NIHRDataInsights/HRCSData huggingface dataset:
Title: Statistical and computational methods for population stratification and prediction of cancer risk
Funder: Cancer Research UK

Abstract: Background_x000D_ _x000D_ Genome-wide association studies (GWAS) have allowed an unprecedented advance in the understanding of several cancers by identifying numerous loci contributing to their phenotypic variation. Because GWAS apply stringent thresholds of statistical significance, the few loci that reach these thresholds explain only a small proportion of the phenotypic variation and have poor overall predictive value. Increasing the number of loci included in the prediction models would increase their predictive value and allow capitalising on the full potential of genetics to inform clinical practice and public health policy._x000D_ _x000D_ Genomic prediction (GP) encompasses the use of large numbers of one or more types of genomic data (e.g. sequence and copy number variants or epigenetic changes) in statistical models of risk prediction. GP is important because genetic variation explains a large proportion of the phenotypic variance in most cancers and allows prediction beyond family history. Genetic information is available at birth, accurate and has the potential to make a significant contribution to preventing and understanding cancer. _x000D_ _x000D_ Aims & Objectives_x000D_ _x000D_ The main purpose is to develop methods that allow effective use of genome-wide genomic information for the prediction of cancer risk, i.e. for GP of cancer, and to use colorectal cancer as a paradigm. _x000D_ The objectives are to:_x000D_ 1.Develop and compare GP methods using simulated data. _x000D_ 2.Apply the best performing method from 1. to colorectal cancer incidence and survival data._x000D_ 3.Develop high-performance computing algorithms for GP._x000D_ _x000D_ Methods_x000D_ _x000D_ The risk prediction accuracy currently achieved by using loci identified through GWAS can be improved by including all (or a larger proportion of) loci contributing to the trait’s variation in the prediction model. We will use mixed linear models, Bayesian hierarchical models and penalised regression methods for GP. These methods can yield better and more robust estimates of risk by omitting significance testing and simultaneously estimating the effects of all loci contributing to the trait._x000D_ _x000D_ How the results of this research will be used_x000D_ _x000D_ GP on its own or combined with risk factors such as family history, age and gender, could be used to stratify the population into risk groups. Risk stratification could be used to tailor the intensity or frequency of screening to the level of risk, with the ultimate aim of reducing cancer incidence and mortality._x000D_


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: CANCER AND NEOPLASMS
Title: Evaluation of ADAM17 as a novel drug target and potential biomarker in colorectal cancer.
Funder: Cancer Research UK

Abstract: Background:_x000D_ We have shown that chemotherapy results in acute increases in (human epidermal receptor) (HER)-ligand shedding that correlated with significantly increased ADAM17 activity in CRC models, and this induction was differentially regulated in a KrasMT versus KrasWT setting. Moreover, ADAM17 inhibition potently blocked chemotherapy-induced EGFR ligand shedding and EGFR/HER3 activation, resulting in significantly increased apoptosis following chemotherapy treatment. We also found that ADAM17 overexpression increased the activity of other growth factor receptors, such as IGF-1R, VEGFR, PDGFR and receptor tyrosine kinases (RTK) regulating migration and invasion (Eph receptor A and B). We hypothesise that targeting ADAM17 (and thereby the activity of multiple pro-survival RTKs) may improve response rates compared to those obtained by inhibiting EGFR or VEGF alone and may also be active in a Kras MT setting. Independent receptor tyrosine kinase (RTK) and Kras synthetic lethal screens identified Eph receptors and Ephrins as potentially important mediators of ADAM17 and Kras oncogenic signalling._x000D_ _x000D_ Aims:_x000D_ 1. Determine the role of ADAM17 as a novel therapeutic target in KrasMT&WT colorectal cancer._x000D_ 2. Investigate the clinical relevance of ADAM17 as a biomarker in KrasMT&WT colorectal cancer tumours._x000D_ 3. Investigate the role of ADAM17 as a regulator of Ephrins (EpH) and their receptors and the role of EpH signalling in maintaining CRC cell viability and cell migration in KrasMT&WT settings. _x000D_ _x000D_ Methods:_x000D_ In vitro cell proliferation, apoptosis and migration studies, in vivo xenograft and orthotopic models, immunohistochemistry, ELISA, TACE activity assay._x000D_ _x000D_ How the results of this research will be used:_x000D_ 1. This work will determine whether targeting ADAM17 could be an important novel treatment strategy for KrasMT CRC tumours which fail to respond to anti-EGFR therapies. In addition, by blocking the activity of multiple pro-survival receptors, targeting ADAM17 may further enhance response rates for patients with KrasWT CRC compared with those obtained with EGFR-specific inhibitors._x000D_ _x000D_ 2. ADAM17 may exhibit potential as a biomarker for response to chemotherapy (FOLFOX/FOLFIRI) or cetuximab that we will test in a prospective conducted trial._x000D_ _x000D_ 3. If Ephrins and their receptors are important mediators of survival/migration in Kras mutant colorectal cancers, these receptors/ligands may themselves become important novel targets for the treatment of KrasMT colorectal cancer. Eph receptor/Ephrins expression/activity levels may also exhibit potential as prognostic/predictive biomarkers.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.4 POPULATION SCREENING
Health categories: CANCER AND NEOPLASMS
Title: Towards a prophylactic Epstein-Barr virus (EBV) vaccine to prevent EBV-associated malignancies
Funder: Cancer Research UK

Abstract: Epstein-Barr virus (EBV) is aetiologically linked to a number of human malignancies. Whilst progress is being made with immune-based therapies for these tumours using the virus-specific T cell response, the ultimate goal remains to develop a prophylactic vaccine capable of preventing EBV infection, thus averting associated disease. Most vaccine work to date, initially in primate models and subsequently in man, has focussed on the induction of neutralising antibodies to the major viral envelope glycoprotein gp340. However recent clinical trials suggest that, whilst such vaccination strategies may protect against symptomatic primary infection, they do not prevent EBV infection per se. _x000D_ _x000D_ The EBV vaccine field therefore faces a number of challenges, three of which we address here: (i) is sterile immunity ever achievable, even by natural infection itself?, (ii) which antigen-specific T cell responses should be recruited as an adjunct to antibody-mediated defence against primary infection?, (iii) can we exploit new humanised mouse models of EBV infection to test candidate vaccines? _x000D_ _x000D_ To address the first question we shall employ deep sequencing techniques to analyse the complete range of EBV strains acquired by infectious mononucleosis patients over time, sampling peripheral blood mononuclear cells at the time of primary infection and for several years thereafter. From this we shall determine if virus-induced immunity does indeed protect against re-infection, as earlier work implies, or if new strains may be serially acquired. Our second objective is to identify those T cell responses (CD4+ and/or CD8+) capable of recognising and killing B cells very early post EBV-infection; such effectors would have the capacity to block the early B cell-transformation events upon which establishment of the carrier state appears to depend. Four sets of candidate target antigens will be examined: first-wave and second-wave latent proteins of the B cell-transforming programme, lytic proteins transiently expressed from the incoming viral genome, and structural components of the incoming virus particle. The results will guide the design of polyepitope vaccine constructs with the aim of inducing T cell responses that could provide a second line of defence, alongside neutralising antibodies, against EBV infection of the naive host. The efficacy of such vaccine constructs will be tested in a new humanised mouse model of EBV infection which recapitulates many key aspects of natural infection in man. Vaccinated animals will be challenged with EBV and subsequently screened for epitope-specific T cell responses and for the presence or absence of EBV DNA in spleen samples.


Research activity codes: 3.4 VACCINES
Health categories: CANCER AND NEOPLASMS
Title: Mechanism of action and inhibition of kinesin-8 mitotic motors
Funder: Cancer Research UK

Abstract: 1) Background: The microtubule-built mitotic spindle orchestrates chromosome segregation, enabled by many regulatory proteins. Kinesins are a superfamily of motors that couple microtubule binding with ATPase activity to produce force. The kinesin-8 family are well-conserved and essential for mitosis in most eukaryotes. They localise to kinetochores, the macromolecular machinery that couples chromosome movement to microtubule dynamics, and are crucial for accurate chromosome segregation through control of kinetochore microtubule length. Recent work on kinesin-8s - including our own - has described their highly unusual ability to both walk along microtubules and depolymerise their ends, but little is known about the molecular basis for this activity. In addition, a recently identified drug that specifically inhibits microtubule-bound human kinesin-8 also blocks cell division, but its precise mode of inhibition is not understood. Relevance to cancer: Errors during mitosis can cause unequal distribution of DNA between daughter cells, resulting in aneuploidy, a common feature of human cancers. Conversely, cancer is a collection of diseases characterised by uncontrolled cell division. Thus, the mitotic spindle acts both at cancer initiation and also represents a target for its treatment. Elucidation of the kinesin-8 molecular mechanism is essential to the ongoing development of anti-mitotic drugs. (2) Aims and Objectives: The project aim is to elucidate the molecular mechanism of the multi-tasking kinesin-8 mitotic motor. Our objectives are to understand the way in which kinesin-8s both step along microtubules and depolymerise them, to define the molecular features that mediate this unusual behaviour and understand how to specifically inhibit their activity. (3) Methods: Elucidation of motor mechanisms requires determination of the structure of the track-bound motor. Cryo-electron microscopy is an essential tool for structure determination of kinesin-microtubule complexes while current processing methods allow detailed visualisation of the motor-track complex at subnanometer resolution. We will use recombinant human kinesin-8 to determine the structure of the kinesin-8-microtubule complex at different points in its ATPase cycle. We will examine complexes of the motor bound both to the microtubule lattice – elucidating motility mechanisms– and formed at microtubule ends – elucidating its depolymerisation mechanism. We will characterise the kinesin-8-specific regions that contribute to this unusual dual mechanism by mutagenesis and will visualise the structure of the kinesin-8-microtubule complex bound by a specific inhibitory drug. (4) How this research will be used: Results from this work will be used both to inform future mechanistic studies of kinesin-8s, especially in vivo, and inform drug discovery efforts.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS
Title: CRUK/11/014: LGG2: Cooperative multicenter Study for Children and Adolescents with Low Grade Glioma
Funder: Cancer Research UK

Abstract: Background Low grade gliomas (LGGs) are the commonest primary central nervous system tumour in childhood. They are associated with neurofibromatosis type 1 (NF I) in up to 25-30% of patients. The commonest site is the visual pathway where vision is endangered with progressive tumour. In the previous LGG trial overall survival was 80% at 5 years; however, progression-free survival (PFS) was 48%. Aims This failure to achieve long term PFS is the justification for attempting to enhance the effectiveness of chemotherapy by testing an intensified induction phase of therapy by the addition of etoposide and prolonging the duration of therapy from 12 to 18 months. Summary Phase III clinical trial with three treatment groups: 1. Children not affected by NF I with LGG of the supratentorial midline 2. Children not affected by NF I with LGG of all other sites 3. Children affected by NF I with LGG of all sites Three strategy sub-groups: - Observation only (after complete resection) - Treatment at diagnosis (after incomplete resection or no surgery) - Treatment after observation (following relapse/progression) Treatment: - 8 years or older - radiotherapy. If NF I also receive standard induction (vincristine + carboplatin) - Less than 8 years old with NF I - standard induction - Less than 8 years old without NF I - standard induction vs. intensified induction (vincristine + carboplatin + etoposide)


Research activity codes: 6.4 SURGERY;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: The effect of death receptor 3 (TNFRSF25) triggering on effector and regulatory T cells and its impact on the generation of anti-tumour immunity
Funder: Cancer Research UK

Abstract: BACKGROUND:_x000D_ T cell immunotherapy has shown promising clinical activity against cancer. However, complete responses are still rare. The tumour environment poses a number of challenges to T cell immunity. On the one hand, alterations in the genetic make up of tumours will generate neo-epitopes that are recognised by cytotoxic T cells. On the other hand, because tumours are self-derived, they are able to promote immune tolerance. Regulatory T (Treg) cells, which maintain tolerance to self tissues, are a key checkpoint to T cell immunity against tumours. We have recently identified signalling by death receptor 3 (DR3; TNFRSF25) as a potential pathway for attenuating immune suppression by Treg cells._x000D_ _x000D_ AIMS & OBJECTIVES:_x000D_ The aim of the studies proposed here is to investigate in detail the effects of DR3 triggering on T cell subsets and examine whether DR3 stimulation in vivo can augment anti-tumour immunity by inhibiting immune suppression and promoting immune activation. The specific aims of this proposal are:_x000D_ _x000D_ 1. To investigate the effect of DR3 signalling on the accumulation of Treg cells in tumours._x000D_ 2. To address the mechanism by which DR3 signalling inhibits generation of inducible Treg cells._x000D_ 3. To address the effect DR3 on the generation of anti-tumour effector T cells._x000D_ 4. To investigate the effect of DR3 triggering on the function of human Treg cells_x000D_ _x000D_ METHODS:_x000D_ We plan to use a combination of in vitro and in vivo studies to address the consequence of DR3 stimulation on the function of T cell subsets, including effector CD4+ and CD8+ T cells as well as CD4+Foxp3+Treg cells. The bulk of the studies will use mouse models to study the effect of DR3 triggering (gain of function) on the accumulation, generation and differentiation of Treg cells and effector T cells within tumours and tumour draining lymph nodes. The role of DR3 signalling during vaccination on the generation of anti-tumour effector T cells will be addressed using both gain-of-function and loss-of-function experiments. We also plan to use in vitro functional assays to address the effects of DR3 triggering on human Treg cells._x000D_ _x000D_ HOW THE RESULTS OF THE RESEARCH WILL BE USED:_x000D_ A better understanding of the signalling pathways that regulate suppression by Treg cells could lead to more effective ways to elicit anti-tumour immunity. For example, DR3 agonists could be used in conjunction with vaccines to promote efficient generation of T cell immunity against cancer. [Cancer focus: melanoma and basic research]


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Transcriptional control mechanisms of immediate-early genes: the convergence of phosphorylation, acetylation, parylation and sumoylation regulatory events
Funder: Cancer Research UK

Abstract: Background: <br/>The control of expression of the proto-oncogene FOS is an important paradigm for understanding how oncogenic signalling cascades regulate gene activity. In particular FOS is one of the crucial targets of the Ras/ERK signalling pathway. We have uncovered a complex series of molecular events which converge in a coordinated manner to promote transcription of FOS. One of these events is PARP-1 recruitment and its subsequent coordination of chromatin remodelling activities. PARP-1 has previously been implicated in DNA repair and hence is a drug discovery target for cancer therapy, but it is becoming increasingly associated with transcriptional events. <br/><br/>Aims and objectives:<br/>Here we wish to study the role of PARP-1 in controlling FOS expression and extend these findings to other immediate-early genes. Our studies will reveal general principles of transcriptional control mechanisms, and how these relate to regulatory post-translational events such as sumoylation, phosphorylation in response to Ras/ERK signalling and poly(ADP-ribosyl)ation mediated by PARP. Specifically, we aim to:<br/><br/>[1] Examine the role of PARP in modulating chromatin structure at the FOS promoter.<br/>[2] Determine the role of sumoylation in FOS regulation.<br/>[3] Investigate the generality of our model for the immediate-early gene transcriptional programme.<br/><br/>Methods: <br/>We will use a range of molecular biological approaches, involving extensive use of RNAi and ChIP-based technologies. Microarray-based approaches will be used to address more global regulatory activities.<br/><br/>How the results of the research will be used: <br/>This is a basic science proposal but the information gained on gene regulatory mechanisms will be of benefit to others studying such mechanisms in a cancer context where cellular regulatory pathways are rewired. Moreover, our studies on PARP-1 will be very useful in understanding the molecular basis to how PARP inhibitors function and hence the effects they might have on cancer cells as therapeutic agents.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Targeting Lipid Metabolism for Cancer Therapy
Funder: Cancer Research UK

Abstract: In order to divide, a cell needs not only to replicate its DNA, but also to double its size – processes that are metabolically demanding, requiring large quantities of lipids, proteins and nucleic acids as well as energy. As opposed to the regulatory mechanism of the cell cycle, the metabolic aspects of cell division are much less clear. In order to support large-scale metabolic demand in rapidly-dividing cells, substantial amounts of metabolic building blocks, particularly glucose and amino acids, must be made available to the cells. However, tumours are situated in a metabolically-challenging environment where blood supply, and the supply of oxygen and other nutrients that comes with it, is scarce. It is now clear that tumour cells develop a remarkably different metabolism compared to the normal tissues from which they are derived. Although the Warburg effect is a well recognised adaptation to cancer, our recent work and that of others demonstrates a much wider range of enzymes and metabolic pathways are affected. Therefore, the extent to which metabolism plays a role in cancer cannot be overstated and drugs that can selectively target these processes are likely to at least delay, if not halt disease progression. In this grant application we propose to study the dependency of cancer cells on lipid metabolism. It is now established that an increase in lipid production in general and particularly in de novo fatty acid synthesis is an important hallmark of many cancers. We will take a systemic approach, combining functional RNAi knockdown, analytical chemistry (metabolomics or more specifically – lipidomics), biochemistry and in vivo imaging techniques to validate new targets, previously identified in the collaborators laboratories, in the distorted lipid metabolic pathways of cancer cells. We propose here an integrated approach to study the dependency of cancer cells on enzymes involved in lipid metabolism, under normoxic and the microenvironmental stress condition of hypoxia, and to use drug-like compounds that inhibit the activity of some of these pathways to develop assays to monitor efficacy that will be of use in future drug discovery and development programmes. Successful outcomes of such an approach would be the disruption of the unique metabolism which support uncontrolled proliferation and the inhibition of cell growth and survival under metabolically-stressed conditions. Target validation in lipid metabolism pathways will lead to active drug development programmes aimed at inhibiting the identified metabolic enzymes to achieve an effective strategy of cancer treatment.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS