NIHRDataInsights/HRCSData huggingface dataset:
Title: Modulation of mTOR signalling by aspirin/salicylate as a mechanism of colorectal cancer chemoprevention
Funder: Cancer Research UK

Abstract: Background: Aspirin prevents colorectal cancer (CRC). The host laboratory, including my contribution, has shown that aspirin modulates NF B in CRC cells, animals and patients. This stimulated studies to elucidate the complex upstream molecular mechanisms underlying aspirin-induced CRC cell death. This proposal focuses on aspirin effects on mTOR signalling, a candidate CRC pathway. Relevance: Worldwide, CRC causes 655,000 deaths/year, underscoring the rationale for cancer prevention strategies. Pilot data & hypothesis: In CRC cells, we show that aspirin modulates mTOR signalling at pharmacologically relevant concentrations; a generic effect on mTOR across a panel of CRC lines; apoptosis in parallel with effects on mTOR. These novel findings lead us to hypothesise that the anti-tumour effects of aspirin are mediated by mTOR. Aims: To investigate mTOR signaling as a key mechanism responsible for the anti-tumour effect of aspirin in CRC. The proposed work is highly complementary to ongoing research in our laboratories and focuses on a promising upstream mechanism by which aspirin exerts chemopreventive activity. Outline Excellent facilities/expertise are available at IGMM, MRC PPU and Coloproctology Unit. 1 Molecular studies of aspirin effects on mTOR signalling in CRC cell lines. 2 Definitively establish the requirement for mTOR in aspirin anti-tumour activity and confirm whole organism relevance using animal models. 3. Translational research studies of rectal mucosa from aspirin-treated human subjects to establish validity of laboratory findings and identify potential biomarkers of efficacy. Application: This research could lead to identification of potential druggable targets in a "pathway medicine" approach. Clinical studies have potential to identify biomarkers of efficacy for chemoprevention trials.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: CANCER AND NEOPLASMS
Title: Cambridge / Barts Molecular Pathology Training Programme: The role of Pygopus and BCL9 in mammalian colorectal neoplasia
Funder: Cancer Research UK

Abstract: Background and relevance to cancer: The majority of colorectal cancers have mutations of APC and b-catenin that result in accumulation of activated b-catenin, which binds to TCF/LEF transcription factors to increase transcriptional activity at downstream targets. The mechanism of downstream Wnt signalling and the recruitment of transcriptional co-activators were shown to involve two recently discovered Wnt signalling components called Pygopus (PYGO1 and PYGO2) and Legless (BCL9 and BCL9L). Studies and preliminary data from the Bienz lab suggest an important role for Pygopus N-box and BCL9 HD6 domains through potential ligands in modulating the transcriptional activity at Wnt downstream targets. However, the identity of these ligands and the mechanism through which they promote TCF-mediated transcription is unclear. Specific aims of the research: This proposal therefore focuses on identifying ligands of the Pygo N-box and the BCL9 HD6 domain involved in modulating transcriptional output at downstream Wnt targets in mammalian cells and tissues, and to link these transcriptional changes to chromatin signalling cascades. Outline plan of research: Pygo N-box and BCL9 / BCL9L HD6 GST-fusion proteins and mutant versions will be used as 'bait' in pull-down assays and interaction panning of a phage display library. In addition, a set of ES cells and cancer cell lines will be transfected with plasmids containing bait constructs followed by cell array protein-protein interaction assays. A human genome-wide shRNA library will also be used to screen for functionally relevant regulators of Wnt signalling. Analysis of expression levels of Pygo and BCL9 as well as validation of targets will be performed in human and double-KO mouse model tissue samples. Last updated 21/07/2010


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/09/022: PulMICC: Pulmonary Metastasectomy in Colorectal Cancer
Funder: Cancer Research UK

Abstract: Background to the proposal Surgical removal of lung metastases from colorectal cancer is an increasing practice. There is no question that there are harms both from the injurious effects of the surgery in the short term and the inevitable loss of lung tissue. Keyhole surgery is not the simple answer because with that approach clearance of all cancer is less likely. There is no randomised trial evidence and there are reasons to be dubious about benefit because of the highly selective series on which clinical impressions are based and new knowledge about the wide range of growth rates of lung nodules. Specific aims of the research To determine the gains and losses in terms of survival and quality of life. In this feasibility study we aim to prove that randomisation can be achieved and to gain data to help power an ensuing RCT of cost effectiveness. Outline plan of research We proposed a randomised controlled trial of management with or without surgical resection. In the active arm, all other therapies apart from other forms of ablation of metastases are permitted. In the control arm all other therapies apart from removal or ablation of metastases are allowed within the trial.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;6.4 SURGERY
Health categories: CANCER AND NEOPLASMS
Title: CRUK/06/034: SCORAD: A randomised phase III trial of single fraction radiotherapy compared to multifraction radiotherapy in patients with metastatic spinal cord compression.
Funder: Cancer Research UK

Abstract: This trial aims to determine whether patients with spinal cord compression can maintain or regain the ability to move and walk as well after one dose of radiotherapy as after five doses. It will also examine whether they have similar quality of life and tolerance to treatment regardless of which treatment they receive. (1) Background to the proposal Spinal cord compression is a common complication of metastatic cancer and is a major cause of morbidity. Most patients receive radiotherapy, with the aim of preserving or recovering neurological function. Currently there is no standard fractionation schedule. Common practice uses 20-30Gy in 5-10 fractions, although patients with poor performance status may also be treated with a single dose of 8- 10Gy. No randomised controlled trial (RCT) evidence directly comparing these schedules in terms of neurological function or quality of life exists, but since the life expectancy of these patients is short (4-6 months), RCT confirmation that a single dose is no less effective than prolonged treatment would inform clinical practice. (2) Specific aims of the research To evaluate single fraction radiotherapy against multifraction radiotherapy in terms of ambulatory status, function, quality of life and toxicity to 3 months and survival to 12 months. This trial is attractive to radiotherapists because either treatment is simple to deliver. Furthermore, the single fraction regimen requires fewer NHS resources. (3) Summary of proposed study. 700 eligible consenting patients will be randomised to receive multifraction or single fraction radiotherapy on admission with acute SCC. Randomisation will be stratified by site, ambulatory status at presentation, primary tumour and extent of bony metastases. Patients will complete QoL forms and will be assessed for neurological function and toxicity at 1, 4, 8 and 12 weeks from beginning of treatment. The main trial endpoint is the change in ambulatory status between baseline and 8 weeks after starting radiotherapy. Last updated 21/07/2010


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Drug Discovery Institute Award
Funder: Cancer Research UK

Abstract: CRUK has moved to expand its small molecule drug discovery capabilities with investment in the core-funded Institutes in Manchester and Glasgow (BICR). Target discovery and validation are core strengths of the BICR and the Drug Discovery Programme will seek to exploit these targets for the development of future cancer therapeutics. Though our understanding of the basic mechanisms involved in cancer progression is improving and new drugs to treat certain cancer types are becoming available there is an ongoing and increasing need for additional novel therapies. The Drug Discovery Programme at the Beatson will work closely with the wider West of Scotland Cancer Community to exploit the potential of these new approaches to treatment. We aim to establish an integrated industry standard Drug Discovery Programme to translate basic biology research from the BICR and other CRUK centres into medicines for the treatment of cancer. In particular we will set up Fragment Based methods of hit identification and Structure Guided Drug Design. Over the next five years we will: a) Design, build and equip a new laboratory facility b) Develop a team of experienced drug discovery chemists, biologists and structural biologists c) Establish core capabilities in Fragment Based Methods of hit identification and, d) Generate a sustainable portfolio of drug discovery projects spanning from target selection to lead optimisation.


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: CANCER AND NEOPLASMS
Title: The determinants of international and socio-economic variations in female breast cancer survival
Funder: Cancer Research UK

Abstract: The goal of this project is to estimate how much of the differences in breast cancer survival between rich and poor women in the UK and Australia can be explained by how often they attend breast screening and primary care (GP) services, and by other serious medical conditions. Last updated 14/01/2009 Background Breast cancer survival among women in England and Wales is lower than in most other developed countries. Persistent socio-economic differences also exist. Explanations for these differences have not been adequately examined. Relevance Differences in cancer survival between population groups challenge the concept of equity inherent in a National Health Service, but they also suggest how overall cancer survival might be improved. Aims Compare survival between screen-detected and non-screen-detected cancers Describe pre-diagnosis consultation patterns, and co-morbidity at the time of diagnosis Quantify the contribution of these factors to international and socio-economic differences in breast cancer survival. Plan We will link cancer registry data to screening history data for women with breast cancer and compare the survival of screen-detected women with those whose cancer was not screen-detected, according to whether they had full, partial or no record of mammography prior to diagnosis. We will compare survival by screening status among the different socio-economic groups, both in England and Australia. National cancer registry data for the UK will be linked to a comprehensive primary care database, in order to examine the role of consultation history, lifestyle factors and concurrent and subsequent co-morbidity upon socio-economic differences in survival. Last updated 14/01/2009


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: CANCER AND NEOPLASMS
Title: CRUKD/11/006: OPARATIC A Cancer Research UK Phase I trial of olaparib (AZD2281), an oral PARP inhibitor, combined with extended low-dose oral temozolomide in patients with relapsed glioblastoma
Funder: Cancer Research UK

Abstract: Background and relevance to cancer: Glioblastoma multiforme (GBM) is the commonest and most aggressive primary brain tumour. Most tumours are resistant to current treatment, which comprises radiotherapy with concomitant and adjuvant temozolomide; average life expectancy is around one year. AZD2281 is an oral, potent and specific inhibitor of poly(ADP-ribose) polymerase that increases sensitivity of human glioma cells to radiation and temozolomide. Phase I studies of AZD2281 demonstrate effective PARP inhibition in tumour tissue at non-toxic doses. Specific aims: The aims of this phase I study of AZD2281 in combination with extended, daily low-dose temozolomide in patients with recurrent GBM is proposed are to establish the optimum biological dose (OBD) of AZD2281 and the maxiumum tolerated dose (MTD) of temozolomide in combination with AZD2281. Associated translational research will document the in vivo effects of AZD2281 on DNA damage responses and identify potential biomarkers for predicting response to this agent. Research plan: Stage 1: Dose escalation study of AZD2281 given for three days prior to surgical resection. Stage 2: Dose escalation study of daily temozolomide combined with AZD2281. Pharmacokinetic and pharmacodynamic analysis of blood and tumour material, and genetic and cellular studies evaluating potential biomarkers of response to AZD2281 will be undertaken.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Regulation of the mitotic apparatus by Aurora- and Polo-like kinases
Funder: Cancer Research UK

Abstract: Background: The discoveries of the Aurora- and Polo-like kinases by the group in the 1980s were made through the characterization of Drosophila mutations affecting behaviour of the spindle poles. These two families of conserved kinases have multiple M-phase functions; they regulate M-phase entry, centrosome maturation and duplication, behaviour of kinetochores and microtubules through modification of their associated proteins, formation of the central spindle and activation of proteins that control cytokinesis. These diverse functions are possible only because of mechanisms that precisely locate these enzymes in time and space._x000D_ Relevance to Cancer: Aurora- and Polo-like kinases are elevated in many tumour types and can serve as prognostic indicators. The pharmaceutical industry has been developing small molecule inhibitors of these kinases that have showed promise in clinical trials. Greater understanding of their functions will enable such compounds to be used more rationally; for example it has recently been found that ras mutant tumour cells are more sensitive to Plk1 inhibition than normal cells. The study will also identify other potential targets for cancer therapy. _x000D_ Specific Aims: The central theme of this proposal is to investigate mechanisms that regulate members of each of these families of protein kinase and identify how the mitotic functions of their substrates are activated or changed as a result of phosphorylation. These substrates are also found on different parts of the mitotic apparatus and in many cases also change location as M-phase progresses. We aim to understand how the kinases localize; how they are activated; how they facilitate the assembly and function of the mitotic apparatus; how they interact with key substrates at centrosomes, kinetochores, on microtubules, and in association with the cytokinesis machinery. _x000D_ Outline plan: A common approach running through this proposal is to use the affinity tagging of components of the mitotic apparatus as a means of purifying that molecule together with its interacting proteins. This will build a map of interacting proteins. If the bait molecules are the kinases themselves, their interacting partners may have regulatory or localisation functions. If they are components of mitotic structures, then the indentification of their partner molecules will help us to understand how such structures are assembled and how they function. Phosphorylation sites on such molecules will be mapped and the importance of this modification tested through studying the effects upon protein affinities in vitro and, by mutational analysis of the phosphorylation sites, upon function in vivo. _x000D_


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS
Title: CRUK/09/032: TREC: Transanal endoscopic microsurgery (TEM) and radiotherapy in early rectal cancer.
Funder: Cancer Research UK

Abstract: Background Bowel cancer screening is changing how rectal cancer presents. Two UK pilots indicate that 49-62% of screen-detected tumours are 'early' (pT1-2N0M0; Stage I). Radical surgery using total mesorectal excision (TME), the standard of care for stage I rectal cancer, offers high rates of cure, but also has a substantial adverse impact upon heath-related quality of life. An organ preserving minimal surgery approach may generate significantly less morbidity without significantly compromising oncological outcomes. Aims We shall: (i) determine the feasibility of randomising between radical TME surgery (current gold standard) and short course preoperative radiotherapy (SCPRT) + delayed local excision; (ii) estimate the efficacy/safety of SCPRT + local excision; and (iii) evaluate measurement tools for pre/post-operative bowel, bladder, sexual function and QoL following each treatment. These data will inform the design, primary outcome measures and sample size of a phase III study. Plan Individuals with T1-2N0M0 'early' rectal cancer will be offered randomisation between: (1) radical TME surgery and (2) SCPRT + delayed local excision at 8-10 weeks. Those who decline will receive their preferred treatment (consent sought for data collection). Oncological efficacy of SCPRT and delayed local excision will be estimated using the relative incidence of high-risk histopathological features in irradiated versus non-irradiated specimens. Functional assessment tools will be evaluated in both arms A parallel qualitative research study will identify factors influencing recruitment and randomisation and define risk-benefit boundaries within which patients, surgeons and oncologists select treatment.


Research activity codes: 6.4 SURGERY;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Infrastructure - Prevention of hormone related cancers
Funder: Cancer Research UK

Abstract: Breast cancer prevention " Long term FU of IBIS-I to see how long protection fro tamoxifen continues and to look at the value of changes in breast density for predicting risk reduction of BC " ATAC - Ongoing studies to understand factors influencing preventive properties of anastrozole and potential side effects. Studies to determine new factors predicting response to treatment - eg CYP 2D6 polymorphisms, mRNA levels for key genes, occurrence of endocrine symptoms( hot flushes and arthralgia " SERM overview - analysis of individual patient data on all prevention trial trials using tamoxifen or raloxifene to clarify risks and benefits " IBIS-II - main trial activities plus substudies related to bone health, cognitive function, breast density, DCIS pathology " Risk assessment - refining model to incorporate weight change, mammographic density and other potential new factors( eg 2D6). " Understanding in detail the value of mammographic density and changes in density in women of different ages and risk profiles Prostate Cancer " Immunohistochemical marker studies on TAP G material from TMAs made from 2500 men managed by watchful waiting " Micro RNA studies on same material " Methylation marker studies " Collection of new material to form validation cohort Colorectal Cancer " Analysis of results from Flexi-sig study " Develop studies to explore chemoprevention in individuals with high risk polyps Molecular Epidemiology - Major new direction " Continue work of evaluating new markers for cervical cancer screening with strong HPV base " Evaluate role of methylation profiles as risk factors for breast , cervix and prostate cancer " Full characterization of 800 biopsies from Predictors study in terms of HPV types and mRNA expression in normal and abnormal microdissected tissues and correlate with smears


Research activity codes: 3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION)
Health categories: CANCER AND NEOPLASMS
Title: Infrastructure - Medical Statistics Group
Funder: Cancer Research UK

Abstract: (1) Background We conduct a large programme of applied statistical research of practical relevance to clinicians and medical researchers relating to prognosis, therapy, and diagnosis, to enhance the value of current and future cancer research. We provide statistical input at all stages of a large number of clinical trials and other research projects from design to publication, to ensure that clear questions are answered to further clinical and scientific knowledge. (2) Relevance to Cancer All our methodological research projects are relevant to the conduct of high quality cancer research. Our extensive programme of clinical and scientific research projects, including clinical trials, relates to many types of cancer. (3) Aims To advance understanding of how to conduct high quality research. To carry out high quality research in cancer of direct relevance to clinicians, medical researchers and patients. To provide high quality statistical collaboration in studies supported by Cancer Research UK. To enhance the general level of statistical expertise in Cancer Research UK. (4) Outline Plan We will carry out a full programme of methodological research projects relating to appropriate statistical methods and reporting of studies of prognosis, therapy, and diagnosis. We will conduct an extensive programme of collaborative clinical research that we expect to yield 6 completed studies, with 10 projects active, 10 being designed and initiated, and a further 6 more being developed.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: Cancer Research UK Contribution to the National Prevention Research Initiative (NPRI)- Phase III
Funder: Cancer Research UK

Abstract: In recognition of the continuing need for research targeted at the primary prevention of chronic diseases, and the success of Phases 1 and 2, an expanded consortium of 16 Funding Partners committed up to £12 million over five years to support NPRI Phase 3. The focus remains on behaviours associated with significant risks to health – such as poor diet, physical inactivity, smoking and alcohol consumption – and on the environmental factors that influence those behaviours. Research will aim to improve health and prevent diseases or conditions such as cancer, heart and circulatory diseases, diabetes, obesity, stroke and dementia. This Phase III call will fund cross-disciplinary translational research which develops and tests interventions that can potentially have a major impact on population health. The Call has now closed. http://www.mrc.ac.uk/Ourresearch/Resourceservices/NPRI/index.htm


Research activity codes: 3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION)
Health categories: CANCER AND NEOPLASMS
Title: Senior Research and Information Nurse
Funder: Cancer Research UK

Abstract: The role of the Senior Research Nurse is: To promote the work of Cancer Research UK and cancer trials awareness amongst health care professionals, patients and the public; Act as a CR-UK spokesperson on appropriate stories and give interviews to local media (in liaison with press officers); Provide a "public face" for clinical trials in liaison with local CR-UK fundraisers and press officers; Engage users in research both for media and promotional activities and to ensure consumer representation on local research agenda; Act as a liaison and information resource for CR-UK within a designated region to promote the patient focused nature of trials; Support the national directives for improving recruitment to clinical trials for cancer treatments, prevention and palliative care with the aim of reducing the time taken to obtain results from cancer research projects; In addition, each Senior Research Nurse will have a local remit which meets the requirements of their CR-UK cancer centre.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: CANCER AND NEOPLASMS