NIHRDataInsights/HRCSData huggingface dataset:
Title: Exploring the metaphase epigenome in normal and leukaemic cells
Funder: Cancer Research UK

Abstract: Background_x000D_ By immunostaining of metaphase chromosome spreads from human lymphoblastoid cell lines, we have recently shown that histones carrying specific post-translational modifications vary widely in concentration from one chromosome region to another. This variation gives each chromosome a characteristic fluorescent banding pattern after immunostaining with the appropriate antibodies. The processes by which these bands are put in place are not understood. Some modifications are closely associated with genomic features such as gene and CpG island density, but the extent to which bands are determined by DNA sequence or non-genetic factors (eg. enzyme or metabolite levels) remains uncertain. Nor do we know in any detail how the banding patterns vary from one cell type to another. _x000D_ _x000D_ Aims_x000D_ A preliminary screen will compare immunofluorescent metaphase banding patterns in normal and leukaemic blood cells stimulated to grow in short term culture. The screen takes advantage of the large number of primary blood and bone marrow samples cultured in the West Midlands Regions Genetics Laboratory (WMRGL) for leukaemia diagnosis and monitoring. The initial focus will be on Acute Myeloid Leukaemia patients with known translocations and Chronic Myeloid Leukaemia, and will compare normal and leukaemic cells in the same spreads. Other leukaemias and cells from non-cancer patients will be added as the work progresses. In parallel, we will explore at high resolution the genome-wide changes in histone modification that occur as cultured human lymphoblastoid cells move into mitosis. This will provide a first indication of how the major cell cycle dependent redistribution of histone modifications suggested by our immunolabelling results, is manifest at the gene and sub-genic level. _x000D_ _x000D_ Methods_x000D_ Immunofluorescence microscopy of metaphase chromosome spreads using antibodies to modified histones will be carried out using procedures established in the Birmingham labs. Chromatin ImmunoPrecipitation (ChIP) linked to Next Generation sequencing (on the in-house SOLiD 4 sequencer) will be used to explore chromatin remodelling as cells enter mitosis. The enzymes involved will be identified using sh/si-RNA mediated knockdown. _x000D_ _x000D_ How the results of this research will be used_x000D_ If disruption of immunofluorescent banding patterns is detected in specific leukaemias, this will open the way to novel diagnostic and prognostic tests. Understanding the mechanisms by which immunofluorescent chromosome bands are put in place may provide insights into the processes that generate the chromosome abnormalities that characterize so many cancers.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Human gammadelta T-APCs: generation, functionality and pre-clinical evaluation
Funder: Cancer Research UK

Abstract: Cancer Immunotherapy is an emerging field which holds the potential for groundbreaking new treatments with few side effects and applicability to refractory metastatic disease. We have found that human blood gd T cells have advantages which could substantially advance this exciting area. _x000D_ The endogenous immune system routinely checks peripheral tissue for the emergence of neoplastic cells and quickly eliminates them before tumours arise. Tumours frequently develop an immunosuppressive environment that neutralizes anti-tumour activity facilitating their spread throughout the body. As such, immune surveillance T cells recognize tumour antigens and kill neoplastic cells whereas immunosuppressive factors, including inhibitory cytokine and regulatory T cells, prevent this from happening. Cellular vaccines are being developed to overcome immunosuppression and reinstall effective anti-tumour immunity. Substantial efforts are focused on human dendritic cells for use in treatment. However, technical difficulties are hampering progress. _x000D_ We and others have recently shown that activated human gd T cells (called gd T-APCs) share many features with professional antigen-presenting cells. Therefore, we believe human gd T-APCs represent an excellent alternative to dendritic cells for use in immunotherapy. _x000D_ _x000D_ Proposal_x000D_ All our previous work was performed with human gd T-APCs derived during short-term culture of freshly isolated blood gd T cells. The limited numbers of “primary” antigen-presenting cells may not be sufficient for immunotherapy. Therefore, we propose to translate our initial experience into a protocol that includes the ex vivo expansion of peripheral blood-derived gd T cells and their further manipulation for the generation tumour antigen-loaded gd T-APCs. In this proposal we will determine:_x000D_ A) the antigen-presenting features in gd T cells after their in vitro expansion_x000D_ B) the functionality of expanded gd T-APCs in terms of T helper cell differentiation_x000D_ The findings will contribute substantially to our understanding of human gd T-APCs, will enable us to develop corresponding animal models and, importantly, will pave the way for first-in-man clinical trials. _x000D_ _x000D_ Relevance to cancer_x000D_ At present, the only FDA-approved cellular vaccine product is Provenge (Dendreon Corp., USA), a peripheral blood product specifically designed to treat prostate cancer patients. Functionally improved and more versatile cellular reagents are desperately needed and we believe that gd T-APCs represent a valuable alternative to dendritic cell-based therapy. We will initially focus on melanoma but our treatment will have relevance to many types of cancer._x000D_ _x000D_ Future studies_x000D_ First-in-man clinical trials in collaboration with the CRUK Clinical Trials unit, University of Birmingham.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Use of murine models for identification and functional validation of mutated genes contributing to BRCA1/2 tumourigenesis
Funder: Cancer Research UK

Abstract: Breast cancer is a leading cause of cancer deaths among women in developed countries. In the UK, nearly 46,000 women are diagnosed with breast cancer each year and around 1,000 women die of breast cancer every month. Mutations in BRCA1 and BRCA2 predispose to breast and/or ovarian cancer, and result in a lifetime risk of heterozygous carriers developing breast cancer of approximately 80%. In BRCA1/2-mutation associated cancers, DNA repair defects due to BRCA dysfunction may cause secondary mutations that drive tumourigenesis. The identification of such drivers should increase our understanding of the process of tumourigenesis in BRCA1/2 human carriers. Recently, we have developed a Brca1-defficient tumour model, which produces mammary carcinomas that phenocopied human BRCA1 and sporadic triple-negative breast cancer (Molyneux et al. (2010) Cell Stem Cell, 7(3):403-17). Ongoing analysis of a Brca2-defficient tumour model also confirms resemblance with human BRCA2 carcinomas. These led us to the hypothesis of screening these Brca1/2-defficient mouse carcinomas in order to find common secondary mutations, which may enhance and drive the tumourigenesis process. We will use Next Generation Sequencing (NGS) to characterise mutations and exomic gains/losses occurring in tumour from Brca1/2 breast cancer models. Our preliminary analysis of five Brca1-defficient mammary tumours has confirmed the technique suitability. We are applying for funding for a postdoctoral scientist to extend this preliminary analysis to more Brca1-associated samples and Brca2-defficient tumours. Our NGS screening will give us a list of potential co-operating genomic drivers, which relevance to human disease will be validated by screening human cancer sample collections to find equivalent changes in orthologous human genes or signalling pathways/networks. We will also aim to correlate these genomic drivers with specific tumour phenotypes, data from gene expression arrays, and immunohistochemical features. We shall further validate the mechanistic role for these potential driver genes in the aetiology of tumour formation with in vitro and in vivo assays. The project we propose here will shed light unto the understanding of tumourigenesis in Brca1/2-mutation associated patients, which ultimately might represent benefits for patient prognosis and/or treatment.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/11/028: A Phase 2 study for older patients with Acute Lymphoblastic Leukaemia
Funder: Cancer Research UK

Abstract: There is no standard regimen for the treatment of older patients with ALL worldwide. No standard protocol is followed within the UK. Patients up to the age of 65 years are eligible for entry onto the national study UKALL14. However, the intensity of UKALL14 and similar protocols leads to the selection of only “fitter” older individuals. For the older patient with ALL who is unfit for or over the upper age limit for treatment on UKALL14, therapy is scheduled according to prevailing local practice, often with 'home made' regimens or applying variable dose reductions to more aggressive regimens. This is increasingly unworkable in day to day practice, particularly with the recommendation for standadised electronic prescribing regimens. Hence there is a strong desire for a UK-wide "elderly study" in ALL. In order to meet this need, the NCRI Adult ALL sub-group will collaborate with the Dutch/Belgian group HOVON to carry out a prospective, non-randomised, multiarm feasibility study (including a choice of regimen intensity) to investigate the safety, tolerability and feasibility of a standardised protocol for patients over 60 years old with de novo ALL. A registration arm will be permitted for eligible patients not wishing to enroll on the main study, so that basic data regarding treatment and outcome can be collected in as many patient as possible. It is not known whether treatment is with ‘curative’ or ‘palliative’ intent. It is not known whether long term disease-free survival equating to cure is even a realistic goal. It is not know how therapies are presently chosen by physicians and patients. It is not clear how therapy choice influences outcome and quality of life. The study will (a) Establish baseline expectations for EFS, OS, Minimal Residual Disease responses and quality of life measures for older patients of all ages and pre-morbid states (b)Disclose how best to use knowledge of pre-morbid characteristics to apply the appropriate intensity of therapy in order to balance the best disease related outcomes against quality of life (c) establish national standards of care for this patient group (d) provide the essential platform for careful design of future randomised advanced phase studies of new therapeutic approaches.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: transSCOT – sample collection for translational studies in colorectal cancer
Funder: Cancer Research UK

Abstract: Background_x000D_ Standard adjuvant chemotherapy for colorectal cancer (CRC) comprises a 6 month schedule of a fluoropyrimidine plus oxaliplatin. The SCOT study (funded by the Mr.C) aims to determine if 3 months of the same drugs will be of equivalent efficacy. Benefits of abbreviated therapy would include decreased toxicity, reduced financial cost and less disruption to patients’ Quality of Life. The study will enrol 9500 patients over a 5 year period and will be the largest single trial ever conducted in CRC._x000D_ _x000D_ Relevance to Cancer_x000D_ All patients entered into the study will have had a stage II or stage III CRC resected. A huge biobank arising from this study aided by CTAAC funding would give unrivalled opportunities to assess the importance of a variety of prognostic markers, to elucidate pharmacogenomic markers of toxicity and to provide access to other scientific groups to matched normal and tumour tissue with excellent quality follow-up data for novel research projects._x000D_ _x000D_ Specific Aims of Research_x000D_ 1) Set up the largest biobank of colorectal tissue (tumour vs normal) and blood (EDTA for DNA plus serum) with complete follow-up data_x000D_ 2) Provide tissue and blood for specific research projects including those looking at prognostic markers and at pharmacogenomics (will be subjects of separate funding calls and specific ethical approvals)._x000D_ 3) Provide a tissue and blood repository for future collaborative research projects and for combined projects with other funded tissue collections. Discussions confirming such agreements have taken place and this application is known to and supported by the NCRN CRC translational study group. _x000D_ _x000D_ Outline Plan of Known Downstream Research_x000D_ Genomic DNA from EDTA samples will be used to test hypotheses surrounding germline determinants of tumour features, presentation and treatment-related toxicity (Tomlinson/McLeod/Johnstone/Seymour). Paraffin-embedded tissue will be tested for RKIP expression (Kolch) and utilised for high throughput transcriptomics.


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: How does Cdc20 activate the APC/C?
Funder: Cancer Research UK

Abstract: The APC/C is an essential ubiquitin ligase that controls mitosis by destroying the right protein at the right time. It is activated by the Cdc20 protein that, in turn, is controlled by the Spindle Assembly Checkpoint that responds to whether chromosomes are attached to the mitotic apparatus or not. This process is an important target for anti-cancer therapy and it is through this that the taxanes and vinca alkaloids have their chemotherapeutic effect. These drugs, however, have deleterious side effects, therefore, other approaches to inhibiting the APC/C could have therapeutic benefits._x000D_ _x000D_ The aim of this project is to determine how Cdc20 activates the APC/C._x000D_ The proposal has two main aims _x000D_ _x000D_ 1) To determine how Cdc20 binds and activates the APC/C_x000D_ 2) To determine how Cdc20 and APC10 recognise D-box substrates_x000D_ _x000D_ We will use a series of biochemical approaches to map the sites on the APC/C that interact with Cdc20 and relate these to the recent APC/C structures. In parallel we will determine how Cdc20 binding to the APC/C is regulated by phosphorylation. The results of these studies could be useful in the design of alternative strategies to inhibit the APC/C that avoid the neuropathy and other side effects of the taxanes and vinca alkaloids.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS
Title: An enhanced role for primary care in bowel cancer screening: development and testing of a brief intervention for non-responders
Funder: Cancer Research UK

Abstract: Background Colorectal cancer is the third most common cancer in both males and females in the UK. Although the recent introduction of bowel cancer screening programmes across the UK has the potential to contribute to reducing deaths from this disease, low participation rates among invitees with lower socio-economic status, men, and ethnic minority populations is a concern. Developing and testing a primary care-based strategy to reduce these inequalities in uptake is the focus of this proposal. Aims The aim of the project is to examine whether a bowel screening ‘brief intervention’ with non-responders, delivered by primary care staff is a feasible approach to increasing participation in the bowel screening programme. Methods 1) In order to identify opportunities for a bowel screening intervention by primary care staff, we will describe patterns of primary care utilisation by non-responders in the bowel screening programme using our already established linkages between the Scottish Bowel Cancer Screening programme and the Midland and North West Programme Hub and the General Practice Research Database (GPRD). 2) drawing on our previous work in this field, we will develop a brief intervention (a set of 3-4 structured questions, and a leaflet providing further specific information on obtaining a test kit from the screening programme). The content of the intervention will be refined through interviews and focus groups with key screening and primary care personnel, and international cancer screening experts; drawing on the identified patterns of use of primary care services, a list of potential consultation where the intervention could be introduced, and patient eligibility criteria for the intervention, will be determined. 3) We will carry out a feasibility study in six general practices: responder status of bowel screening invitees will be provided to practices and recorded and flagged in patient notes; that will act as a catalyst in suitable consultations for delivery of the brief intervention. How the results of this research will be used If the feasibility study indicates that the necessary processes can be implemented, that the brief intervention can be incorporated into routine general practice consultations (either with GPs or practice nurses), and that patients respond to the intervention, we will seek funding to more rigorously test whether the intervention is effective and cost-effective in increasing uptake of bowel cancer screening in an adequately powered randomised controlled trial across the UK. Positive findings of such a study would be considered for implementation across the UK.


Research activity codes: 4.3 INFLUENCES AND IMPACT;4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: Defining heterogeneity and tumorigenicity in paediatric glioblastoma
Funder: Cancer Research UK

Abstract: Glioblastoma is recognised for a pronounced intratumoral heterogeneity within its neoplastic cells. The generation of composite genomic profiles from bulk tumour samples by ourselves and others has recently demonstrated that there is a spectrum of genomic aberrations in high grade glioma covering patients of all ages, with paediatric cases tending to have an overlapping, but distinct biology from their adult counterparts. Co-amplification of multiple receptor tyrosine kinases (RTKs) is frequently observed, however with detailed multi-colour FISH mapping in pathology specimens, we have noted a mutual exclusivity of RTK gene amplification to be present in a significant proportion of glioblastoma specimens, both paediatric and adult. The relative contributions of cell populations harbouring one or other gene amplification to disease propagation, and the implications for targeted therapies, are not known. We will identify paediatric glioblastoma specimens harbouring multiple RTK amplification events at surgery using multi-colour FISH, and segregate primary cultures according to expression of the cell surface receptor by FACS. These purified subpopulations will be expanded under neurosphere culture conditions, undergo detailed molecular profiling, and classical stem cell assays carried out both in vitro (self-renewal, differentiation) and in vivo (serial intracranial xenografts in NOD/SCID mice), and drug efficacy assays. A clearer mechanistic understanding of this intratumoral genetic heterogeneity will provide the rationale, and the resources, to allow for the identification of the most appropriate novel therapeutic strategies aimed at targeting the most clinically important subpopulations of tumour cells, and has implications for multiple human cancers.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.4 POPULATION SCREENING
Health categories: CANCER AND NEOPLASMS
Title: Identifying targets for intervention to promote earlier diagnosis of cancer
Funder: Cancer Research UK

Abstract: Background Most UK excess cancer mortality occurs within the first year following diagnosis. Comparative survival analyses for lung and colorectal cancer indicate that a large component of excess mortality occurs within three months of diagnosis. One in three lung cancer patients and one in eight colorectal cancer patients die within 8 weeks of diagnosis. The nature and extent to which early cancer death is linked to factors such as disease characteristics, treatment, co-morbidities, patient lifestyle and engagement with primary care is unclear and requires urgent attention. While molecular studies hold promise, this study examines readily available disease characteristics in the context of the person and the service environment. The identification of key determinants of poor survival may facilitate identification of patient groups within a UK population who would benefit from interventions to promote early diagnosis. While international literature has uncovered many causes of diagnostic delays, their importance as determinants of survival is not well understood. The purpose of this research is to identify ways of improving early detection of lung and colorectal cancer by comparing patient, clinical, disease and service-related factors in people with these cancers who survived less than 2 months to those who survived between 6 months and 2 years from diagnosis. Aim To identify factors that discriminate between early and later death in patients with lung and colorectal cancer. Method Retrospective case-control study, frequency matched on age and sex, of 2,400 patients diagnosed with lung or colorectal cancer in Northern Ireland (NI) between 2008 and 2011. Patient identification and data collection will exploit the existence of unique, timely, electronically available data from a variety of sources including the NI cancer patient management system, developed by and available to the NI Cancer Registry. It will also involve GP and hospital note review by experienced staff. A pilot has confirmed feasibility. Data on patient, disease, clinical and service factors will be assimilated and analysed for cases (600 lung, 600 colorectal with survival less than 2 months) and controls (600 lung, 600 colorectal with survival 6 months to 2 years). How the findings will be used Results should assist in identification of population sub-groups and service factors for targeting to promote earlier cancer diagnosis. Findings will contribute additional important information on diagnostic delay to enhance International Cancer Benchmarking Partnership research while offering a methodology for similar study in other countries. Findings may also identify specific sub-groups for molecular-based investigation.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: CANCER AND NEOPLASMS