NIHRDataInsights/HRCSData huggingface dataset:
Title: Bioinformatics Group
Funder: Cancer Research UK

Abstract: Previous and current research This research focuses on statistical methods in molecular biology, human genetics, population genetics, molecular evolution and cancer biology. He is currently building a group in cancer computational biology and bioinformatics that is involved in the analysis of data from a variety of microarray technologies including expression, array CGH, methylation and alternative splicing experiments, and uncovering the genetic basis of variation in gene expression. Dr Tavaré also studies stem cell evolution, part of a broader study of mechanisms of tumour progression. His research in Monte Carlo inference methods includes Markov chain Monte Carlo without likelihoods and approximate Bayesian computation, often applied in the setting of population genetics (for example, linkage disequilibrium mapping) or paleobiology. Future projects Research in computational molecular biology will cover topics such as: Methods for the analysis of microarrays (quality assessment, background correction, normalization, downstream analysis) on a variety of platforms (spotted, bead and oligo arrays), used in contexts such as expression, arrayCGH, methylation, ChIP-chip and alternative splicing. Quantitative methods for systems biology, including dynamics of regulatory networks and protein interaction networks. Statistical and population genetics. This includes the development of statistical approaches for whole-genome association studies and for understanding the genetic basis of variation in expression. Statistical methods for image analysis. Molecular modelling of cell lineages for understanding stem cell fates and cancer epidemiology. Phylogenetics and comparative genomics.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: CANCER AND NEOPLASMS
Title: Chromatin modifying enzymes: their function and role in cancer
Funder: Cancer Research UK

Abstract: Our goal is to characterise the function of chromatin modifying enzymes with the specific aim of understanding how the modifications they lay down have an effect on gene expression. In addition, we have a program to identify new types of chromatin modifications in the hope of discovering novel classes of enzymes that modify chromatin. The rational is that these new enzymes may also be miss-regulated in cancer and could serve as novel targets for drug discovery. We have research programs that deal with numerous pathways leading to histone modifications, including acetylation, lysine and arginine methylation, deimination, proline isomerisation and histone clipping. Some of these pathways are being characterised in yeast and others in mammalian cells. In general terms, to understand the role of a particular modification in gene expression, we raise antibodies that recognise it and then use it in chromatin immunoprecipitations (ChIP). The genomic location of the modification (in either yeast or human cells) is determined by ChIP-sequencing. Effects on gene expression are monitored by deleting the enzymes or knocking-down their expression by siRNA. To understand the mechanism by which modifications function, we have programs for identifying the proteins that recognise the modification. Together, such data outline the functional pathway of a given modification. Wherever possible, the identification of a novel enzyme leads us to monitor its mis-regulation in cancer cells and efforts are made to define if this mis-regulation is causal. Last updated 21/07/2010


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Cancer Prevention Trials Unit (CPTU)
Funder: Cancer Research UK

Abstract: To provide the necessary support to enable scientifically excellent clinical trials and population studies of cancer prevention and cancer screening to be successfully completed. To stimulate and facilitate new multi-centre trials in cancer prevention and screening. To develop tools to help design and run large clinical trials in healthy volunteers. Background: The CPTU was set up in 2006 to develop and run clinical trials in cancer prevention and screening. There are certain aspects of running trials in healthy volunteers that differ from cancer treatment trials. Relevance: All studies in the unit are related to cancer. Aims: The CPTU aims to provide world-class support to clinical trials of cancer prevention. We aim to become the focus of such research in the UK by stimulating the development of new randomised trials, assisting with the design and running of such trials and developing tools and methodology for use in prevention and screening studies. Plan: To implement a quality assurance programme across all staff and studies linked to the CPTU. To provide leadership in electronic data capture, web-based databases and remote monitoring. To continue to run IBIS-II and POET. To help design and develop two extremely large randomised trials in cancer prevention. To increase the number and diversity of trials in the unit's portfolio. To run a series of workshops to stimulate new clinical trials in cancer prevention and screening. Last updated 21/07/2010


Research activity codes: 3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION)
Health categories: CANCER AND NEOPLASMS
Title: Hales Clinical Fellowships
Funder: Cancer Research UK

Abstract: The Cambridge Oncology Fellowships Committee (COFC) is working to establish a run-through training programme which will provide trainees with an excellent training in all aspects of medical oncology. This will include training in clinical practice, Phase I, II and III clinical trials, translational research and basic scientific research. The Cambridge University Hospitals NHS Foundation Trust Department of Oncology, Cancer Research UK and the University of Cambridge Department of Oncology will provide this wide-ranging training in close collaboration. We are confident that the training scheme will allow us to develop the key clinical and translational investigators of the future.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: CRUK/09/021: TUXEDO - Phase I/II feasibility study of cetuximab with or without cisplatin with concurrent radiotherapy in muscle invasive bladder cancer
Funder: Cancer Research UK

Abstract: Combining radiotherapy with drug therapy has produced impressive outcome gains in a number of cancers. We aim to combine radiotherapy with a new drug, cetuximab and a chemotherapy drug cisplatin and evaluate the safety of combination therapy for forthcoming trials comparing the new combination with standard therapy in bladder cancer.


Research activity codes: 6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: TRAIL-induced signal transduction pathways in cancer cells
Funder: Cancer Research UK

Abstract: We previously showed the tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) can kill cancer cells in vivo without causing toxicity. On the basis of these findings various TRAIL receptor (TRAIL-R) agonists are currently in clinical development as potential novel cancer therapeutics. Recently we have shown that many primary tumour cells are resistant to apoptosis induction by TRAIL. Fortunately, in many cases tumour cells can be sensitised to TRAIL-induced apoptosis by chemotherapeutics whilst normal cells remain resistant. Other studies have shown that tumour cells can also proliferate or migrate in response to TRAIL. Our current understanding of the biochemical mechanisms which govern these drastically divergent outcomes of TRAIL stimulation in different tumour cells is insufficient to explain them. However, a detailed understanding of the biochemical basis for these differences is necessary if we want to take TRAIL-R-agonistic new cancer drugs forward clinically. To unravel the biochemical cause for the differences in outcome of TRAIL stimulation in cancer cells we have devised a research programme that consists of two parts. In the first parts we will employ genome-wide RNA interference to identify novel components of TRAIL-stimulated signal transduction pathways. In the second part we will use a modified tandem affinity purification (moTAP) technology we recently developed to identify novel components of TRAIL-induced receptor-associated signalling complexes responsible for triggering the different outcomes. The factors we identify as novel TRAIL signalling pathway components may serve as novel diagnostic markers which in future may allow to predict whether or not TRAIL-R agonists can be successfully applied to treat a patient with a particular tumour. Our functional analysis of these factors may identify them as novel drug targets which, when inactivated, may help to overcome resistance to a therapy comprising a TRAIL-R agonist or render such a therapy more efficient. As a result, in the future it should be possible to sensitise cancer cells to TRAIL-induced apoptosis in a more targeted fashion and on an individualised basis after the tumour of a particular patient has been appropriately analysed at the molecular level. Last updated 21/07/2010


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/10/002: DEPICT - Dose Escalation Pelvic IMRT in Cervical Tumours (A Phase I/II dose escalation study of simultaneous integrated boost intensity-modulated radiotherapy for locally advanced cervical cancer)
Funder: Cancer Research UK

Abstract: Background In cervical cancer, there is a dose-response relationship for local control and survival but with a corresponding relationship for toxicity which restricts the current radiation dose. Simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) enables delivery of differing doses to discrete areas within the pelvis allowing sparing of normal tissues whilst increasing tumour dose. Relevance to cervix cancer Dosimetric studies in gynaecological cancer have demonstrated reductions in normal tissue doses with IMRT by 20-50% with a subsequent decrease in both acute and late toxicity. This study is the first to assess the potential of IMRT to increase dose to sites of pelvic disease. Aims The primary objective is the feasibility of dose escalation with SIB-IMRT and brachytherapy in advanced cervical cancer assessed with the incidence of gastrointestinal toxicity at six months. Secondary objectives are objective response rates, local control and toxicity correlation with dose-volume histogram data. Outline This single arm study has three proposed dose levels (54, 58, 60Gy) treating macroscopic disease while maintaining standard dose to microscopic disease. Six patients will enter the first dose level and dose escalation will occur with acceptable toxicity profile for the whole cohort. This will determine the dose for a subsequent randomised trial.


Research activity codes: 6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Northern Ireland Cancer Trials Network
Funder: Cancer Research UK

Abstract: NICTC has been successful in obtaining a research grant from Cancer Research UK (CR-UK) and the Northern Ireland Health and Social Care Research and Development Division of the Public Health Agency (NI HSC R&DD) to support the formation of the Northern Ireland Cancer Trials Network (NICTN). This joint financial support is augmented by additional core funding to support network activities by the NI HSC R&DD. This will enable us to achieve our goals of promoting high quality cancer care in Northern Ireland by inclusion of patients on a geographically more equitable basis into cancer clinical trials, translational research and other well-organised cancer research studies. The established strengths of NICTN, based on NICTC activity over the years lie in the following areas of clinical and translational research: haematological malignancy, GI, GU, gynaecological, breast and lung cancer, radiation and paediatric oncology. There are other areas that NICTN wishes to strengthen and develop over the next five years, and which are also of high priority. These include: (1) supportive and palliative care, (2) surgical trials (3) imaging trials (4) prevention and early diagnosis trials (5) survivorship studies. NICTC will organise and co-ordinate their own and others' trials for both NICTC and NICTN staff in Belfast Health and Social Care Trust and also for NICTN staff in the other four Northern Irish HSC Trusts. The NICTN staff based outside BHSCT will deliver only a proportion of the overall trials portfolio (eg they will not perform early phase trials, paediatric trials or certain complex interventional trials). Their trials will also depend on the cancer services based in the units and the particular patient groups treated there. (http://www.qub.ac.uk/research-centres/nictc/NorthernIrelandCancerTrialsNetwork/)


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);7.4 RESOURCES AND INFRASTRUCTURE (DISEASE MANAGEMENT);3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: The Pathophysiology of Breast Cancer-Related Lymphoedema
Funder: Cancer Research UK

Abstract: Background A side-effect of axillary lymph node excision and radiotherapy for breast cancer is a permanent arm swelling, breast cancer-related lymphoedema (BCRL). Interference with drainage of lymph from the arm is the initiating cause but the mechanisms leading to BCRL are poorly understood. Evidence indicates that the conventional ‘stopcock’ view, namely lymph drainage from the whole limb is impaired by axillary lymphatic obstruction, is inadequate. Our research, measuring fractional removal rates of injected 99mTc-human IgG to measure lymph flow, indicates a more complex pathophysiology. This prospective study addresses why some women develop BCRL, what factors protect those who escape swelling, and may identify means to predict BCRL risk. Relevance to cancer Lifetime risk of breast cancer is 1-in-9; BCRL occurs in ~25% after axillary dissection. Sentinel lymph node biopsy will reduce BCRL risk but still results in 6% prevalence. The 30-45% of node positive patients require axillary clearance, of whom up to 40% develop lymphoedema. Improved cancer survivorship will increase total numbers with BCRL, which causes physical and psychological morbidity, carries infection risk, and is difficult and costly to treat. Specific aims To test the hypotheses: I. Constitutional Risk due to a Constitutively High Lymph Flow: Women who later develop BCRL have a higher lymph flow in both arms before cancer treatment than women who do not develop BCRL. II. Constitutional Risk due to a Constitutively High Capillary Filtration Rate (CFR): Women who develop BCRL have a higher CFR in both arms before cancer treatment than women who do not develop BCRL. III. Constitutional Risk due to a Constitutively Weak Lymphatic Pump: Women who later develop BCRL have weaker lymphatic pump function, even before cancer treatment, than women who do not develop BCRL. IV. Lymphovenous Communications (LVCs) Open as a Rescue Mechanism: After axillary surgery, LVCs open in the axilla or forearm and allow free transfer of interstitial plasma protein and fluid from lymph to blood, to an extent that differs between women who do and do not develop BCRL. Outline plan Breast cancer patients recruited in years 1-2 will be studied pre-operatively, 2-4 weeks and 36 months post-operatively (by when most BCRL cases are evident). Pre- and post-operative parameters will be compared, and BCRL with non-BCRL. CFR will be measured by venous occlusion plethysmography, lymph flow (removal rate constant, kdepot) by quantitative lymphoscintigraphy, and pump function (Ppump) by lymphatic congestion lymphoscintigraphy. Blood samples will be assayed for labelled erythrocytes.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Strangeways Programme 2
Funder: Cancer Research UK

