NIHRDataInsights/HRCSData huggingface dataset:
Title: CRUK/02/018: SIOP Wilms Tumour 2001 Clinical Trial and Study
Funder: Cancer Research UK

Abstract: Background: Intensity of treatment for Wilms tumour is currently decided according to a combination of clinical and pathological parameters. Approximately half the children have an excellent outcome with chemotherapy with only two drugs, vincristine and actinomycin D, plus nephrectomy. The remainder require additional treatments with the potential for permanent side effects, particularly in the young children affected by Wilms tumour (median age 3 yrs): ~50% are exposed doxorubicin and ~25% to radiotherapy. These carry lifelong risks of cardiotoxicity and second malignancies, which may take decades to manifest. There is an ongoing clinical need to define more accurately the children whose risk of relapse justifies such therapies first line and to improve the efficacy of treatment for the highest risk subgroups. Existing prognostic factors in Wilms tumour identify only half of the children who subsequently relapse. This international trial, SIOP WT 2001, uses in vivo histological response to prenephrectomy chemotherapy to define a new high risk ‘blastemal’ subtype whose treatment is intensified. Aims: 1. To test the hypothesis that doxorubicin can be safely removed from the postoperative chemotherapy of stage II/III intermediate risk histology Wilms tumours without any adverse effect on event free or overall survival. 2. To determine prospectively the prognostic significance of tumour volume, specimen weight and histological subtype defined after response to pre-nephrectomy chemotherapy. 3. To investigate the prognostic significance of allele loss at chromosomes 1p & 16q in Wilms tumours treated according to a new histological-response based risk stratification. 4. To recruit sufficient patients with suitable material for molecular analyses to support rigorous evaluation of additional biomarkers – both as prognostic markers and for molecular characterisation of the newly defined histological risk groups. Summary: All children with a primary renal tumour can be registered in this international trial and consent to tissue banking. All those aged 6 months are treated with neoadjuvant chemotherapy. The intensity of chemotherapy and decision about use of radiotherapy following nephrectomy is determined by tumour stage, histological risk group and, for stage 4 disease, metastatic response. Approximately 30% of all Wilms tumour patients are eligible for the randomised question. The trial also makes new, single arm, treatment recommendations for certain risk groups, some of them newly defined. It includes a comprehensive tissue collection to be analysed for certain molecular markers and retained for future biological studies.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/10/011: LIHNCS: Lugol's iodine in head and neck surgery
Funder: Cancer Research UK

Abstract: Dysplasia or carcinoma-in-situ at margins following resection of SCC of the head and neck (SCCHN) is associated with increased recurrence 1,2. Pre-malignant disease is not distinguishable clinically but Lugols iodine technique is effective at other histologically similar body sites. This technique has never been evaluated in SCCHN. We plan a randomised, controlled multicentre study to evaluate; 1) Reduction in dysplasia positive margins with Lugol's 2) Acceptability of the technique to surgeons. 3) Estimation of the magnitude of reduction of locoregional recurrence. Patients will be randomised, stratified by centre and surgeon to Lugol's or control at tumour resection. Margins will be assessed by pathology teams locally and reassessed centrally. Acceptance will be assessed with qualitative interviews of surgeons, recurrence assessed at follow up.


Research activity codes: 6.4 SURGERY
Health categories: CANCER AND NEOPLASMS
Title: CRUK/10/012: TRYMS: Testosterone replacement in young male cancer survivors
Funder: Cancer Research UK

Abstract: A quarter of young male cancer survivors have low or borderline testosterone levels. Low testosterone is associated with reduced muscle, increased fat and an impaired quality of life. This study will determine whether testosterone treatment of young male cancer survivors will reduce body fat and improve quality of life. Last updated 24/08/2009 Approximately 1% of UK men aged 25-50 are cancer survivors. We have previously shown that a quarter of male cancer survivors aged 25-45 have testosterone levels below that of age matched controls (27% below 10th centile, and 13% below 2.5th centile). Survivors had a higher fat mass and fasting insulin:glucose ratio, and worse quality of life (QOL) than controls, specifically impaired physical functioning, vitality and sexual function. Survivors had on average 2.2kg greater truncal fat mass and 2nmol/l lower testosterone and the evidence suggested the low testosterone was causative of the increased fat mass. Low testosterone and high truncal fat are associated with an increased risk of vascular disease and diabetes independently of BMI, and waist circumference is associated with increased all-cause mortality, even in subjects with a normal BMI. Our study aims to determine whether testosterone replacement in young male cancer survivors improves adverse metabolic parameters and quality of life. We propose a multi-centre double-blind, randomised, placebocontrolled trial of 6 months treatment with testosterone gel, followed by a 3 month open-label treatment extension. This study will provide the evidence base for testosterone replacement in young male cancer survivors. Last updated 24/08/2009


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: CANCER AND NEOPLASMS
Title: Fatalism and stigma: Ethnic differences in prevention and early detection of cancer
Funder: Cancer Research UK

Abstract: Background - Ethnic minorities are less likely than the white majority population to attend for cancer screening or to say they would go to a doctor with cancer symptoms There is little research exploring this in the UK, but several small qualitative studies have implicated ‘fatalism’ and ‘stigma/taboo’ as two cancer-related attitudes that may play a role in non-adherence to early detection behaviours among UK ethnic minorities. These findings clearly warrant further consideration. Relevance to cancer – If there are ethnic differences in beliefs about cancer, addressing these may help to limit inequalities in uptake of prevention and screening services, and consequently save lives. Aims of Research - Ethnicity is a complex construct and there are many different aspects that might affect beliefs about cancer and early detection behaviours including, language, acculturation, religion and cultural norms Using both qualitative and quantitative methodologies, the proposed research aims to i) investigate ethnic variation in fatalistic and stigma-related beliefs about cancer, ii) examine their associations with early detection of cervical and breast cancer (through screening or symptom presentation) and iii) explore more specifically which ethnicity-related factors play a role in cancer fatalism and stigma. Outline plan of research - The research will begin with a qualitative study to explore the nature of fatalistic and stigmatising beliefs about cancer in Indian, Caribbean and white-British women. A larger quantitative study will then explore ethnic variation in fatalism and stigma across these three groups, considering which ethnicity-related factors (e.g. acculturation, religion) influence these beliefs and establish their association with cancer detection behaviours. A second quantitative study will then further this by exploring ethnic variation in fatalism and stigma in a sample of women from a wider range of ethnic minority groups (Indian, Pakistani, Bangladeshi, Caribbean and African).


Research activity codes: 4.3 INFLUENCES AND IMPACT;3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: CANCER AND NEOPLASMS
Title: Molecular and Computational Diagnostics
Funder: Cancer Research UK

Abstract: Research Goals <br />1. Combine molecular technologies with computational and genomic approaches to develop new diagnostic strategies; in particular, explore and exploit the potential of circulating nucleic acids. <br />2. Effects of cell-to-cell variation on gene regulation and on the way we study it Last updated 01/08/2010


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Exploiting mitosis towards designing novel anti-cancer strategies
Funder: Cancer Research UK

Abstract: A striking feature of human tumour cells is that they are typically aneuploid due to chromosome instability (CIN); in other words, during mitosis, tumour cells frequently make mistakes. This raises the possibility that CIN could be exploited as an oncogenic lesion in synthetic-lethality-based approaches. For example, mitotic inhibitors might be selectively toxic towards tumour cells which exhibit CIN. A major limitation however is that we do not know what causes CIN or how this drives tumorigenesis. The dogma during the last 10 years has been that CIN is caused by defective spindle checkpoint function. However, this is not the case; emerging evidence suggests that CIN arises due to an elevated frequency of merotelic orientations. This notion is based on analyzing established human tumour lines in culture. Therefore, in the first part of this proposal, we will genetically engineer mice to increase merotely and determine whether this can indeed cause CIN in vivo, and whether this can then drive tumour formation. We already know that mitosis is amenable to chemotherapy: microtubule toxins such as Taxol are used extensively to treat a variety of cancers. Because these existing agents are rather blunt tools, second generation anti-mitotic drugs are now being developed. In the event that it is not possible to exploit CIN to design synthetic lethality approaches, an alternative avenue would be to improve the efficacy of traditional and second generation anti-mitotic drugs. The major limitation here however is that we do not understand how anti-mitotic drugs actually kill cancer cells. Therefore, in the second part of this proposal we will exploit our recent discoveries to perform RNAi screens designed to identify the mechanisms that activate cell death in response to microtubule toxins. Understanding these mechanisms may in the longer run allow us to sensitise tumour cells to existing anti-mitotic agents. Last updated 09/09/2009


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/10/010: REALISTIC: A phase I, dose esclation trial of recombinant listeria moncytogenes (Lm)-based vaccine encoding human papilloma virus serotype 16 target antigens (ADXS11-001) in patients with HPV-16+ oropharyngeal SCC.
Funder: Cancer Research UK

Abstract: Background: HPV-16 causes 40-50% of OPSCC. Constitutive expression of viral proteins E6 and E7 appears essential for malignant transformation. 425-530 patients, typically younger non-smokers, are affected in the UK annually. Using current treatments 70-90% are cured but suffer significant post-treatment morbidity. Our aspiration is to de-escalate treatment for these patients using ADXS11-001 in combination with radiotherapy. Aims: We will assess safety, define toxicity and identify the most appropriate dose of ADXS11-001 in patients who have received treatment for HPV-16 positive OPSCC. Summary: Patients with HPV-16 positive OPSCC will enter a 3-centre, Phase I, dose-escalation clinical trial. Following definitive treatment, 3 cohorts of 9 patients (3 CRT +/- surgery; 3 RT +/- surgery; 3 ICT + CRT) will receive 3 intravenous vaccinations of ADXS11-001 at 4 week intervals. The first cohort receives a dose of 3.3 x 108 cfu; subsequent cohorts 1 x 109 and 3.3 x 109 cfu respectively. Following identification of a Maximum Tolerated Dose expansion of the relevant cohort by n=9 is planned to confirm effect. Vaccine-related systemic and local adverse events will be monitored as primary outcomes. Measurements by ELISPOT assay, of changes in the functional T cell response against HPV-16 E7 will constitute the secondary outcomes.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;6.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: New approaches to modelling human leukaemia
Funder: Cancer Research UK

Abstract: Our group is interested in cancer gene discovery using in vivo models. The current programme centres on the RUNX/CBF genes, which can promote or suppress cancer development and are frequently mutated by chromosomal translocations in human leukaemia._x000D_ The three mammalian Runx genes play essential roles in the development of blood, bone and neuronal cells and are implicated in tumour suppression as shown by loss of function mutations in some human leukaemias and epigenetic silencing in cancers of epithelial tissues (see Nature Reviews on Cancer 2005, 5: 376-87). We have found that the Runx genes can also act as oncogenes when activated by retroviral mutagenesis or expressed ectopically. This dualistic role is due in part to the ability of Runx to drive cell death, senescence-like growth arrest or survival according to context. The mechanisms and pathways by which the Runx genes control these fundamental processes are currently being explored with the aim of identifying novel targets for therapeutic intervention. We are also investigating the possibility of adapting established mutagenesis screening methods to probe the human cancer cell genome in vivo._x000D_


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Chemical biology of nucleic acids
Funder: Cancer Research UK

Abstract: In this programme we are focusing on the occurrence, structure and function of four stranded nucleic acid structures called quadruplexes. There is evidence to suggest that quadruplexes formed by specific DNA sequences play an important role in cancer-specific mechanisms, and that they may constitute a new class of molecular target for the chemical intervention of such mechanisms Two principal mechanisms connect quadruplexes with cancer. The first invokes the formation of quadruplexes in telomeres and is supported by data demonstrating telomerase inhibition, telomere shortening and cellular senescence by quadruplex stabilising agents. A second is the observation that quadruplex forming sequences have been found to occur proximal to proto-oncogenes in promoter elements. Our research approach comprises the synthesis of agents that stabilise quadruplexes plus an evaluation of their interaction with specific quadruplexes using biophysics, biochemistry and cell biology.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Gene expression patterns predictive of relapse from melanoma and in relation to subtype
Funder: Cancer Research UK

Abstract: Background Survival for melanoma patients is related to tumour thickness, site, sex and age. Some of these determinants are likely to be related to biological differences between tumours, which this project is designed to identify. Relevance to cancer An increased understanding of the biological basis of melanoma will allow the identification of prognostic and predictive biomarkers for use in the clinic. Critically, understanding these biological pathways will also identify new drug targets for a cancer, which is currently notably chemoresistant. Specific aims • To use new technology to measure genome wide gene expression in 500 tumours from the Leeds Melanoma Cohort • To identify genes whose expression is independently predictive of relapse/chemoresistance • To investigate variation in gene expression by tumour site, and BRAF mutation status and to establish both if that gene expression explains the effect of site on outcome, and if it mirrors pathogenetic "routes" to melanoma. • To validate these findings in 500 samples from patients recruited to the Lifestyle Study. Outline plan of research 1. We will use Cohort study samples (C8216/A8168) as the test set and samples from the “Lifestyle Study”, (C8216/A8777) to validate. 2. From the cohort samples of RNA we will sample 500 tumours in equal-sized groups of relapsed (all fatal cases) and non-relapsed patients (randomly selected). 3. We will use cDNA produced from the RNA to screen for BRAF and NRAS and C-Kit mutations using the Pyrosequencer. 4. The Illumina DASL whole genome (WG) Panel (Illumina Inc., CA, USA) will be used to perform gene expression profiling of 500 samples. The WG Panel allows assay of 24,500 transcripts targeting 18,400 mRNAs. 5. We will validate the technical findings from the DASL WG array, by testing up to 96 of the top hits on the Fluidigm system on a subset of 94 of the Cohort samples. Thus two platforms will be used to identify individual genes whose expression is related to outcomes of interest. 6. The DASL expression data will generate false positive results because of multiple testing. Gene expression identified as associated with outcomes of interest will therefore be further investigated by quantitative real-time PCR (qRT-PCR) in RNA extracted from tumours in patients who have participated in the Lifestyle study. 7. The statistical focus will be on gene-specific expression levels. Ingenuity Pathway Analysis (IPA) will be applied to investigate molecular and cellular functions involving genes most predictive of relapse, and, separately, response to treatment.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Colorectal tumour cell survival mechanisms and chemoprevention
Funder: Cancer Research UK

Abstract: Background: We have long standing expertise in colorectal tumour biology and chemoprevention. Our work has led us to play a lead role in the initiation of local and National clinical trials. Relevance: Colorectal cancer remains the second most common cause of cancer deaths in the UK, and incidence is set to rise with an aging population and from increased risk associated with other major health issues such as obesity and type 2 diabetes. Primary and secondary prevention provides one of the greatest opportunities to impact significantly on colorectal cancer-associated mortality. Aims: 1. Discovering novel context-dependent targets for ß-catenin: exploiting the tumour microenvironment for chemoprevention. 2. Unravelling the regulation of PGE2 catabolism: can we target the earliest events in colorectal carcinogenesis? 3. Understanding the mechanisms by which PGE2 promotes tumour growth and cell survival; uncovering a potential role for prostaglandins in intestinal stem/progenitor cell biology. 4. Determining whether BAG-1 is a modifier of prostaglandin metabolism: does the function of BAG-1 as a regulator of transcription explain its oncogenic role in colorectal tumorigenesis? Research plan: To use gene expression profiling to interrogate the mechanisms regulating hypoxia-induced gene expression in order to comprehensively identify novel (and direct) ß-catenin/HIF-1 targets that are important for tumour cell survival, adaptation and progression. Deregulated prostaglandin catabolism represents one of the earliest events in colorectal carcinogenesis and hence constitutes an excellent target for chemoprevention. Our unique adenoma-derived culture system will be used to gain an understanding of regulated prostaglandin turnover, the pathways controlling it and functional consequences. Rapid and extensive dissection of the mechanisms underlying PGE2-stimulated growth and survival in human cell culture models of early tumorigenesis will be carried out. Included will be interrogation of the novel and potentially important interaction between wnt, Notch and Lgr5 in PGE2 signalling during the early stages of human intestinal neoplasia. Flexibility of transcription factor function in response to the tumour microenvironment provides new avenues for selective targeting of tumour cells. Using both array and functional-based approaches we will interrogate the potential of BAG-1, as a newly identified regulator of the NF-kappaB - COX-2/PGE2 signalling pathways, as a novel target for chemoprevention.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;3.3 NUTRITION AND CHEMOPREVENTION
Health categories: CANCER AND NEOPLASMS
Title: Regulation of the human papillomavirus life cycle by E4 functions
Funder: Cancer Research UK

Abstract: Human papillomaviruses (HPV) cause various clinical manifestations; ranging from anogenital warts and laryngeal papillomas to cancers at anogenital sites, on the skin and in the oropharynx. Whilst prophylactic vaccines to protect against the two most prevalent types, HPV16 and HPV18 in cervical cancer have been developed they do not protect women already infected with the virus, do not protect against infection with all high risk HPV types and have yet to be adapted for use in the developing world. Furthermore, the efficacy of these vaccines against HPV16 and HPV18 infection at non-anogenital sites is not unknown. Thus the worldwide burden of HPV-associated disease will remain high for many decades, with a demand for new anti-viral therapies and treatments. To fulfil these demands a better understanding of the productive cycle is necessary and this will require detailed knowledge of the virus-host interactions that contribute to this process. The vegetative phase of the HPV life cycle is characterized by abundant expression of the HPV E4 protein. The precise role of E4 in the virus life cycle is not known. Definition of E4 function has largely been derived from ectopic E4 expression systems These have revealed multiple and diverse biological actions of E4 including deregulation of the cell cycle, repression of cellular DNA synthesis and induction of apoptosis. Many of the biological activities have been attributed to distinct protein sequence elements. It is hypothesized that E4 is a major regulator of the virus life cycle and that E4 functions at multiple stages within the infectious cycle. We aim to test this hypothesis by investigating the significance of disruption of specific E4 functions in a cell-based model that mimics the natural scenario of the HPV18 replication cycle; to validate the phenotypic consequences of these mutations by exogenous E4 expression; and to observe if E4 functions include disturbance of keratinocyte biology in stratified cultures. A cell-based model of HPV18 replication uses primary human keratinocytes - the natural host cell of the virus - transfected with HPV18 genomes. This model has been proven to be a robust system of HPV18 propagation to produce infectious virus following stratification by growth as organotypic rafts. Genetic analysis of the E4 ORF will be comprehensive and targeted to specific E4 sequence elements of known function and assessment of the effects of the mutations on the complete profile of virus functions including the ability of the mutant genomes to support production of infectious virus.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS