NIHRDataInsights/HRCSData huggingface dataset:
Title: CRUK/11/015: UKMCC-1 (previously PAZAM!): Pazopanib in Advanced Merkel Cell Carcinoma
Funder: Cancer Research UK

Abstract: Merkel cell carcinoma (MCC) is a rare neuroendocrine cancer of the skin with poor prognosis. The annual incidence is thought to be 0.6 per 100,000 of the population, with approximately 400 cases per year in the UK. The overall 10 year survival rate is 57%. Approximately 200 patients per year present with or develop advanced unresectable disease and are candidates for systemic therapy. The prognosis of patients with stage IV disease is very poor, the 10 year survival rate is 20% and the median overall survival is estimated to be approximately 1 year although some series report even lower survival. The disease is generally sensitive to palliative chemotherapy. Small Cell Lung Cancer type regimes are used and response rates of 60-75% are seen. Median response duration is however only in the order of 3-6 months. A novel polyoma virus, Merkel Cell Virus (MCV), has been described with viral genomic integration into the MCC genome in over 80% of cases. The significance of this finding regarding prognosis and response to treatment is uncertain. There have been few prospective trials of new agents in advanced MCC, principally because of the rarity of the disease. Pazopanib, a multi-targeted tyrosine kinase inhibitor is licensed for the treatment of advanced renal cell carcinoma. PDGF receptors ƒ¿ and ƒÀ and VEGF receptors 1, 2 and 3 are amongst its targets. A patient with advanced MCC who had failed 1st line chemotherapy experienced a partial response lasting 6 months in a pazopanib phase I study. A 1432T¨C mutation in the PDGFRƒ¿ gene was seen in patient germ-line and tumour DNA as well as in two other tested MCC samples. Aim: to perform a single arm 2-stage open label phase II study of pazopanib in a maximum of 25 patients with advanced MCC. The primary objective is to determine whether the response rate is sufficient to justify further investigation of the clinical benefit of pazopanib for advanced MCC. The secondary objectives are to estimate the response rate, duration of response, disease control rate, progression free survival and overall survival. The objective of the sub-study is to explore the relationships with clinical outcomes in patients with MCC treated with pazopanib therapy of mutations in tumour and germ-line polymorphisms in the c-KIT and PDGFRA genes. This sub-study will provide the framework to establish a UK wide central biorepository of tissue with associated clinical data from patients with MCC.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: CRUK/06/016: CHHiP-BIOBANK: Blood Sample Collection Study
Funder: Cancer Research UK

Abstract: Background: Radiotherapy is am important curative treatment for cancer used in an estimated 40% of cancer survivors. Side effects, which can appear several years following treatment, have a negative impact on quality of life and their development in a minority limits the potentially curative doses that can be described to the majority of patients. There is a need to develop risk prediction models for not only toxicity but also survival. CHHiP is phase III randomised trial testing the hypothesis that hypofractionated radiotherapy for localised prostate cancer will improve the therapeutic ratio by either improving the tumour control or reducing the normal tissue side effects. The trial has a planned recruitment of 3,160 patients with actual exceeding target accrual. The trial involves the prospective collection of toxicity data, which are rarely collected within routine clinical practice. The trial provides an excellent opportunity to collect blood samples from a well defined cohort of prostate cancer patients. Some bloods (n=482) were collected for RAPPER (Radiogenomics: Assessment of Polymorphisms for Predicting the Effects of Radiotherapy) - a study linking genotypeand radiation toxicity data. RAPPER funding ended August 30th 2010 and, although additional funding was secured to cover genotyping, no further money is available to support continued sample collection. Power calculations suggest 10,000 patients should be analysed to link genotype with radiotherapy toxicity data. Aims: To collect blood samples from as many of the remaining 2,678 CHHiP patients as possible with a target recruitment of 2,400. The long term goal of the sample is to link genotyping and radiotherapy toxicity data. A secondary aim is to link genotyping and survival data. Both goals require the eventual analysis of many thousands of samples and consortia have been established to address this need: the Radiogenomics and ELLIPSE Consortia. Methods: Blood samples will be collected before or after (a minimum of 6 months following completion of radiotherapy) treatment. Samples will be posted to Manchester. The methods are well established and associated with success rates in extracting DNA off 99.7% and genotyping of 99.7%. Use of results: The ultimate goal of the Radiogenomics Consrtium is to derive risk profiles that can be used to individualise radiation dose prescriptions and reduce the number of cancer patients suffering long-term toxicity following radiotherapy. The ultimate goal of the ELLIPSE consortium is to develop progression and treatment outcome risk prediction models for prostate cancer patients for use in individualising radiotherapy to improve survival.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: CRUK/06/008: TeloVac: prospective, phase III, controlled, multicentre, randomised trial comparing combination Gemcitabine & Capecitabine therapy with concurrent & sequential chemoimmunotherapy using a telomerase vaccine
Funder: Cancer Research UK

Abstract: 1. Background_x000D_ Pancreatic cancer is a significant health problem for which there is a huge unmet therapeutic need. The disease carries a uniquely poor prognosis with incidence rates and mortality rates being almost equivalent_x000D_ Telomerase is a ribonucleoprotein enzyme which is involved in the DNA replication of the cell cycle. The enzyme is over-expressed in the majority of human cancers including 90% of advanced pancreatic cancer patients and therefore is a natural therapeutic target in the treatment of cancer. GV1001 is a 16mer peptide vaccine representing aa611-626 pof the human telomerase reverse transcriptase catalytic sub-unit which elicits telomerase-specific CD4+ and CD8+ in patients with cancer._x000D_ 2. Aims and Objectives_x000D_ To investigate if the addition of GV1001 in patients with locally advanced or metastatic pancreatic adenocarcinoma, when given concurrently or sequentially, to combination gemcitabine and capecitabine, improves survival over treatment with combination gemcitabine and capecitabine alone._x000D_ 3. Methods_x000D_ Prospective phase III, controlled, open-label, multicentre, randomised clinical trial._x000D_ Patients will be randomised equally between three treatment arms:_x000D_ Arm 1: Standard treatment - Gemcitabine and Capecitabine_x000D_ Arm 2: Sequential - Gemcitabine and Capecitbaine for two cycles followed by GV1001 vaccine alone then further gemcitabine and capecitabine at disease progression (provided no progression was seen on the week 8 CT scan)._x000D_ Arm 3: Concurrent – administration of gemcitabine, capecitabine and GV1001 vaccine._x000D_ Patients will be stratified by:_x000D_ - Stage of disease (locally advanced vs, metastatic) and_x000D_ - ECOG Performance status (0 versus 1 versus 2)_x000D_ 4. How the results of the research will be used_x000D_ This is a pivotal study investigating the interaction of chemotherapy and immunotherapy in cancer and the largest global vaccine study in pancreatic cancer ever performed. The clinical results together with the translational analyses from this study will inform the design of all future studies of chemo-immunotherapy particularly with respect to whether there is a qualitative difference between a sequential or concurrent approach, the true survival impact of immune system priming in conjunction with a cancer vaccine and the mechanisms by which such priming works. TeloVac is one of only a small number of studies to test the survival impact of immunotherapy in cancer in adequately powered trials. The survival of patients with pancreatic cancer remains dismal and any significant improvement in outcome as a result of the integration of a vaccine into standard therapy would be of enormous clinical importance


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/11/043: De-ESCALaTE-HPV: Determination of Epidermal growth factor receptor-inhibitor (cetuximab) vs Standard Chemotherapy early and Late Toxicity Events in Human Papilloma Virus Positive oropharyngeal carcinoma
Funder: Cancer Research UK

Abstract: Background: Oropharyngeal squamous cell carcinoma (OPSCC) incidence is increasing rapidly in the developed world, and is caused by Human Papillomavirus (HPV) infection. HPV+OPSCC is a distinct disease, which affects younger patients and has a good prognosis, meaning that patients will live with the considerable side effects of treatment for several decades. Radiotherapy and Cetuximab (Epidermal Growth Factor Receptor-inhibitor) demonstrated similar efficacy to platin chemoradiotherapy (current standard treatment) in head neck cancer, but is potentially less toxic._x000D_ _x000D_ Aims: For HPV+OPSCC, compared to current standard, will cetuximab + radiotherapy result in:_x000D_ 1. Less morbidity (late and acute toxicity)?_x000D_ 2. Better quality of life?_x000D_ 3. Better cost effectiveness?_x000D_ _x000D_ Methods: Pragmatic RCT - 296 patients with HPV+OPSCC will be randomised to Cetuximab + radiotherapy (study treatment) or cisplatin + radiotherapy (control)._x000D_ The main outcome will be severe late toxicity, with acute toxicity, survival, recurrence quality of life, swallowing, and health economics as secondary outcomes, with close monitoring of any deviation between the two arms_x000D_ _x000D_ Uses: Results will be used to determine the optimum treatment of this rapidly rising and debilitating cancer, with the aim of decreasing toxicity and improving quality of life in good prognosis HPV+ patients._x000D_


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/11/022: DESKTOP III: A randomised multicentre study to compare the efficacy of additional tumour debulking surgery versus chemotherapy alone for recurrent platinum-sensitive ovarian cancer
Funder: Cancer Research UK

Abstract: Background:_x000D_ Previous studies have shown significant survival benefit in patients with complete macroscopic cytoreduction whilst the AGO score appears to reliably predict complete resectability in this population of patients. However, it is unclear if both the AGO score or complete resectability at late cytoreduction merely reflect a less aggressive biological variable of the tumour and thus might achieve the same outcome with chemotherapy alone. The alternative is that surgery confers a real benefit._x000D_ Aims:_x000D_ 1. To compare overall survival in patients with platinum sensitive recurrent ovarian cancer with a positive AGO-score randomized to tumour debulking surgery followed by chemotherapy of physician.s choice versus chemotherapy of physician.s choice alone._x000D_ 2. Quality of Life. To compare progression-free-survival in treatment groups. To analyze complications associated with surgery and perioperative mortality in patients with relapsed ovarian cancer in a multicenter setting. Exploratory analysis of surgical and treatment characteristics._x000D_ Summary of proposed study:_x000D_ This is an open-label, prospective, randomized, international, multicentre phase III surgery trial following an international protocol developed in Germany. 408 patients (204/group) will be randomized to experimental or control treatment in a 1:1 ratio over a period of 30 months. All participants will be followed up until observation of 244 events, which is expected at 36 months after randomization of the last patient (i.e. 72 months after start of the trial). The UK is expected to recruit approximately 100 of the total patients.


Research activity codes: 6.4 SURGERY;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/10/056: PARAGON: Phase II study of aromatase inhibitors in women with potentially hormone responsive recurrent/metastatic gynaecological neoplasms
Funder: Cancer Research UK

Abstract: Background A substantial proportion of gynaecological cancers express steroid hormone receptors, are potentially hormonally responsive and may therefore respond to treatment with an aromatase inhibitor Aims To investigate the response of patients with ER/PR + ve gynaecological cancer to treatment with an aromatase inhibitor Summary We are proposing a phase II study of arimidex in hormone receptor positive, recurrent or metastatic, endometrial cancers, granulosa cell tumours and endometrial stromal sarcomas. The design of the study will allow each tumour subgroup to be analysed independently, but the single protocol reduces the administrative burden making a study in these relatively rare subgroups more feasible.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Investigation of the roles for the APC/C in the cell cycle control of the centrosome activity and integrity and its spatiotemporal regulation on the centrosome
Funder: Cancer Research UK

Abstract: The Anaphase-Promoting Complex or Cyclosome (APC/C) is a master regulator of_x000D_ cell cycle progression. APC/C-mediated ubiquitinylation of key cell cycle molecules_x000D_ promotes their destruction. Successful passage through the cell cycle is therefore_x000D_ reliant upon tight spatial and temporal control of APC/C activity._x000D_ The centrosome nucleates microtubules that drive chromosome segregation and cell_x000D_ motility in higher eukaryotes. It plays a critical role in maintaining stem cell fate by_x000D_ regulating the spindle orientation that is key to their asymmetric division. The_x000D_ association of APC/C subunits and cofactors with the centrosome is likely to be_x000D_ functionally significant as over-expression of the centrosomally associated APC/Cspecific_x000D_ E2 enzyme, UbcH10, generates supernumerary centrioles and drives_x000D_ carcinogenesis._x000D_ Deregulation of the centrosome function is a recurrent theme in chromosome_x000D_ instability and over-proliferation of stem cells. Furthermore, supernumerary_x000D_ centrosomes are a hallmark of cancer, suggesting that the precise control of the_x000D_ centrosome integrity and activity is essential for preventing tumourigenesis. HsSas-6_x000D_ is down-regulated by APC/C to prevent centrosome over-amplification while critical_x000D_ regulators of centrosome maturation, Polo/Plk1 and Aurora A, are destroyed by_x000D_ APC/C during mitotic exit. These and other data suggest that elucidating APC/C_x000D_ functions at the centrosome could be key to understanding the well documented, yet_x000D_ poorly understood, link between supernumerary centrosomes and cancer and_x000D_ identifying new avenues for chemotherapy._x000D_ I will define the significance of APC/C-mediated proteolysis of centrosomal proteins_x000D_ in driving cell cycle progression in the widely exploited model system Drosophila_x000D_ melanogaster. After identifying which key centrosome components and regulators_x000D_ are APC/C substrates, I will address the importance of their destruction for_x000D_ centrosome integrity and activity. The molecules that dock the APC/C to the_x000D_ centrosome and regulate its centrosome-localised activity will be identified. Finally,_x000D_ the role played by centrosomal APC/C in regulating spindle orientation and_x000D_ asymmetric division will be explored in neural stem cells.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS
Title: Mammalian target of rapamycin (mTOR) regulates innate immune function in the tumour microenvironment
Funder: Cancer Research UK

Abstract: Tumour-stroma interactions are increasingly recognised as critical components of tumour biology, including invasion and metastatic potential. Macrophage infiltration is a hallmark of the majority of haematological and solid malignancies. Such microenvironment-mediated changes account, at least in part, for the inability of conventional chemotherapies to cure such diseases as pancreatic cancer._x000D_ _x000D_ We hypothesise that mammalian target of rapamycin (mTOR) signalling in tumour-associated macrophages is responsible for their inability to respond adequately to new challenges, failure to control tissue homeostasis, support of the stromal ‘fortress’ and promotion of malignant disease. _x000D_ _x000D_ The following questions will be addressed in vitro/in vivo: _x000D_ 1. How do mTOR kinases influence macrophage phenotype and function?_x000D_ 2. What is the impact of mTOR deletion on myeloid differentiation and response to tumour development?_x000D_ 3. How does differential mTORC1 vs. mTORC2 deficiency impact on innate immune function in young versus aged mice? _x000D_ 4. Can we ‘re-educate’ innate immunity to improve its function during cancer progression or in later life?_x000D_ _x000D_ We will use genetically modified mice that spontaneously develop pancreatic cancer and combine these with mice in which macrophage-specific mTOR kinase pathways can be manipulated. We will test the functional roles of these mTOR complexes in macrophages on their role in tumour progression and in conditions where innate immunity declines such as age. _x000D_ _x000D_ A unique dataset on myeloid subsets from pancreatic cancer patients will provide the first comprehensive comparison between human and murine myeloid subsets. We will identify the effect of macrophage-specific delivery of mTOR pathway inhibitors and ask if this can influence tumour development and response to systemic chemotherapy. This project will generate extensive data showing many potential aberrations and connections, allowing visualisation and integration of the data into testable hypotheses._x000D_ _x000D_ Understanding the underlying mechanisms could lead to new preventions and treatments that complement conventional therapeutic approaches to target malignant disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: A genetic dissection of tumour progression and invasion in the context of a living epithelium
Funder: Cancer Research UK

Abstract: We have recently established a system that enables us to visualise the behaviour of individual mutant epithelial cells in a living tissue in the fly. By combining sophisticated drosophila genetic techniques with high resolution microscopy, we will use this animal model to visualise in real time the very early events in tumour development._x000D_ _x000D_ We will use live cell imaging to compare the behaviour of individual transformed cells with different genotypes, lacking polarity regulators or tumour suppressors, in the presence or absence of different oncogenes. By focusing on how polarity regulators, tumour suppressors and oncogenes cooperate to affect cell morphology, EMT and invasion, we hope to produce work of very high significance to human health._x000D_ _x000D_ Additionally, we will screen for genes that may promote or inhibit tumour progression and invasion in this in vivo system. Using a combination of classical genetics and RNAi we will create tumours on the back of the fly and use RNAi to knock-down an additional gene within the genome. In this way, we will be able to see if this additional gene knock-down promotes or inhibits tumour progression by affecting tumour size and/or the number of invading cells._x000D_


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Analysis of reciprocal tumour-stroma signalling in pancreatic cancer.
Funder: Cancer Research UK

Abstract: The aim of this project is to analyse reciprocal signalling between pancreatic cancer cells and cells of the tumour stroma._x000D_ _x000D_ In addition to cancer cells, solid tumours contain a multitude of infiltrating cells constituting the tumour stroma. Pancreatic ductal adenocarcinoma (PDA) is one of the most intractable human malignancies and is characterised by a highly abundant stroma, which promote metastasis and confer resistance to chemotherapy and radiotherapy. While the genetic aberrations contributing to the development of PDA have been studied in detail, the interplay between the cancer cells and the tumour microenvironment is much less well characterised. _x000D_ Key to the tumour promoting effects of the stroma is reciprocal signalling events exchanged between the cancer cells and the stromal cells. However, analysis of reciprocal cell signalling between tumour and stromal cells has thus far been scarce and as a consequence, our understanding of these context-specific signalling events and subsequent effects on tumour promotion is limited. _x000D_ To further elucidate reciprocal signalling events between pancreatic cancer cells and cells of the stroma, we propose to utilise an unbiased proteomics approach to identify and characterise these signalling events. Targets of interest will subsequently be validated in vitro and in vivo to identify key signals promoting tumour progression and metastasis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Mechanisms of inflammation and hypoxia-induced responses mediated by HIF and NF-kappaB in cancer
Funder: Cancer Research UK

Abstract: In solid tumours such as breast and pancreatic cancer, hypoxic regions are often present and these regions are particular resistant to chemo- and radiotherapy. The Hypoxia Inducible Factor (HIF) transcription factor family is best know for its role in mediating cellular responses to hypoxic stress. HIF-1 is a master transcriptional regulator of theses responses. We recently found that HIF is also induced by inflammatory cytokines such as TNF-alpha by distinct mechanisms This suggests that HIF has a important role not only in the response of tumours to hypoxia but also in the pathology associated with prominent inflammation found in cancers such as colorectal and pancreatic cancers. We recently identified a mechanism for the activation of NF-kappaB (a major transcription factor controlling the inflammatory response) by hypoxia that does not involve HIF. The importance of these pathways for tumourigenesis makes them attractive targets for therapy. However, a detailed understanding of the underlying molecular mechanism and the relationships between the molecules involved is required before appropriate therapeutic targets can be investigated. To this end we aim to: _x000D_ 1. Identify the contribution of individual HIF subunits to specific steps that accompany inflammation-mediated tumour progression._x000D_ 2. Identify the molecular mechanisms responsible for pathological responses in cancer mediated by HIF._x000D_ 3. Identify the role of hypoxia-induced NF-kappaB in tumour progression._x000D_ Using state of the art proteomics, imaging and molecular biology techniques we will determine the role of these pathways in the pathology of cancer. Furthermore, we will employ the power of drosophila genetics to further investigate cancer induced pathological changes mediated by HIF and NF-kappaB in the context of an organism. Taken together these approaches will identify novel pathways for targeted therapeutic intervention in solid and inflammation derived tumours.


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