Abstract: The overarching theme of Strangeways' research is the identification of genetic and lifestyle determinants of common disease, and their application to prevention. A wide range of disciplines are relevant to this field, and the Laboratory has brought together researchers in epidemiology, molecular genetics, bioinformatics, statistics and public health. This programme is specifically concerned with: identifying gene variants that are common in the population and i) influence susceptibility to ovarian cancer ii) are associated with the pathological features of breast and ovarian cancer, and iii) affect the clinical characteristics of breast and ovarian cancer.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION)
Health categories: CANCER AND NEOPLASMS
Title: Strangeways Infrastructure: Core Samples Collection
Funder: Cancer Research UK

Abstract: The overarching theme of Strangeways' research is the identification of genetic and lifestyle determinants of common disease, and their application to prevention. A wide range of disciplines are relevant to this field, and the Laboratory has brought together researchers in epidemiology, molecular genetics, bioinformatics, statistics and public health.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION)
Health categories: CANCER AND NEOPLASMS
Title: Structural and mechanistic studies of signal activation, transduction across the ER membrane, and propagation of the unfolded protein response and its link with other signalling pathways
Funder: Cancer Research UK

Abstract: Background The endoplasmic reticulum (ER) is a major compartment within the eukaryotic cell and is responsible for a variety of functions including synthesis and folding of secretory proteins. A balance exists between protein synthesis and the folding capacity within the ER. If this is disrupted then a series of signalling pathways called the unfolded protein response (UPR) is activated. This response includes transcriptional upregulation, protein translation attenuation and activation of ER associated degradation (ERAD). If however the effort to rectify the imbalance is not successful, then the UPR switches from being pro-cell survival to eliciting an apoptotic response. Relevance to cancer The UPR is activated in a variety of human tumours and is one of several mechanisms tumour cells exploit to survive hypoxic conditions. The ERN1-XBP1 branch of signalling is particularly important in Multiple Myeloma. Along side its role in the UPR response, XBP1 is responsible for plasma cell differentiation and is dysregulated in myeloma cells, thus inhibition of this branch of signalling would drive the cell into apoptosis, with consequences for drug development. Aim and outline plan of research The main objectives of the proposed research programme is to gain structural and mechanistic insights into the 'sensor' proteins of the Unfolded Protein Response (UPR), towards a better understanding of how the UPR signal is activated and its subsequent propagation. The research will initially focus on aspects of human IRE1/ERN1, towards understanding the role of phosphorylation in activating endoribonuclease action. The work will also address the link between UPR and other signaling systems involved in apoptosis, and to further our understanding of the mechanism of UPR activation. Last updated 21/07/2010


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Development of risk prediction algorithms for breast, ovarian and other cancers
Funder: Cancer Research UK

Abstract: Background: Several breast cancer susceptibility genes have been identified, the most important being BRCA1 and BRCA2. The residual familial aggregation may be explained by a large number of alleles each having a small effect on risk. The BOADICEA risk prediction algorithm models these effects and can be used to compute the probability that an individual carries a BRCA1 or BRCA2 mutation and the probability of developing breast or ovarian cancer. Recent genome-wide association studies (GWAS) have identified several common breast cancer susceptibility variants. A consortium of studies in BRCA1/2 (CIMBA) has demonstrated that these variants also modify the risks in BRCA1/2. However, the majority of the genetic variance of breast cancer risk for mutation carriers still remains unexplained. Relevance to cancer: Risk models are important in genetic counselling for identifying high risk individuals and can lead to individually tailored clinical management. They are also important for planning screening and intervention trials. Identifying genetic modifiers of risk will improve the understanding of the biology of BRCA1/2 associated tumours. Specific aims: 1) To develop risk prediction algorithms for familial breast, ovarian and prostate cancer; 2) to identify and characterise genetic modifiers of cancer risk in BRCA1 and BRCA2, through GWAS and candidate gene studies. Outline of research plan: The BOADICEA model will be extended to incorporate the effects of recently identified breast cancer susceptibility variants, tumour pathology, additional breast cancer risk factors and to model the residual familial ovarian cancer risk not due to BRCA1/2. The methodology in BOADICEA will be used to develop a prostate cancer risk prediction algorithm. I will be responsible for the analysis of a three-stage GWAS in BRCA1 mutation carriers using the CIMBA cohort and I will lead the CIMBA statistical analyses of candidate gene studies. Related statistical methods will be developed. Last updated 21/07/2010


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS