NIHRDataInsights/HRCSData huggingface dataset:
Title: Translational Cancer Research Prize 2011
Funder: Cancer Research UK

Abstract: The Prizes panel awarded the 2011 Translational Cancer Research Prize to a multi-organisation collaborative team in Manchester, who have substantially contributed to the field of translational biomarker research and early clinical trials. The team, led by Caroline Dive and comprising Malcolm Ranson, Fiona Blackhall and Andrew Hughes, represent several Manchester research organisations - the Paterson Institute for Cancer Research, the Manchester Cancer Research Centre, the University of Manchester, Christie Hospital NHS Foundation Trust and AstraZeneca. Their outstanding work in biomarker-enhanced early clinical trials is internationally acknowledged. Caroline Dive and Malcolm Ranson were noted for successfully championing the use of GCP-validated biomarkers in clinical trials through their joint leadership of the Clinical and Experimental Pharmacology (CEP) laboratory. The prize will help support a junior scientific officer and 2 new clinical fellow to facilitate collections of lung cancer blood samples for CTC analysis and help with linking the data to the clinical data base and to support the clinical pharmacology fellowship scheme.


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: CRUK/12/018: Efficacy of adjuvant mitotane treatment in prolonging recurrence-free survival in patients with adrenocortical carcinoma at low-intermediate risk of recurrence (ADIUVO)
Funder: Cancer Research UK

Abstract: Background Mitotane (o,p'DDD) is the current first-line therapy in metastatic adrenocortical carcinoma (ACC), a very rare cancer with a poor prognosis. A recent multi-centre retrospective trial has provided convincing evidence for a beneficial effect of adjuvant mitotane treatment on recurrence-free and overall survival in ACC. Subsequently, adjuvant mitotane treatment has become the routine approach to patients with apparently high risk of recurrence (signs of capsule invasion/violation, Ki67 greater than 10%). However, the evidence base of adjuvant mitotane use in the setting of low to intermediate risk of recurrence of ACC is scarce and this gap is addressed by the current trial. Aims Primary: To compare the efficacy of adjuvant mitotane treatment vs observation only in prolonging recurrence free survival (RFS) in patients with ACC at low-intermediate risk of recurrence after complete resection. Secondary: • Comparison of Overall Survival (OS) • Comparison of time to recurrence (TTR) • Comparison of disease free survival (DFS) • Comparison of quality of life • Assessment of toxicity • Assessment of the impact of mitotane plasma levels and time needed to reach the therapeutic interval on the efficacy of treatment Assessment of the efficacy of the mitotane administration on subgroups of patients stratified according to: type of hormone secretion, stage of disease, histopathologic characteristics. Methods This is a prospective, randomized, open-label, controlled multi-centre international phase III trial. Patients fulfilling the inclusion criteria (ENSAT stage I-III, Ki6710%, microscopically complete resection and surgery no earlier than 12 weeks prior to inclusion) will be randomized to either adjuvant mitotane treatment or observation only. Randomisation will be stratified for ACC stage (ENSAT 1/II vs. III) and the availability of FDG-PET for baseline staging). Mitotane will be administered until ACC relapse, intolerable toxicity or for a period of two years. How the results of this research will be used The results of this study will form the basis of the future routine management of patients with ACC.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Price paid for cigarettes and tobacco and its association with smoking cessation
Funder: Cancer Research UK

Abstract: Background Increasing the retail price of cigarettes is widely regarded as one of the most effective tobacco control interventions available. However, price increases have not always resulted in smoking prevalence reductions. The evidence underpinning use of retail price increases has been based primarily on supply side data on price of popular cigarette brands or weighted average price of brands on the market. Part of the explanation for lack of impact in some contexts may be changes in smoking and purchasing patterns that mitigate the increased cost. It is important to understand how the amount actually spent on cigarettes and tobacco by smokers responds to changes in supply side price variables and other policy initiatives, how price actually paid for cigarettes/tobacco influences motivation to stop smoking, quit attempts and success of quit attempts, as well as the role of sociodemographic factors in all this. Aims Funding is requested to continue to include a question in the Smoking Toolkit Study (STS), an ongoing series of monthly national surveys of smokers in England, on a) the amount smokers report paying each week for their cigarettes/tobacco; and b) their sources of supply. The aim is to examine associations over time between smokers’ reports of price paid for cigarettes/tobacco and a) supply side price data, b) sociodemographic variables, c) source of supply (including illicit), d) events such as introduction of the point-of-sale ban and plain packaging, e) motivation to stop smoking, f) incidence of quit attempts, and g) probability of success of quit attempts. Methods The proposed duration is 3 years. STS is funded primarily by a CRUK programme grant and the Department of Health and has core funding until 2017. Aside from questions on cost of smoking and source of supply, it includes questions on smoking status, consumption of manufactured and hand-rolled cigarettes, motivation to stop smoking, quit attempts made in the previous 12 months, triggers for quit attempts, methods used to quit and how long the quit attempts lasted. Data are collected each month from new nationally representative samples of approximately 500 smokers by means of computer-assisted household surveys. Time series analyses (ARIMA) will be used to examine the temporal associations of interest taking account of auto-correlations, secular trends and seasonality. How the results of this research will be used The results will be communicated to the Department of Health to help shape implementation of the tobacco control strategy.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION)
Health categories: CANCER AND NEOPLASMS
Title: Macromolecular Structure and Function
Funder: Cancer Research UK

Abstract: Our lab is interested in understanding how chromosomes, once replicated, are separated into daughter cells during cell division. It is essential the this process works accurately over many generations, otherwise cells may gain or loose chromosomes, an event that can have severe consequences for the cell, and in turn lead to the onset or progression of diseases such as cancer. We primarily study these processes by determining the three-dimensional structure of proteins that bind chromosomes using techniques such as X-ray crystallography and electron microscopy. By designing experiments based on the resulting structures, we can gain insights into the way in which the proteins operate in the cell.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS
Title: ASH Wales: collaborative campaigning in Wales on the harm that tobacco causes to Welsh communities.
Funder: Cancer Research UK

Abstract: Wales Tobacco Control Alliance (WTCA) The WTCA is a partnership which enables member organisation involved in tackling tobacco use in Wales to inform and influence policy development and implementation, at both a UK and Wales level. The Alliance also facilitates an increase in the knowledge base of organisations with a tobacco control interest in Wales, and acts as a conduit for information within the sector. The Alliance currently consists of 32 voluntary sector and professional bodies in Wales (full list attached at Annex A). Membership of the Alliance is a key influencing tool on the political scene in Wales to raise awareness and drive the tobacco control policy agenda. It is a central resource for co-operation and joined up working. Key Objectives of the Project – August 2011-August 2013 The main objectives for the project are detailed below:- To lobby Welsh Ams and other stakeholders to support the implementation and evaluation of the Tobacco Control Action Plan for Wales and ensure it is effectively monitored To explore and drive the development of Welsh specific primary tobacco control legislation including a ban on smoking in cars, tobacco retailers register, and proxy purchasing To support the tobacco control calls within the Wales Cancer Alliance manifesto and to ensure the commitments contained in “Together against cancer” are implemented To support the work of the Smokefree Action Coalition and lobby Welsh MPs and Ams on non-devolved tobacco control issues including the plain packaging campaign, tobacco taxation, tobacco smuggling etc To develop good relations with Ams, the Health Minister, and members of the Health and Social Care Committee, briefing them on tobacco control issues To support and drive the Welsh Government’s campaign to promote smokefree cars carrying children and raising awareness of the issues in Wales Keeping up the political and media pressure to ensure the Point of Sale and Vending Machine regulations are implemented effectively, and in a timely manner, in Wales To facilitate a collaborative campaigning programme in Wales. Particular emphasis will be given to collaborative working between the WTCA, the Wales Cancer Alliance, Respiratory Alliance Wales, Age Alliance Wales and Council for Wales of Voluntary Youth Services To steer and drive the work of the WTCA by providing campaigning and lobbying expertise and developing effective campaigns, strengthening the membership and influencing role of the Alliance Keeping tobacco control initiatives high on the political and media agenda in Wales


Research activity codes: 3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION)
Health categories: CANCER AND NEOPLASMS
Title: Telomere Biology Lab
Funder: Cancer Research UK

Abstract: Formidable challenges are presented by linear chromosome ends, as their resemblance to damage-induced DNA breaks makes them vulnerable to degradation and end-joining pathways that provoke cancer. Telomeres protect chromosome ends from these events. My laboratory has uncovered crucial principles underlying these classically recognized telomere functions, and has identified unanticipated additional functions. We utilize fission yeast as this model provides easy genetic manipulation, airtight controls that are difficult to achieve in mammalian systems, and telomeres similar to those of human. Replication fork obstruction through telomeres as a key challenge and trigger for telomerase We made the surprising discovery that ‘naked’ telomeric repeats impede replication fork (RF) progression, but when bound by the telomere binding protein Taz1, RFs progress smoothly through telomeres; an analogous role for the mammalian Taz1 ortholog TRF1 was later demonstrated. We find that the fission yeast RecQ helicase (ortholog of the helicase mutated in human Werner Syndrome – a premature aging disease) instigates deleterious outcomes of stalled telomeric RFs. We also find that stalled RFs generate powerful telomerase substrates. Survival without telomeres Cells can occasionally survive the absence of telomerase, eg by maintaining telomeres via recombination. We recently identified a novel mode of telomerase-minus survival we dubbed ‘HAATI’. In HAATI cells, telomere repeats are absent but tracts of ‘generic’ heterochromatin jump to each chromosome end and, along with a non-telomeric 3’-overhang, recruit Pot1, which protects HAATI chromosome linearity. HAATI resembles the chromosome end-maintenance strategy found in drosophila melanogaster, which lacks specific telomere sequences but assembles terminal heterochromatin structures that associate with specific end-protection factors. This discovery reveals an alternative mode by which cancer cells might survive without telomerase activation. Surprising functions for telomeres during meiosis The spindles that form at mitosis and meiosis are often thought of as semi-autonomous architectural structures that control the movement of chromosomes. Our recent findings have overturned this notion by revealing that telomeres, which gather together near the centrosome in early stages of meiosis to form the highly conserved ‘bouquet structure’, control both the formation of meiotic spindles and the attachment of chromosomes, via their centromeres, to those spindles. We are using an array of strategies to define the mechanisms by which telomeres accomplish their meiotic tasks, as well as the relevance of these observations to mitosis.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Chromosome Replication
Funder: Cancer Research UK

Abstract: My laboratory studies the mechanism and regulation of DNA replication. We are especially interested in mechanisms involved in initiating DNA replication and we study the regulation of DNA replication during the cell cycle and in response to DNA damage. We exploit the facile genetics and simple DNA replication origins of the budding yeast Saccharomyces cerevisiae to make basic discoveries. Increasingly, we use human cell lines and mouse models to explore similarities and differences in control mechanisms


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Exploring the molecular mechanisms of mitotic spindle formation and organisation: nucleation and anchoring at the centrosome and dynamics at the spindle-kinetochore interface
Funder: Cancer Research UK

Abstract: The microtubule is a polarised biopolymer consisting of a dynamic plus end and a less dynamic minus end. The bipolar mitotic spindle emanates from the centrosome, where the minus end is tethered. In contrast, the plus end is free and captures chromosomes through stable attachment to the kinetochore. In this QQR, I propose two sub-projects to answer central questions on the functions of these two ends. Despite being divided into two, these sub-projects are inter-related and mutually complementary. Sub-project 1: The minus end – Exploring common principles for centrosome/SPB organisation and function Long-term Goals: We will identify the functional network in which the conserved Msd1 and Msd2 proteins act at the centrosome/SPB. We will also unveil the molecular mechanisms of the spatiotemporal regulation on microtubule nucleation and anchoring. The centrosome (the spindle pole body, SPB, in fungi) plays the myriad roles in controlling cell division, proliferation and differentiation. The centrosome acts as the major MicroTubule Organising Centre (MTOC) in a cell, by which the microtubule polymers emanate and assemble. Centrosome abnormalities, such as overduplication and fragmentation, are often observed in tumour cells that exhibit genome instability and aneuploidy. Understanding how the centrosome is structurally and functionally organised is, therefore, critical to the basic research of human cancers. In this sub-project, by using fission yeast, zebrafish and human cells, we will decipher common principles for centrosome/SPB organisation and function as the MTOC. Sub-project 2: The plus end – Mechanistic understanding of microtubule dynamics at the spindle-kinetochore interface Long-term Goals: We will uncover the mechanism by which the plus end of the spindle microtubule captures the kinetochore and establishes stable yet dynamic attachment in vivo. We will furthermore visualise and recapitulate the microtubule dynamics at the spindle-kinetochore interface in vitro. Establishment of proper spindle-kinetochore attachment lies at the heart of accurate chromosome segregation, yet we are still largely ignorant of the underlying molecular mechanism. We recently obtained an important clue using fission yeast by which to answer this question; we have shown that the conserved microtubule associated protein Dis1/TOG and the Ndc80/Hec1 kinetochore component are key players in stable spindle-kinetochore attachment. In this sub-project, we will explore our findings by implementing fission yeast genetics and cell biology, and further expand our research to the Total Internal Reflection Fluorescence (TIRF) microscopy system. We hope to reconstitute and visualise the spindle-kinetochore interface in vitro at the single molecule level.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS
Title: Chromosome Segregation Laboratory
Funder: Cancer Research UK

Abstract: Aneuploidy, i.e. missing or supernumerary chromosomes in the cell nucleus, is a hallmark of malignant tumour progression. A large number of genes that orchestrate faithful chromosome segregation during mitotic cell divisions are tumour suppressors or turn into potent oncogenes if misregulated. The aim of the Chromosome Segregation Laboratory is to investigate the function of these genes and the cellular mechanisms that safeguard accurate chromosome segregation. In particular, we are investigating the contribution of structural chromosomal proteins to sister chromatid cohesion and chromosome condensation, processes that ensure faithful segregation of centimetre-long chromosomal DNA molecules within micrometre-sized cells. We also investigate how the kinases and phosphatases of the cell division cycle machinery bring about ordered progression though mitosis.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS
Title: The actin cytoskeleton in cell movement and invasion: SCAR/WAVE, WASH and chemotaxis from Dictyostelium to melanoma.
Funder: Cancer Research UK

Abstract: We propose three projects, all connected with the role of the actin cytoskeleton in cell migration, chemotaxis and invasion: 1. Regulators of the Arp2/3 complex in cell migration. We will map the localization and dynamics of SCAR/WAVE regulators to analyze which are the most important in controlling cell steering, and illuminate the mechanisms behind it; we will generate biomarkers for SCAR/WAVE activation and improved biomarkers for Rac activity; and we will unpick the connections between SCAR/WAVE-driven pseudopod generation and the formation of cell:substratum adhesions. 2. WASH complex regulation and the identification of interacting proteins. We have generated a system that allows us to screen for WASH regulators and targets. We will perform a saturating, whole-genome screen in Dictyostelium, then analyze important hits in depth and test the resulting discoveries in mammalian cells. WASH function appears to be important in tumour invasion; we will investigate the mechanism using mouse genetics. 3. Melanoma chemotaxis and metastasis. We have developed a new assay that allows us to study cancer cell chemotaxis in unprecedented detail. In preliminary experiments we have shown that all melanoma cell lines tested are remarkably chemotactic to serum, and identified the attractant. We will now find in which steps of melanoma development and invasion this chemotaxis is important, whether blocking chemotaxis blocks invasion, and the receptors and enzymes that are required for chemotaxis to work efficiently. We will also address whether the fundamental chemotactic mechanisms we have discovered using Dictyostelium also operate in melanoma cells. In each of the three projects, we use Dictyostelium genetics to identify basic mechanisms and unknown pathways, then apply the knowledge and experience gained to mammals and cancer.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Actin Dynamics in Cancer Invasion and Metastasis
Funder: Cancer Research UK

Abstract: Our group studies the role of actin cytoskeletal proteins in cell migration, invasion and metastasis. Metastasis is the leading cause of death from cancer and yet there are no therapies against metastatic spread. We have identified the WASP-family proteins and the Arp2/3 complex as primary controllers of cell migration. WASP family proteins receive extracellular signals through Rho-family small GTPases and kinases, leading to actin assembly and driving protrusion of the plasma membrane. The actin bundling protein fascin modulates actin networks generated by Arp2/3 complex and drives microspike generation. Fascin is not expressed in normal epithelium, but is expressed in many epithelial cancers and correlates with poor prognosis and advanced stage. We are currently determining the role of WASP-family proteins and fascin in invasion of cells in 3D matrix and in cell migration in vivo. Cells use microspikes and long actin-rich pseudopods to migrate in 3D and we find that specific types of actin structures also promote matrix remodelling and degradation by matrix metalloproteases. We aim to uncover those motility proteins that are important for cancer invasion and metastasis and determine the cytoskeletal mechanisms that cancer cells use to breach matrix barriers. We use in vivo models for melanoma, colorectal and pancreatic cancers to test the roles of actin cytoskeletal proteins in metastasis. We also have a collaboration with the Beatson Drug Discovery Programme to develop inhibitors of cytoskeletal proteins such as fascin and to test whether they inhibit invasion and metastasis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: The inositide laboratory
Funder: Cancer Research UK

Abstract: Integration of various signalling inputs permits finely-tuned outputs which culminate in the regulation of a multitude of cellular processes. Imbalance in either signal input, integration or outflow invariably causes undesirable phenotypes. Delineation of signalling pathways implicated in driving tumour phenotypes is a pre-requisite for understanding the complexities of cancer biology. The phosphoinositide PtdIns(4,5)P2 resides in a key position in the inositide map as bifurcation of PtdIns(4,5)P2-dependent signalling leads to PI-3-kinase- and PLC-related second messenger generation, both of which are up-regulated in tumours. PtdIns(4,5)P2 is formed in membranes via the actions of both PIP5Ks and PIP4Ks. The former is thought to be the major route of PtdIns(4,5)P2 synthesis. PIP4K, in generating PtdIns(4,5)P2, negatively regulates the level of PtdIns5P, an emerging lipid second messenger with diverse actions. Despite the PtdIns5P/PIP4K pathway being poorly characterised its potential to play a key role in regulating signalling networks characteristic of tumour phenotypes is remarkably high. Using a barrage of different techniques including knock-in mouse models, immunohistochemistry, tissue microarrays, heterologous gene expression, RNAi interference, proteomic analysis, a PIP5K inhibitor discovery pipeline and traditional biochemical techniques we aim to uncover novel aspects of the PtdIns5P/PIP4K and PIP5K pathways. Unravelling the mechanisms behind how the individual enzymes, their substrates and their products influence signalling processes that drive tumour phenotypes is the key objective. Unsurprisingly such an important field of research lies within the boundaries of CR-UK’s research interest portfolio. The Inositide Laboratory is therefore perfectly placed and capable of performing ground-breaking research at the cutting edge of cancer biology.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS