NIHRDataInsights/HRCSData huggingface dataset:
Title: What are the opportunities for preventing deaths due to venous thromboembolism in people with cancer?
Funder: Cancer Research UK

Abstract: Venous thromboembolism (VTE) is responsible for approximately 32,000 deaths a year in the United Kingdom. Cancer patients are known to have an increased risk of VTE of around 4-7 fold and account for approximately 20% of all deaths from VTE. Risk assessment tools previously developed to predict patients at highest risk are somewhat limited because they do not recognise the fact that cancer patients may have varying risks on the basis of factors such as cancer type, cancer stage, and treatments received as well as whether an increased risk persists during non-hospitalised periods. Identifying high risk groups and periods is therefore essential to allow appropriate targeting of interventions which are known to be safe and effective in reducing deaths from VTE. The project is relevant to cancer because VTE is an event which accounts for an appreciable level of mortality and decreased quality of life. Even when they survive the initial event, cancer patients with VTE have been shown to have a worse overall prognosis and a poorer quality of life. Recognising which groups would benefit most from receiving anticoagulants (and at what times) and disseminating this knowledge appropriately should therefore be deemed a priority in terms of providing care for people with cancer. The aims of our research are therefore to, i) determine the absolute and relative risks of VTE in patients with the most common cancers that occur in the UK compared with the general population, ii) quantify the how these risks of VTE vary by cancer treatment, time since diagnosis, comorbidty and episodes of hospitalisation be they inpatient stays or day case admissions. These questions will be addressed using the General Practice Research Database (GPRD) and utilising recent linkages with Hospital Episodes Statistics (HES) and cancer registry data. Patients with a cancer diagnosis will be frequency matched to controls on the basis of age and general practice. We will estimate absolute and relative risks of VTE using Cox regression and within-person time series techniques. All analyses will be stratified according to whether patients are hospitalised or ambulatory. Using HES data only, information on cancer-related hospital admissions over a 13 year period will be used to determine with greater statistical power the relative VTE risk for patients hospitalised with different cancer types. We will incorporate linked information from subsequent hospitalisations to compare rates of recurrent VTE and mortality between patients initially diagnosed with different cancer types.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/10/041: BEST2: Evaluation of a Non-Endoscopic Immunocytological Device (Cytopill) for Barrett’s Esophagus Screening via a Case-Control Study
Funder: Cancer Research UK

Abstract: BACKGROUND AND RELEVANCE TO CANCER: Oesophageal cancer is a public health concern in the UK due to its increasing incidence and high mortality. RCT evidence has shown that endoscopic treatment for early cancer arising in the precursor lesion Barrett's oesophagus is effective. However, most cases of Barrett's oesophagus are undiagnosed. We have developed an MHRA approved non-endoscopic immunocytological screening test (Cytosponge) and pilot data on 500 individuals support its safety and acceptability. HYPOTHESIS: The Cytosponge could be used as a Barrett's screening test in primary care, which when coupled with appropriate biomarkers could also diagnose the degree of dysplasia. STUDY DESIGN: A case:control study of patients with known Barrett's attending for surveillance (cases) and individuals with dyspepsia referred via their GP for endoscopy (controls). PRIMARY OUTCOME OF THE STUDY: To determine the performance characteristics of the Cytosponge test for diagnosing Barrett's oesophagus compared with endoscopy, including specificity (from controls) and sensitivity (from cases). OUTLINE PLAN OF RESEARCH: Case:Control study: In parallel 500 individuals with known Barrett's oesophagus and 500 patients referred for dyspepsia will be recruited from 3 tertiary referral centres to swallow the Cytosponge prior to endoscopy. The endpoint will be TFF3 positivity in cases compared with controls. In addition, risk stratification biomarkers (ploidy, Mcm2, cyclin A, TP53, methylation probe set) will be applied to all TFF3 positive Cytosponge samples from both study arms and data compared with the histopathological dysplasia grade from endoscopic biopsies. Impact of screening on psycho-social well-being will be undertaken using standard questionnaires. Cost data will be collected to enable future studies of the health economic impact of the Cytosponge. These data will inform a future RCT to compare the effects of screening, coupled with endoscopic treatment for those individuals diagnosed with high risk Barrett's oesophagus, compared with no screening on mortality form oesophageal adenocarcinoma.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Identification of molecular link between telomeres and telomerase and investigation of the mechanism underlying telomerase recruitment and activation
Funder: Cancer Research UK

Abstract: Telomeres protect chromosome ends from inappropriated activations of DNA damage checkpoint and repair pathways so as not to induce cell cycle arrest and chromosome end-to-end fusions. Chromosomes lose telomeric DNA progressively with every round of replication. Short telomeres elicit checkpoint dependent cell cycle arrest or cellular senescence. Checkpoint-deficient cells harbouring short telomeres experience chromosome fusions and often become aneuploid. In germ cells, stem cells and cancer cells, a specific reverse transcriptase, telomerase counteracts at short telomeres to replenish telomeric repeats, thereby extension of cell proliferation. In the majority of human cancer cells, telomerase is highly active although relatively short telomeres are maintained, resulting in immortal cells that sustain a high risk of chromosome instability. Hence, understanding how telomeres are maintained in different cells is crucial for cell biology and cancer study. _x000D_ _x000D_ However, only a little is known about how telomerase are recruited to short telomeres in human cells. One key observation in human and fission yeast is that telomerase associates with the telomeric protein Pot1 complex. Further, in fission yeast, this association is required for telomerease recruitment to telomeres. Therefore, I will investigate the molecular link between telomerase and the telomere complex using biochemical and genetic approaches. Regulation of the association may include DNA damage checkpoint factors. I will investigate how these factors participate in telomerase action without activating cell cycle arrest. I speculate that activation of telomerase and inactivation of downstream target of DNA damage checkpoints are coupled._x000D_ _x000D_ Understanding the fundamental mechanisms underlying telomerase action will illuminate the regulatory mechanisms that operate in different cell lines. These studies will further our understanding of key parameters that change telomere states and telomerase action through cell differentiation and malignant transformation and will significantly advance our ability to design drugs that target telomerase action specifically in cancer cells.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS
Title: Defining the mechanisms underpinning the function of regulatory and effector tumour-reactive CD4+ T cells during tumorigenesis: applications to cancer immunotherapy
Funder: Cancer Research UK

Abstract: CD4+ T cells play a key role in the regulation of the immune to tumours through the balance of two opposing activities: one that restrains effector functions and maintains tolerance to self- and tumour-antigens, and an opposing one that provides help to the effector arm of immunity. Thus understanding and modifying the function of different tumour-reactive CD4+ T cell subsets (i.e. eliminating negative regulation whilst increasing effector activity) becomes a relevant and powerful tool for the generation of potent and durable anti-tumour immunity. Nevertheless, deep understanding of the interplay between the immune system and cancer has been limited by the poor attention to the tumour-reactive CD4 compartment as well as by the lack of murine models that better represent human malignancies._x000D_ _x000D_ We will use a newly described inducible murine melanoma model as well as a recently described self/tumour reactive CD4+ TCR Tg mouse to study the regulation of CD4+ T cell function during tumour progression and immunotherapy. The data obtained will allow evaluation of immune-regulatory pathways that are potential relevant targets for the treatment of cancer. The specific goals of my future research plan are:_x000D_ 1) To study the regulation of T cell function and the interplay between effector T cells, regulatory T cells and the tumour micro-environment in murine models of cancer that more faithfully recapitulate human disease._x000D_ 2) To identify relevant immune-regulatory circuits limiting the function of tumour reactive lymphocytes, and to manipulate them for the generation of potent anti-tumour immunity._x000D_ 3) To establish a parallel research program in which the findings from our murine models will directly inform the development of novel and effective anti-cancer therapies for the use in humans. Importantly, we will also gather information from ongoing clinical trials and use it to devise and test, in our murine models, ways to target immune-pathways that regulate anti-tumour responses.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: The identification and characterisation of novel genome maintenance factors
Funder: Cancer Research UK

Abstract: Cellular responses to DNA damage involve the orchestration of cell cycle checkpoints and DNA repair factors, which are rapidly activated and mobilised to sites of DNA damage. Defects in checkpoint and DNA repair factors are causal for several genetically unstable human disorders that predispose to cancer. A detailed molecular understanding of these pathways will expand our knowledge of cancer development and progression, which may lead to novel or improved treatments._x000D_ _x000D_ We have recently described HCLK2 as a novel factor required for the cellular response to DNA damage. Through proteomic and yeast two-hybrid approaches we have now discovered a number of novel HCLK2-interacting proteins (CIPs) which we are characterising further using a combination of proteomics, loss of function (RNAi), sub-cellular localisation, and biochemical studies to determine their role in DNA_x000D_ damage response pathways. Encouragingly, our preliminary studies have shown that cells depleted for several CIPs confer defects in DNA damage signalling. In addition, we have recently completed a human genome-wide RNAi screen to identify novel genome maintenance factors (GMFs). A high proportion of known DNA replication and DNA damage/checkpoint factors were identified in the primary screen, in addition to a number of new GMFs. Secondary screens are now underway to refine the list of candidates, which will then be depleted individually in cells using RNAi treatments and subjected to various assays to determine their roles in DNA damage signalling and/or repair. Preliminary studies using 4 individual RNAis_x000D_ against two novel GMFs have confirmed evidence of genome instability in these cells._x000D_ _x000D_ Based on these and future experiments, we will also investigate if mutations in any CIPs or GMFs are causal for cancer and/or human genetically unstable disorders, as well as defining their potential as putative anti-cancer drug targets.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Targeting intracellular protein handling as a strategy for cancer therapy; using Multiple Myeloma as a model
Funder: Cancer Research UK

Abstract: BACKGROUND TO THE PROPOSAL:_x000D_ The requirement of plasma cells to synthesise immunoglobulin and their dependence on protein turnover is central to myeloma cell differentiation, growth and survival, and therefore, provides a unique differential target that can be exploited therapeutically. Our previous work demonstrates myeloma cell apoptosis can be induced either by forcing the premature degradation of survival molecules by inhibiting heat shock protein 90, or by interfering with the unfolded protein response (UPR), a key regulatory pathway of protein folding._x000D_ _x000D_ RELEVANCE TO CANCER:_x000D_ Although this work uses myeloma as a model, it is clear that a number of secretory solid tumours also rely heavily on protein turnover for cell survival and metastatic potential, and therefore results will be applicable to other tumours._x000D_ _x000D_ AIMS OF THE RESEARCH:_x000D_ In this work we seek to characterise two important intracellular protein turnover pathways in myeloma, and to identify novel therapeutic compounds targeted against them. The project will address two main areas:_x000D_ 1. The development of effective therapeutic strategies to target the heat shock protein response. _x000D_ 2. The development of effective therapeutic strategies to target the UPR via IRE1alpha and XBP1._x000D_ _x000D_ OUTLINE PLAN OF RESEARCH_x000D_ Using ShRNA we will demonstrate the downstream effects of targeting the heat shock protein response concentrating on the HSP70 family members HSP72, HSC70 and HSF1. In order to identify a clinically relevant approach, we will then demonstrate the in-vitro and in-vivo anti-myeloma effects of small molecule inhibitors of the heat shock response._x000D_ _x000D_ In order to develop effective therapeutic strategies to target IRE1alpha, XBP1 and the UPR, we will identify IRE1alpha interacting proteins and determine their dependence on IRE1alpha kinase and endoribonuclease activity. In addition we will determine the presence and role of Regulated IRE1aplha Dependent mRNA Decay in myeloma. This data will be used to inform high throughput inhibitor screens, and structure-based drug design aimed at identifying small molecule inhibitors of IRE1alpha kinase and endoribonuclease activity.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/10/023: IESLG-32: Randomised Phase II Trial on primary CT with Methotrexate & Cytarabine +/- Thiotepa & Rituximab, followed by brain irradiation vs. high-dose CT supported by ASCT for immunocompetent patients with CNS lymphoma
Funder: Cancer Research UK

Abstract: Randomised Phase II Trial on primary CT with Methotrexate & Cytarabine +/- Thiotepa & Rituximab, followed by brain irradiation vs. high-dose CT supported by ASCT for immunocompetent patients with CNS lymphoma. Primary central nervous lymphoma (PCNSL) in a rare cancer but its inidence is increasing. The treatment (CT+/- RT)is challenging as a treatment aim is cure but optimization of neurocognitive funtion and quality funstion and quality of life also remain important goals.


Research activity codes: 6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/10/021: CASPS: A phase II study of Cediranib (AZD2171) in Alveolar Soft Part Sarcoma.
Funder: Cancer Research UK

Abstract: Alveolar soft part sarcoma (ASPS) is a rare subtype of soft tissue sarcoma characterised by the translocation t(X;17)(p11;p25). There is a high rate of metastatic disease but relatively good prognosis. It does not respond to chemotherapy but the inhibitor of vascular endothelial growth factor receptors (VEGFR), cediranib, appears to be highly active. _x000D_ _x000D_ The aim is to confirm the ability of cediranib to control the growth of metastatic disease in patients with ASPS. _x000D_ _x000D_ In this phase II trial, 36 patients will be randomised to cediranib or placebo for up to 24 weeks. The key endpoint is change in tumour size at 24 weeks.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: CRUK/10/031: CARMENA: A randomised phase III trial to evaluate the benefit of nephrectomy in patients with metastatic at diagnosis kidney cancer treated with Antiangiogenics (Sunitinib)
Funder: Cancer Research UK

Abstract: Background: The introduction of tyrosine kinase inhibitors in patients with metastatic renal cell cancer has led to improved survival and raised debate about the benefit of a cytoreductive nephrectomy in this group of patients. Aim: To determine if cytoreductive nephrectomy has a survival benefit in the era of targeted therapy. Summary: A Phase III randomized non-inferiority study of 1134 patients will be performed randomizing patients with Mr.CC to nephrectomy followed by sunitinib therapy or sunitinib alone to determine if there is any difference in overall survival between the 2 groups.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES;6.4 SURGERY
Health categories: CANCER AND NEOPLASMS
Title: CRUK/11/042: DAHANCA 21: Hyperbaric Oxygen Treatment of Mandibular Osteoradionecrosis. A randomised clinical trial.
Funder: Cancer Research UK

Abstract: 1. Backgroundbr/Osteoradionecrosis is a feared complication to head and neck radiation therapy. Hyperbaric oxygen (HBO) may be beneficial in healing after surgical removal of the necrotic bone, however, evidence is lacking.br/2. Aimsbr/This multicenter study aims at estimating the clinical effect of HBO on osteoradionecrosis.br/3. Summary of proposed studybr/114 patients with mandibular osteoradionecrosis (ORN) stage 2, 3 or 4 (according to Common Terminology Criteria for Adverse Events (CTCAE) v3.0) are randomised to group 1 (30 preoperative and 10 postoperative HBO sessions and surgical intervention) or group 2 (surgical intervention without HBO). Each HBO session implies inhalation of 100% oxygen during decompression to 14-15 meters for 90 minutes.br/Primary endpoint is healing of bone exposure according to the CTCAE v 3.0 criteria, and is estimated one year after surgery.br/Secondary endpoints are quality of life, pain intensity, antibiotics and pain medication, trismus, xerostomia and body mass index.br/Clinical evaluations are performed at baseline, 1 week, 1 and 3 months and 1 year after surgery. Copenhagen University Hospital is the main centre. Aarhus, Odense, Liverpool (&amp; other UK units), Gothenburg and Rome are participating centres.br/The study is supported by Danish Cancer Association, Danish Cancer Research Foundation and Danish Dental Association.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/04/001: aTTom: adjuvant Tamoxifen Treatment offer more? Follow-up, Data Cleaning and Analysis
Funder: Cancer Research UK

Abstract: The aim of this study was to assess among a population of women who had taken adjuvant tamoxifen for 5 years, how many were prepared to enter a randomised trial looking at the duration of tamoxifen treatment and what was the preference of those who declined trial entry. There is uncertainty as to the optimum duration of adjuvant tamoxifen and this is the subject of the aTTom (adjuvant Tamoxifen Treatment offer more?) trial in which patients are randomised to continue or stop tamoxifen after 5 years. Patients have been recruited to the aTTom trial in Dundee since 1996 and a record has been kept of all the patients with whom the trial was discussed. Patients who declined trial entry were allowed to choose whether to electively stop or continue tamoxifen. 306 patients were eligible for trial entry of whom 171 (56%) consented to randomisation (82 to continue and 89 to stop). Amongst the 135 (44%) who declined randomisation, 28 (21%) elected to stop tamoxifen treatment, 90 (67%) elected to continue and in 17 (13%) their decision was unclear. These results illustrate that patients eligible for the aTTom trial share our clinical equipoise. A majority (56%) of patients were agreeable to randomisation, but among those who declined, some (67%) preferred to continue, some (21%) to stop tamoxifen. This trial is unusual in that the patients have already experienced the treatment options, so the patients' preferences reflect a truly informed choice.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/10/030: ICON 8: An international 2-stage randomised trial of dose-fractionated CT compared to standard 3-weekly CT, following immediate primary surgery or as part of delayed primary surgery, for women with epithelial ovarian cancer
Funder: Cancer Research UK

Abstract: Background: Despite past therapeutic improvements, most patients diagnosed with advance ovarian cancer die from their disease. Dose-fractionated chemotherapy has shown promise in other studies, improving the control of cancer with reduced toxicity. Specific aims: To assess the risks and benefits in terms of toxicity, progression free and overall survival of dose-fractionated chemotherapy with paclitaxel and carboplatin compared to standard three weekly carboplatin and paclitaxel in the setting of immediate or delayed primary surgery. The impact of these interventions on patient reported outcomes (quality of life) and health economics will also be explored. An associated program of translational research will be developed alongside the trial. Summary of proposed study: A phase II randomised three-arm trial comparing conventional three-weekly chemotherapy (arm 1 carboplatin AUC5 and paclitaxel 175mg/m2 every 3 weeks) with two dose-fractionated chemotherapy regimens (arm 3 carboplatin AUC5 d1, paclitaxel 80mg/m2 d1,8,15 every 3 weeks; arm 3 carboplatin ACU1.67, paclitaxel 80mg/2 d1,8,15 every 3 weeks) in the first-line treatment of advance ovarian cancer. Patients will be stratified at randomised based on intention to perform delayed primary surgery after 3 cycles of protocol chemotherapy.


Research activity codes: 8.2 HEALTH AND WELFARE ECONOMICS;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/06/014: AVAST-M: A randomised trial evaluating the VEGF inhibitor, Bevacizumab (Avastin®), as adjuvant therapy following resection of AJCC stage IIB (T3bN0M0 & T4aN0M0), IIC (T4bN0M0) and III (TxN1-3M0) cutaneous melanoma.
Funder: Cancer Research UK

Abstract: Background: Melanoma incidence is rising in a young population age-group. The mainstay of treatment is surgery, but for many, surgery is not curative. Patients at high risk of recurrence have around 45% 5 year survival. No adjuvant chemo- or immuno-therapy has been shown to improve survival in these patients. Effective adjuvant treatment is urgently needed. Relevance to cancer: Angiogenesis is essential for growth, invasion and spread of all types of cancer and a key regulator of angiogenesis is vascular endothelial growth factor (VEGF). Bevacizumab (Avastin) is a humanised monoclonal antibody against VEGF which, in recent randomised clinical trials in various solid tumours, has shown significant benefits to patients. Phase II data in metastatic melanoma has shown some evidence of activity, justifying evaluation of this drug in the more optimal setting of earlier stage disease. This research aims to determine whether bevacizumab may be an effective adjuvant therapy for high risk melanoma patients. Outline of research: This randomised trial compares bevacizumab treatment with standard observation in 1320 patients with resected melanoma at high risk of recurrence.The primary endpoint is survival. Secondary endpoints are disease-free interval, distant metastasis-free interval, toxicity, quality of life and biological markers of response to treatment.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES;6.4 SURGERY
Health categories: CANCER AND NEOPLASMS