NIHRDataInsights/HRCSData huggingface dataset:
Title: CRUKD/12/015: PANtHER a Phase I/II study of EGFR inhibitor AZD8931 in combination with FOLFIRI to determine the importance of schedule and activity in colorectal cancer
Funder: Cancer Research UK

Abstract: BACKGROUND Chemotherapy for colorectal cancer induces clinical responses in a proportion of patients and extends progression-free and overall survival. Cetuximab, an antibody inhibiting the epidermal growth factor receptor (EGFR) has shown modest efficacy as monotherapy and in combination with irinotecan-based chemotherapy. Small molecule EGFR inhibitors such as gefitinib have not shown synergy with chemotherapy. The reason for differences between responses of these agents and antibodies remain unclear but suboptimal administration schedules may contribute. Studies of gefitinib and erlotinib combined with chemotherapy in lung cancer suggest that pulsatile administration of EGFR inhibitor may improve responses compared with chronic administration. Additionally, recent research indicates that erbB2 and erbB3 contribute to cetuximab resistance. AZD8931 is a novel oral small-molecule inhibitor with equipotent activity against EGFR, erbB2, and erbB3. It is therefore a potentially active agent for the treatment of colorectal cancer. AIMS Objectives of Phase Ib design: a) To determine Maximum Tolerable Dose (MTD) in patients receiving FOLFIRI and chronic administration AZD8931 b) To determined MTD in patients receiving FOLFIRI and pulsatile administration AZD8931 c) To determine the pharmacokinetic interaction of AZD8931 given with FOLFIRI. d) To investigate pharmacodynamic endpoints including HER dimerization status, DNA damage and pathway analysis Objectives of Randomized Phase II design: Three arms FOLFIRI alone, MTD determined AZD8931 chronic administration + FOLFIRI MTD determined from AZD8931 pulsatile administration +FOLFIRI ) Primary: To compare the efficacy and safety of AZD8931 plus FOLFIRI compared to FOLFIRI alone Secondary: a) To assess the efficacy of AZD8931 plus FOLFIRI arm compared to FOLFIRI alone in terms of progression-free survival (PFS) b) To investigate efficacy of AZD8931 plus FOLFIRI arm compared to FOLFIRI alone by assessment of objective response rate (ORR) METHODS PHASE Ib Primary • Safety and tolerability of AZD8931 in combination with FOLFIRI (pulsatile and continuous dosing) Secondary • Pharmacokinetic parameters (AUC, Cmax, t1/2) of AZD8931 and FOLFIRI and active metabolite SN38 PHASE II Primary • Change in tumour size at 12 weeks Secondary • Objective response rate • Progression-free survival • Safety and tolerability Tertiary Pharmacodynamic endpoints Correlations between PD endponts and PK parameters and/or concentrations How the results of this research will be used This is a study which will investigate efficacy of panHER inhibition in colorectal cancer in combination with chemotherapy and the importance of schedule of administration. It will also incorporate novel pharmacodynamic endpoints to establish the molecular effects of this approach.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Epstein-Barr virus infections and lymphomagenesis
Funder: Cancer Research UK

Abstract: Background Epstein-Barr virus (EBV), a herpesvirus widespread in human populations, is normally carried as a life-long asymptomatic infection of the B lymphoid system. However the virus has B cell growth-transforming ability in vitro and is linked to three B cell malignancies in vivo: Burkitt’s lymphoma (BL), Hodgkin’s lymphoma and post-transplant lymphoproliferative disease (PTLD). The roles of EBV in the development of these malignancies are incompletely understood. Aims Through studying the fundamental biology of the interactions of the virus with B cells, both in cell culture and in the virus-carrying host, we aim to improve our understanding of the pathogenesis of these diseases. The programme consists of 2 interrelated areas of work, addressing: (1) Mechanisms of clonal selection of EBV-transformed B cells in vitro, and (2) In vivo infections of B cells in immuno-competent and immuno-compromised individuals, and the viral contribution to PTLD and BL pathogenesis Methods The methods will encompass experiments on in vitro models of EBV infection and cell transformation, and the analysis of virus infection in lymphoid tissues and blood from asymptomatic virus carriers and patients with EBV-associated malignancies. The work will use state of the art molecular and cell-biology techniques and a range of methods for characterising EBV-target cell interactions established in our laboratory. Clinical studies complementing the in vitro work will draw on several collaborations established to obtain tissues from relevant patients and controls. Prospective studies on patients will allow key laboratory findings to be correlated with detailed clinical data relating to patient and disease characteristics, therapy, response and outcome. How the results of this research will be used The spectrum of EBV-associated lymphoproliferations/lymphomas has diverse etiologies and outcomes. The results of our work will provide a better understanding of the pathogenesis which, through our close interactions with clinicians and Clinical Trial groups, will pave the way for the design of optimal therapies.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Epidemiology of oral HPV infection, impact of vaccination and surveillance in young people
Funder: Cancer Research UK

Abstract: Background Human papillomavirus (HPV) causes a distinct subset of oropharyngeal cancer (OPCs), and the incidence of OPCs is increasing, particularly among those aged 45-69 years in England. There are no existing data on the population burden of oral HPV infection in England. In addition, there is no validated sampling method for detection of oral HPV infection. If vaccination is as effective in preventing oral HPV-16/18 infection as it does for cervical infection, a substantial burden of OPCs can be reduced in a vaccinated population. Therefore, there is a need to monitor trends of oral HPV infection and to measure the impact of the vaccine through surveillance. Aims •To evaluate three different oral sampling methods for HPV detection using (ii) oral scrapes at four mucosal sites (tonsil, base of the tongue, soft palate and pharyngeal wall); (i) oral rinse samples (saline vs. mouthwash); and (iii) saliva •To evaluate the feasibility of detecting HPV-antibodies in oral mucosal transudate (OMT) to identify vaccination status •To determine the concordance of oral and cervical HPV infection among women •To measure the population prevalence of oral HPV infection in young women and men •To evaluate HPV vaccine efficacy against oral HPV infection among women Methods Three types of oral sampling methods (oral scrapings (gold standard), oral rinse sample with mouthwash and saline, and saliva) will be compared to identify the optimal method for HPV detection in 100 participants attending a genitourinary clinic (Study 1). A sensitive quantitative PCR test will be used to determine the level of HPV DNA present in oral samples to determine the analytic sensitivity required for larger epidemiological studies. A small feasibility study (n=20) to detect HPV-antibodies in oral fluids and sera will be conducted in the same clinic. Using the optimal method identified in Study 1, an oral HPV prevalence study will be conducted among 3000 young women (n=2400) and men (n=600) ages 18 to 22 years attending university (Study 2). How the results of this research will be used Results from this research will identify an appropriate oral sampling method for HPV detection in large epidemiological studies. Baseline data will also be provided on the burden of oral HPV infection and the early impact of vaccination, which will be needed for monitoring type-specific trends in the long-term.


Research activity codes: 4.4 POPULATION SCREENING
Health categories: CANCER AND NEOPLASMS
Title: Signalling Networks in Tumour Cell Proliferation and Fate control
Funder: Cancer Research UK

Abstract: Defects in proliferation and fate control are fundamental for the development of cancer and found in cancer cells of all cancer types. Because of such defects cancer cells enter division independent of external cues and remain proliferation active under conditions where normal cells are unable, or cease, to divide. Loss of division control is critically important for the ability of cancers to expand at their primary site as well as for the ability of cancer metastasis to establish following spreading of individual cancer cells to remote tissues. In this programme of work funded by Cancer Research UK we are seeking to delineate the molecular machinery required for cells to enter the cell division cycle and the mechanisms that leads cells to cease division activity transiently and terminally. The decision whether to enter cell division arises in the GAP1 (G1) phase of the cell cycle and normally requires stimuli from the external environment. Once the decision is made the cell progress through the division cycle generating two daughter cells. We are using high contend cell-based assays in combination with RNA interference to map signalling networks that are required for G1 checkpoint transit and others required for the activation of G1 checkpoint control by environmental and cancer therapeutic stress.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Evaluating population-based screening for localised prostate cancer in the United Kingdom: the CAP (Comparison Arm for ProtecT) randomised controlled trial
Funder: Cancer Research UK

Abstract: Background and relevance In 2008, there were 37,000 newly diagnosed prostate cancers and 10,000 prostate cancer deaths in the UK. Screening for prostate cancer, however, is worthwhile only if the prospect of benefit outweighs the potential for harm. Despite recent publication of two landmark randomised controlled trials, the debate around PSA-based prostate cancer screening continues to generate controversy, with concerns about overdiagnosis, overtreatment and the accuracy of the estimation of mortality benefit. Current UK health policy does not advocate population screening for prostate cancer, but awaits the findings of the two linked trials in this proposal: CAP and ProtecT. Specific aims The principal research question is whether screening using PSA-testing of men aged 50-69 years will reduce prostate cancer mortality and be cost-effective. Our specific aims are to: i) estimate the effect of a single testing round for prostate cancer on prostate cancer-specific and all-cause mortality; ii) investigate the impact of testing on morbidity and health status; and iii) estimate the cost-effectiveness of prostate cancer screening in the UK. Research Plan CAP is an ongoing CRUK-funded cluster randomised controlled trial in which 587 GP practices in eight centres in England and Wales have been allocated to either population-based PSA testing, akin to screening (the ProtecT study) or standard (unscreened) practice. In ProtecT practices (n = 276), 204,068 men aged 50-69 years were invited between 2001-2008 to undergo PSA testing. Men subsequently diagnosed with clinically localised prostate cancer were invited to participate in a randomised controlled trial of radical surgery, radical conformal radiotherapy and active monitoring (regular PSA testing and treatment review). In the comparison arm practices (n = 311), 231,251 men aged 50-69 years undergo standard NHS management (provision of an informed choice to any man over the age of 50 who requests a PSA test). All men are being followed-up for incident and fatal prostate cancer via the National Health Service Information Centre (NHSIC). The primary outcome is prostate cancer mortality after a median 10 years follow-up (reached by March 2016), analysed by intention-to-screen. Secondary outcomes include all-cause mortality, cost-effectiveness and disease grade and stage. The current proposal is to complete follow-up and undertake primary analyses. Implications This UK trial is unique, because methods of recruitment, screening and treatments differ from the major published trials, and will make a much awaited contribution to UK policy development and international understanding of the cost-effectiveness of prostate cancer screening.


Research activity codes: 8.2 HEALTH AND WELFARE ECONOMICS;4.4 POPULATION SCREENING
Health categories: CANCER AND NEOPLASMS
Title: AMP-activated protein kinase - a tumour suppressor that opposes the metabolic changes in proliferating cells
Funder: Cancer Research UK

Abstract: BACKGROUND: AMP-activated protein kinase (AMPK) is a cellular energy sensor that regulates growth and metabolism of all eukaryotic cells. By a mechanism requiring LKB1 (a known tumour suppressor), AMPK is switched on by metabolic stresses that deplete ATP. This triggers cell cycle arrest and switches cells away from the glycolytic, anabolic metabolism typical of proliferating cells towards the catabolic, oxidative metabolism of quiescent cells. AMPK is activated by the anti-diabetic drug metformin and the aspirin metabolite salicylate, both of which have been proposed to provide protection against human cancers. AIMS: 1) to study global changes in protein phosphorylation, expression and translation of specific mRNAs, and metabolism in proliferating cells in which AMPK is acutely activated or inactivated; 2) to test, using mouse models, whether AMPK acts as a tumour suppressor in vivo, whether metformin delays tumour onset by direct, cell-autonomous effects on AMPK in tumour cells, and whether AMPK activation has any role in the protective effects of aspirin in gastrointestinal cancer; 3) to follow up, by establishing the mechanisms involved, previous observations showing that AMPK activation is down-regulated in human breast cancer. METHODS: Aim 1 will be addressed using two cell models: (i) human tumour cells lacking LKB1, in which AMPK is reactivated by inducible expression of upstream kinase; (ii) T cells derived from T cell-specific AMPK knockout mice or wild type controls. Protein phosphorylation will be analyzed by SILAC, mRNA expression/translation by next-generation sequencing, and metabolism by flux analysis. Aim 2 will be addressed using mouse models of lymphoma and lung cancer in which AMPK has been conditionally knocked out in the tumour cells, the mice being treated with or without metformin, and by crossing APCmin mice (which are prone to gastrointestinal cancer) with knock-in mice bearing a novel mutation that renders AMPK salicylate-resistant. Aim 3 will be achieved by immunohistochemistry of tumour tissue microarrays, using antibodies against subunit isoforms and phosphorylation sites in the AMPK pathway newly validated for immunohistochemistry. HOW THE RESULTS WILL BE USED: By confirming that AMPK is a tumour suppressor, they may focus future cancer research efforts on this signalling pathway. By establishing the mechanism for the protective effects of metformin and salicylate drugs in mouse models, they may aid the design of future prospective trials in human cancer. By elucidating mechanisms of AMPK down-regulation in breast cancer, they may aid development of markers useful for patient stratification.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;3.3 NUTRITION AND CHEMOPREVENTION
Health categories: CANCER AND NEOPLASMS
Title: The Clinical Translation of Breast Cancer Predisposition Genes
Funder: Cancer Research UK

Abstract: Background Breast cancer is very common condition. 1 in 8 women in the UK now develop the disease and there are 45,000 new cases each year. The causes of breast cancer are still largely unknown, but there is abundant evidence to suggest that genetic factors are important. Over the last 15 years there has been tremendous progress in the understanding of the genetic causes of breast cancer and our group has been central to many of these endeavours. However, despite these successes at least 50% of the genetic risk of breast cancer remains unexplained. Aims The programme has four overarching aims: 1) Collection and curation of 12,000 breast cancer families. 2) Identification of breast cancer susceptibility genes using next-generation sequencing approaches. 3) Characterisation of the prevalence, penetrance, phenotype and interactions of mutations in breast cancer susceptibility genes. 4) Clinical translation of breast cancer susceptibility genes. Methods In 2001 we set up the Familial Breast Cancer Study to recruit families with breast cancer in the UK. It now includes over 8,000 families of which 7,000 are BRCA1/2-negative. This is the largest, and best curated, series of families in the world. In the forthcoming programme we aim to extend the series to 12,000 families, and to increase the depth of clinical and molecular information available from the families. In our previous programme we pioneered candidate-based familial case-control resequencing analysis to successfully identify several new cancer susceptibility genes. We now propose to extend this strategy to all protein-coding genes (known as the exome). We are sequencing the exome in 1,000 familial BRCA1/2-negative cases and 1,000 controls. We will analyse the data to select likely breast cancer predisposition genes which we will then analyse in up to 5,000 additional cases and controls. For all new genes that we identify we will characterise the associated clinical features and cancer risks. We will use these data to develop clinical protocols and diagnostic tests, so our findings can be rapidly, and robustly, used in clinical practice. Outcomes We believe the research will lead to the discovery of new breast cancer susceptibility genes. This will foster new research and advancements in our understanding of the biological basis of breast cancer. It may also provide new targets for the development of genetically-targeted therapies. Finally, the research will deliver new, clinically useful information and diagnostic tests that will facilitate personalised management of individuals with cancer and their relatives.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Structure, function and regulation of the eukaryotic replisome
Funder: Cancer Research UK

Abstract: The eukaryotic replisome is a highly complex molecular machine that duplicates chromosomes and preserves genome integrity. In contrast to our familiarity with the structure and mechanism of its bacterial counterpart, the eukaryotic replisome is still understood very poorly and must deal with many other challenges in addition to just copying DNA. We aim to define the composition, structure, mechanisms and regulation of the eukaryotic replisome. Key questions will include how the eukaryotic replisome is able to traverse chromatin so quickly and duplicate epigenetic histone modifications at the same time as copying chromosomal DNA. Another goal will be to understand the complex mechanisms by which the replisome controls its own progression and ensures that genome integrity is preserved during chromosome replication. A further objective will be to undertake a systematic study of post-translational modifications of replisome subunits that only occur in the context of the replisome complex, to understand how these might regulate replisome function both during the normal process of chromosome replication and also in response to replication stress. There is considerable evidence now to indicate that defects in chromosome replication contribute to the earliest stages of cancer development and are an inherent feature of many human tumours. We aim to establish a model system with which to study systematically the nature and regulation of the replisome in primary mouse cells. Our long term goal will be to compare directly the regulation of the replisome in genetically matched primary mouse cells and tumour cells, in order to inform the future use of novel anti-cancer therapies that will better exploit the defects in chromosome replication that typify many human tumours.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Roles of NF-kB in the control of inflammation and metabolism in cancer
Funder: Cancer Research UK

Abstract: BACKGROUND: NF-kB promotes oncogenesis by linking cancer with its inflammatory microenvironment. Efforts to target the NF-kB pathway in cancer patients, however, have failed due to the pleiotropic functions of this pathway. Recently, we discovered new tumourigenic functions for NF-kB in cancer and inflammatory cells. NF-kB upregulates Gadd45b in inflammatory cells to stimulate tumour progression, and reprograms metabolism in malignant cells to enable metabolic adaptation. The objective of this application is to gain an in-depth mechanistic understanding of how NF-kB exercises these distinct tumourigenic functions in order to develop better therapies for malignant disease. This proposal will achieve this objective in three Components, which will test the hypotheses that: AIMS & OBJECTIVES: (1) Gadd45b mediates the activity of NF-kB in tumour-infiltrating inflammatory cells, and via this mechanism enables inflammation to promote tumourigenesis (Component 1). (2) NF-kB promotes tumourigenesis partly by stimulating mitochondrial metabolism, and this activity of NF-kB can be exploited therapeutically (Component 2). (3) NF-kB regulates metabolic networks beyond respiration, and this NF-kB-dependent bioenergetic function controls energy substrate selection during nutrient limitation, in normal and cancer cells (Component 3). Component 1 will maintain continuity with the past quinquennium; Components 2 and 3 will explore the new and exciting area of NF-kB signalling in cancer metabolism. It is important to emphasise that these are not isolated projects, but rather are part of a wider strategy of comprehensively understanding how NF-kB contributes to tumorigenesis. All experimental models proposed in this application were validated experimentally in our laboratory. In order to gain expertise we do not have, we have established a network of collaborators, who possess this expertise. METHODS: We will use molecular and cell biology techniques, as well as animal models, to investigate the new roles of NF-kB and Gadd45b in metabolism and pro-inflammatory cells in cancer. HOW THE RESULTS OF THIS RESEARCH WILL BE USED: Translationally oriented research is a significant aspect of this application, built upon our interest in drug discovery and promising preliminary results with novel candidate therapeutics specifically targeting the NF-kB pathway in cancer. Our investigations into how NF-kB links malignancy with inflammation will therefore not only further our understanding of cancer, but potentially also provide better anti-cancer treatments.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Clinical translational studies of colorectal cancer susceptibility alleles
Funder: Cancer Research UK

Abstract: Studies will be undertaken to enumerate the risk associated with colorectal cancer susceptibility alleles both in terms of individuals risk prediction and value in public health settings. These analyses will be undertaken using case-control , cohort and families strategies. Coupled with these analyses we shall perform studies to delineate associated clinical phenotypes.


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