NIHRDataInsights/HRCSData huggingface dataset:
Title: Leeds Cancer Research UK Centre (Non-Clinical Training Account)
Funder: Cancer Research UK

Abstract: Non-clinical training associated with: The Leeds Cancer Research UK Centre brings together internationally-respected scientists with doctors and nurses at one of the largest hospital complexes in the UK. Jointly they are carrying out world-leading research to benefit people with cancer. The Centre is a partnership between Cancer Research UK, Leeds Teaching Hospitals NHS Trust and the University of Leeds, one of the UK's leading research universities. Researchers at the Centre are focusing on bowel, bladder and kidney cancers, as well as melanoma skin cancer. They are also specialising in children's cancers, lung cancer, and leukaemia and lymphoma. Leeds boasts world-class experts in a number of key areas. A particular strength is research into the gene faults that cause cancer, and how patterns of gene activity are controlled in cancer cells. Another area is biomarkers - investigating the molecular 'hallmarks' of cancer cells, to help doctors detect the disease earlier and track how well treatment is working. Researchers at the Centre are also working on exciting new targeted treatments for cancer - discovering and developing novel drugs and testing them in early stage clinical trials. And they have great experience in running large-scale clinical trials and studies, investigating the effectiveness of new treatments or the causes of cancer. There is a strong tradition of research training in Leeds, and the Centre will provide a further boost. This will help to train the next generation of cancer researchers, ensuring that we continue to make progress in beating cancer for decades to come. Grants support a variety of training projects - where available coding is done on the basis of these individual pieces of research.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: Barts Cancer Research UK Centre (Non-Clinical Training Account)
Funder: Cancer Research UK

Abstract: The Barts Cancer Research UK Centre brings together world-class scientists, doctors and nurses working in the heart of London. Their aim is to to push the boundaries in our understanding of cancer and use this information to save more lives from the disease. Alongside this high quality research, a new NHS Cancer Clinical Academic Unit provides the very latest treatments for patients in the area._x000D_ _x000D_ The Centre is a partnership between Cancer Research UK, Barts and the London School of Medicine and Dentistry (part of Queen Mary, University of London) and Barts and the London NHS Trust._x000D_ _x000D_ Researchers at the Centre will focus on blood cancers, such as leukaemia and lymphoma, and pancreatic cancer. They will also develop their existing expertise in cancers that specifically affect men and women, including breast, cervical, ovarian, prostate and testicular cancer._x000D_ _x000D_ The Barts Centre will build on its international reputation for research into cancer prevention and public health. Scientists at the centre are leading experts in studying cancer risks in large numbers of people and their work has influenced both the breast and cervical cancer screening programmes._x000D_ _x000D_ Another area of excellence at the Centre is research into the faulty genes and proteins involved in specific cancers. Work in this field is leading towards so-called 'personalised medicine' – tailored treatment based on the genetic makeup of an individual's cancer._x000D_ _x000D_ Barts is also the location of one of our Experimental Cancer Medicine Centres, developing and testing the latest cancer treatments in early stage clinical trials. And this work is supported by the highest quality laboratory research into the biology of cancer. Scientists at the Centre are leading the way in understanding how cancer grows and spreads, devising new ways to track the disease within the body._x000D_ _x000D_ Finally, through the new Centre of the Cell, researchers at Barts will be able to reach out to the community, including local schools, to engage the public in their vital work to beat cancer. And by building on their excellent reputation for academic development, the Barts Centre will play an important role in training the cancer experts of the future._x000D_ _x000D_


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES);3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: Role of homologous recombination activities and shelterin components in telomere replication and elongation
Funder: Cancer Research UK

Abstract: Genome instability is a hallmark of human tumours. DNA mutations and genome rearrangements are in almost all cases responsible for the aberrant proliferation and metastatic behaviour of cancer cells. Our work aims to understand the causes of genome instability and the cellular mechanisms responding to it. This will not only enhance possibilities of cancer prevention, but also the development of treatment modalities that exploit the DNA damage tolerance of cancer cells. Telomeres are structures at chromosome ends, consisting of repetitive DNA sequences and associated proteins. They protect chromosome ends from degradation and fusion, both of which cause genome instability similar to unrepaired DNA double-strand breaks. Telomere dysfunction is often associated with the onset of tumorigenesis. Our work investigates how factors involved in DNA repair by homologous recombination (HR) contribute to the establishment of protective telomeric structures and how they facilitate the successful completion of telomere replication. These studies will be extended in this proposal to analyse how additional components of telomeres contribute to telomere protection and tumour suppression. The three specific aims to be addressed in this proposal are: 1. to determine the role of HR factors (e.g. BRCA2, RAD51, RAD51C), as well as shelterin components other than TRF1 (e.g. RAP1, TPP1) in telomere replication and protection; 2. to determine whether localization of the telomeric repeats at the end of the chromosome, in addition to their repetitive nature, affects replication efficiency; 3. to determine telomere architecture and composition in the absence of RAP1 and TPP1, proteins whose contribution to mammalian telomere protection and tumour suppression is poorly understood. To examine replication fork progression through telomeric DNA, a combination of fluorescence in situ hybridization and single-molecule analysis of replicated DNA. These will be established in wilde type MEFs and then applied to MEFs conditionally deleted of HR activities and shelterin components. Fork progression through internal telomeric repeats and potential breakage and repair will be monitored by cytological analysis of repair factor recruitment and by ChIP against these factors followed by PCR detection using primers designed against unique sequences of the integrated construct. We anticipate that these lines of research will advance the basic understanding of telomere function and help implement effective cancer prevention and potential cures.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: An evaluation of biomarkers in hypofractionated and dose escalated prostate cancer radiotherapy: Trans-CHHiP Study
Funder: Cancer Research UK

Abstract: 1. Background: The CHHiP Trial (Conventional or Hypofractionated High dose intensity modulated radiotherapy in Prostate cancer) tests the hypothesis that prostate cancer has a high radiation dose sensitivity characterised by a low alpha/beta ratio. The trial will recruit 3160 men whose radiation treatment is randomised between conventional 2Gy fractions (total dose 74Gy in 7.5 weeks) and experimental 3Gy fractions (total doses 57Gy and 60Gy in 4 weeks). There is a modest dose escalation between the experimental groups. The primary end point is freedom from biochemical (PSA) failure. 2. Aims and Objectives: To develop and test a panel of tissue biomarkers to predict which patients benefit from hypofractionation and dose escalated radiotherapy. To construct tissue microarrays (TMA) as a resource for future prostate cancer biomarker studies. 3. Methods: We will construct TMA’s from the original formalin fixed prostate biopsies from =2150 men using novel methodology developed by the investigators. Biomarkers related to radiation response, eg. proliferation, hypoxia, apoptosis, DNA repair and signaling and prognostic markers in prostate cancer will be evaluated. A panel of biomarkers which predict for improved outcome with different fractionation and dose schedules will be developed. Model selection using Cox regression and Akaike information criteria (AIC) will be performed with internal validation. The proposed biomarker panel will be additionally tested on routinely prepared tissue sections 4. How the results of this research will be used: If successful the predictive biomarker model will be used to individualise patients’ prostate radiotherapy treatment in the future. The findings may have general relevance to other cancer types, which would need testing in appropriate patient cohorts. The TMA’s constructed in this study will be a valuable resource for future biomarker discovery and evaluation.


Research activity codes: 4.4 POPULATION SCREENING;4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: Investigation of interaction between germline and somatic genetics at the JAK2 locus in myeloproliferative neoplasms
Funder: Cancer Research UK

Abstract: BACKGROUND: The myeloproliferative neoplasm’s (MPNs) are clonal haematological malignancies characterised by over production of functional mature blood cells. They represent a paradigm for the earliest stages of tumorigenesis not accessible in most solid cancers. Many patients with an MPN have a single activating mutation of JAK2. Recent data have demonstrated a powerful genetic predisposition involving one particular JAK2 haplotype. AIMS & OBJECTIVES: We propose to test the hypothesis that the 46/1 JAK2 haplotype houses a variant that predisposes to the development of myeloproliferative neoplasms Specific aims are: - identification of all candidate variants on the 46/1 haplotype - fine mapping of risk variants - to search for evidence of hypermutability within the JAK2 locus - to characterise functional attributes of candidate sequences responsible for the predisposition METHODS: Next generation sequencing will be used to identify causal variants. Subsequently a variety of functional approaches will be utilized to clarify the mechanism of predisposition. OUTCOME: Results will be published in peer-reviewed journals. These experiments will provide a mechanistic understanding of the genetic predisposition to MPNs. In addition to providing a paradigm for other tumors, the data are likely to illuminate additional pathways that contribute to MPN pathogenesis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Functional analysis of the interaction between the chromosomal passenger complex and the_x000D_ ESCRT-III complex during cytokinesis
Funder: Cancer Research UK

Abstract: BACKGROUND: Many cancer cells present numerical chromosomal abnormalities such as aneuploidy and/or polyploidy. Therefore, an understanding of the mechanisms that control genome segregation during cell division can unveil some of the processes that promote cancerogenesis. The final act of cell division, cytokinesis, is crucial to maintain a normal diploid content of the cell’s genome. Our understanding of the initial events during cytokinesis has largely improved in the last years, but the knowledge of the mechanics and regulation of the final step – the abscission of the two daughter cells – is still poor. AIMS: The overarching aim of this proposal is to dissect the functional significance of the interaction between two protein complexes that have been implicated in abscission in human cells: the endosomal sorting complexes required for transport (ESCRT-III) and the chromosomal passenger complex (CPC). ESCRT-III components have been proposed to mediate abscission through the constriction of midbody membranes while the CPC is known to control the timing of abscission in both yeast and human cells. To determine the functional implications of this interaction during cytokinesis in human cells we will try to achieve the following objectives: (1) study the functions and dynamics of ESCRT-III proteins during cytokinesis in the presence or absence of an active CPC; (2) characterise the molecular interaction between ESCRT-III and CPC proteins; and (3) investigate the role of the phosphorylation of ESCRT-III proteins by Aurora B kinase, the enzymatic component of the CPC. METHODS: We will use immuno-fluorescence and time-lapse analysis to study the role of three ESCRT-III components during cytokinesis in human cells and to investigate the effects of Aurora B inactivation on the dynamics of these ESCRT-III proteins. We will also identify the binding domains involved in the interaction between these two complexes and study the effects of binding-defective mutants on abscission. Finally we will identify the residues in these ESCRT-III proteins that are phosphorylated by Aurora B in vivo and in vitro using mass spectrometry and will investigate the role of these phosphorylation events in human cell cytokinesis. IMPLICATIONS AND USE OF RESULTS: Our findings unravel for the first time a link between a mitotic regulator and a membrane component necessary for abscission and could elucidate the mechanisms that control the timing of abscission during cytokinesis. This study will identify a new target of Aurora B and could also provide important clues for the design and identification of novel chemotherapeutic drugs.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS
Title: Mechanism of NFkappaB activation by the tumour-associated viruses Kaposi's sarcoma-associated virus and human T cell leukaemia virus type 1
Funder: Cancer Research UK

Abstract: Background Kaposi’s sarcoma associated herpesvirus (KSHV) causes endothelial cell tumours (KS) and B cell lymphomas in immuno-suppressed individuals. Because of the the AIDS epidemic in sub Saharan Africa, KS is a common cancer, with a prevalence of 5-15% amongst AIDS patients. One protein from KSHV, called viral FLICE-like inhibitory protein (vFLIP), is essential for transformation of the virally–infected tumour cells and activates the NFkappaB pathway by binding to the gamma subunit of inhibitor of NFkappaB kinase (IKKgamma). A fragment of a cellular homologue, p22-cFLIP, also binds IKKgamma and is over-expressed in haematopoietic tumour cells. Remarkably, the Tax protein of human T cell leukaemia virus-1, which transforms human T cells to cause adult T cell leukaemia, also activates IKK by binding IKKgamma, though it has no homology to vFLIP. Both Tax and vFLIP also harness IKK to enhance the processing of the p100 NFkappaB precursor to generate active p52, and p52 expression is critical for the survival of KSHV-transformed primary effusion lymphoma cells We recently obtained a crystal structure of vFLIP/IKKgamma which led us to propose a model for IKK activation driven by a vFLIP induced “twisting” of a rod-like IKKgamma dimer. This would lead to a change in proximity or conformation of the IKKalpha and IKKbeta kinase subunits, which bind to the N-terminal regions of the IKKgamma dimer resulting in trans- or auto-phosphorylation and activation. Aims and Objectives This proposal poses three questions based on the model: 1. What is the role of IKKgamma conformational change in the activation of IKK by either vFLIP or cFLIP or Tax? 2. What is the role of other cellular pathways in IKK activation by vFLIP or Tax? 3. How does the vFLIP/IKKgamma complex enhance p100 processing? Methods These questions will be addressed firstly by mutational analysis of IKKgamma, expressing mutants in IKKgamma null cell lines then examining vFLIP, cFLIP and Tax interaction and function. The role of other cellular pathways will be probed both by knock–down of candidate genes using shRNAmir lentiviral vectors and also by an unbiased screen using an shRNAmir lentiviral library. Complementary biochemical experiments with recombinant proteins will be used to probe IKKgamma conformational changes by electron spin resonance, and to examine p100 interaction with vFLIP/IKKgamma. How the results of this research will be used Understanding the mechanism by which the Tax, p22cFLIP or vFLIP/IKKgamma interaction activates IKK could eventually lead to therapeutics for viral and non-viral tumours.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Biomarker classifiers to predict prognosis following treatment of oropharyngeal carcinoma (PredicTr-OPC)
Funder: Cancer Research UK

Abstract: Background Oropharyngeal carcinoma (OPSCC) is one of the most rapidly increasing cancers in the UK, thought to be due to a rise in human papilloma virus (HPV)–related disease. HPV status is a strong prognostic factor for outcome following either chemoradiotherapy or surgery plus radiotherapy - with 3 year overall survival rates of approximately 90% vs 60% for HPV+ and HPV- cases, respectively. Recent analysis of a large randomised study showed that prognostication can be improved further by using a combination of complex (and difficult to standardise) clinical factors including smoking, T(umour) and N(odal) stage. This produced three prognostic groups with 3-year overall survival rates of 92%, 70% and 46%. Aims We aim to develop a reliable and reproducible prognostic classifier (PC) based on clinical factors, HPV status and widely studied but not yet validated biomarkers that could be easily and widely-applied within routine clinical practice. Methods 14 head and neck cancer centres will provide a well-characterised cohort of 750 OPSCC cases with complete data and tissue samples. We will utilise our extensive expertise in rapid throughput techniques to build tissue microarrays and stain them using immunohistochemistry for p16, EGFR, Bcl-2, FHIT, MVP, CD31, HIF-1a, cyclin D1 , COX-2, c-met, survivin and PLK and in-situ hybridisation for HPV status and EGFR copy number. We have previously optimised and/or published on all but one of these markers. Scoring will be performed independently by two blinded, trained pathologists, who have undergone calibration and certification. We will then utilise our group’s extensive bio-informatic modelling expertise to develop and validate the PC using training and test cohorts. How will results be used? The PC will allow the classification of patients into several risk groups. The PC will identify patients with a highly favourable prognosis for selection for de-intensified treatment, e.g., radiotherapy alone or with cetuximab rather than the current standard of radiotherapy plus cisplatin. The latter de-escalation regimen (cetuximab instead of cisplatin) is being examined in the De-ESCALaTE HPV study funded by CR-UK, and run by the lead applicant. De-ESCALaTE will also provide material for future PC qualification. In addition, identification of a poor prognosis group would allow intensification of treatment, e.g., the use of induction TPF (doxetacel-cisplatin-5 fluorouracil) prior to concomitant chemoradiotherapy, or the use of neo-adjuvant chemotherapy followed by surgery and chemoradiotherapy (currently being studied by the pilot TiTAN study funded by CR-UK). TiTAN will also provide material for future PC qualification.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Risk Stratification, Early Detection and Diagnosis of Ovarian Cancer
Funder: Cancer Research UK

Abstract: Background: The prognosis for ovarian cancer (OC) is poor despite efforts to improve surgery and chemotherapy but there is an opportunity to improve outcomes through advances in risk stratification, early detection and diagnosis. Our group is well placed to translate these opportunities through linking a multidisciplinary team with laboratory, clinical research and modelling expertise to our unique population cohorts, databases and sample biobanks. Relevance: OC is the 4th commonest cause of death from cancer amongst women in the UK. Over 70% of patients have advanced stage disease and less than 40% of these patients survive 5 years. Aims: The overall aim is to develop and validate models for risk stratification, early detection and diagnosis of OC which incorporate clinical, epidemiological, genetic, proteomic and imaging data and to then assess how best to apply them in large populations. Outline: The research plan involves 2 Themes ‘Risk Stratification’ and ‘Early Detection/Diagnosis’ with 3 ‘Workstreams’ for each theme (1–model development, 2-model validation and 3-Health Behaviour/Implementation). Collaborative links will add expertise in modelling, psychology and health economics. The risk stratification model in Theme A will incorporate epidemiological and genetic data including rare high-penetrance genes and low-moderate penetrance common genetic variants. Using our unique resource of biobanks and databases algorithms will be developed for each data type and predictors of risk combined in order to develop an OC risk prediction algorithm. This will be validated using DNA from our sample bank, family history and epidemiological data in our population based low-risk (UKCTOCS, 202,000 women) and high-risk (UKFOCSS, 5000 women) cohorts. We will evaluate acceptability, feasibility, psychological impact and affect on quality of life of the new risk stratification models and we will compare novel approaches with traditional counselling methodologies. In Theme B novel biomarker data obtained from our in house discovery programme, ongoing collaborative studies and published literature will be used to improve our ROCA and RMI models for screening and diagnosis. Further clinical and ultrasound data will be incorporated into model development. The models will be validated in independent data sets from our UKCTOCS, UKFOCSS and UKOPS studies. Pilot studies will assess the feasibility and psychological impact of the optimal risk stratification and early detection models in population screening.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.4 POPULATION SCREENING
Health categories: CANCER AND NEOPLASMS