics to reveal the critical molecular components and networks downstream of TACC3 in BTSCs as compared to NSCs. These synergistic approaches will examine TACC3 as driver of brain tumour development and progression and explore 'normal' versus 'malignant' stem cell growth. Our research will validate TACC3 as potential therapeutic target in BTSC-driven brain tumours and is of relevance for neural stem cell/ cancer stem biology and cancers with TACC3 alterations, and may ultimately be exploited for drug development and anti-cancer therapies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: IMPROVING RADIOIODINE TREATMENT OF THYROID AND OTHER TUMOURS
Funder: Medical Research Council

Abstract: Our recent unpublished data reveal a potential therapeutic strategy for overcoming the potent repression which PBF exerts on the sodium iodide symporter, NIS. We show that PBF is tyrosine phosphorylated at residue Y174, and that abrogation of this residue prevents PBF binding NIS. Since PBF is a protein which interacts with NIS, alters NIS subcellular localisation and governs NIS activity, phosphorylation of PBF thus represents a direct therapeutic opportunity in the restoration of iodide uptake which no other group is pursuing. We will investigate the precise mechanism by which PBF represses NIS activity in vitro, using our recently developed phospho-specific antibody to PBF. Through the use of the human kinome siRNA library, as well as an expression screen using a cDNA expression library of all known kinases and phosphatases, we will identify the kinase(s) responsible for phosphorylating PBF. In parallel, we will evaluate a tyrosine kinase inhibitor (TKI) library to identify a TKI capable of ameliorating PBF phosphorylation. Subsequently, we will modulate tyrosine phosphorylation of PBF in vitro and in vivo. We will utilise our recently constructed transgenic mouse model of thyroid-specific PBF over-expression, as well as human thyroid cell lines and human thyroid tumour samples. An orthotopic model of murine thyroid cancer, coupled with iodide uptake and ablation experiments, will provide a final proof of principle. Our ultimate experimental goal is to overcome PBF's inhibition of NIS and hence exploit the innate ability of thyroid cells to concentrate radioiodine. This would have clear clinical impact in the treatment of recurrent and metastatic thyroid disease, where prognosis is poor, and other currently available therapeutic avenues are largely ineffective.


Research activity codes: 5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Development of a novel drug targeting MRCK and ROCKII for the treatment of invasive and/or metastatic cancer.
Funder: Medical Research Council

Abstract: The vast majority of deaths from cancer directly result from the metastatic spread of the disease; however, currently there are no drugs available that specifically combat this process. The structurally related Rho kinases (ROCK) and Myotonic dystrophy kinase-related Cdc42-binding kinases (MRCK), key effectors in Rho GTPase signalling pathways that control the actomyosin cytoskeleton, have emerged as attractive therapeutic targets for the treatment of metastasis. Our pre-clinical evaluation indicates that whilst targeting either kinase alone reduces the ability of tumour cells to invade, a strategy targeting the inhibition of both ROCKII and MRCK should have a significantly greater effect on inhibiting the invasive processes that contribute to metastasis. We propose to develop candidate small molecule MRCK/ROCKII and/or MRCK inhibitors for further pre-clinical/clinical evaluation as anti-metastatic or anti-invasive agents.


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