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Results

Towards a quantitative comprehension of the Spindle Assembly Checkpoint 28 Nov 2017

My aim is to complete a quantitative analysis of the dynamic signalling pathways that control mitosis. By combining mass spectrometry with cutting-edge microsopy I intend to measure the number of active molecules of the key mitotic regulators and determine how and where they interact to generate a highly responsive signal transduction network that ensures genomic stability by controlling sister chromatid separation and mitotic exit. I have four main aims: 1) Measure the numbers of the mitotic regulators controlling chromosome separation and analyse how they are modulated by post-translational modifications (PTMs). 2) Determine the dynamics of the spindle assembly checkpoint (SAC) in living cells by measuring the generation of the SAC effector complex and the flux of its components through the pathway. 3) Determine how changes to a kinetochore affect its ability to catalyse the generation of the MCC. 4) Determine how a defined change in the number of molecules of specific regulators alters the dynamics and strength of the SAC, and in consequence their effect on genomic stability. Together, these studies will be used to inform and discriminate between models of mitotic control to determine how the SAC combines the properties of potency and responsiveness.

Amount: £2,249,139
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

In silico functional assessment of pleiotropic cancer risk loci 31 May 2018

Genome-wide association studies (GWAS) have identified greater than 450 common low-penetrance susceptibility single nucleotide polymorphisms (SNPs) for various cancers. Approximately one third of these SNPs map to genomic regions harbouring multiple cancer-SNP associations. This project aims to investigate the properties of "pleiotropic" cancer risk SNPs and derive insights into their effect on tumour development. We will initially extract all reported cancer risk-SNP associations with P -8 and use linkage disequilibrium metrics between risk SNPs at nearby genomic locations (e.g. within 1Mb) to determine if they represent distinct or shared association signals. Where available we will make use of tumour and normal tissue mutation, epigenomic, Hi-C and expression data to determine the likely molecular mechanism underlying cancer risk associations, for example regulating target gene expression. Combining all these analyses we aim to classify regions with multiple cancer associations as those exhibiting a) genuine pleiotropy, where the same association signal is shared by multiple cancer types; b) shared molecular mechanism but distinct disease-specific signals, suggestive of tissue-specific regulation; c) shared location by chance, where both disease-association signal and molecular mechanism appear distinct.

Amount: £0
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

Epigenetic analysis of the LSP1-rs3817198 breast cancer risk locus 31 May 2018

rs3817198 at 11p15.5 is associated with estrogen receptor-positive breast cancer risk. This locus shows a parent of origin effect and effect modification by parity. Fine-scale mapping of this region identified seven possible single nucleotide polymorphisms (SNPs), all within 11kb of the 5’ end of Lymphocyte Specific Protein (LSP1), any of which could be causally associated with risk. Four of these map within a region that shows differential methylation and one of them (rs686722) co-localises precisely with a CpG methylated site. We hypothesise that rs686722 influences breast cancer risk because both the allele (C/T) and the methylation of the "C" affect expression of LSP1. The mechanism by which LSP1 could influence breast cancer risk is not clear; one possibility is via an effect on the motility of lymphocytes within the breast stroma. For this project we will use lymphocyte DNA from women participating in the Generations Study and CEPH individuals. The key goals are to investigate the methylation of rs686722 with regard to the parental origin of a woman's C allele and her parity. We will also use lymphoblastoid cell lines from heterozygous CEPH individuals to test for allele specific expression of LSP1.

Amount: £0
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

Replication through structure-prone DNA – mechanism and impact on genome stability 21 Feb 2018

This proposal is aimed at understanding how repetitive and structure-prone sequences are replicated accurately. Repetitive DNA comprises over half of the human genome. Repeat instability due to unusual DNA secondary structures causes many neurodegenerative diseases and is a diagnostic and prognostic cancer marker. While genetic studies revealed that repeats impair DNA replication and that replication can induce repeat instability, mechanistic insight is lacking. It is therefore crucial to understand how repeats are accurately replicated in normal tissues and how they become unstable in disease. First, I will determine the nature of replication-dependent DNA structures. Building on my recent advances in sequence-specific in vitro replication, I will delineate the effects of DNA secondary structures on replication dynamics, including DNA unwinding, DNA synthesis, Okazaki fragment maturation and replisome stability. Finally, I will discover factors that enable faithful replication of structure-prone DNA using a combination of biochemistry, candidate genetics and proteomics. As a long-term goal, I aim to elucidate the interplay between replication and repair pathways, such as mismatch repair. Altogether, these aims will define the relationship between DNA sequence, structure and replication and may lead to identification of novel factors that modulate the formation and resolution of toxic DNA structures.

Amount: £1,283,217
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

Open Access Awards 2017/18 30 Sep 2018

Not available

Amount: £60,832
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

The Chemical Probes Portal: An Open Resource Empowering High Quality Chemical Biology 05 Jul 2018

The Institute of Cancer Research (ICR), in partnership with the Structural Genomics Consortium (SGC), proposes to assume responsibility for the Chemical Probes Portal (http://www.chemicalprobes.org/) (Portal) and move its operations to the UK. We request funds to complement existing in-kind and financial support in order to: maintain, enhance and expand the Portal; ensure its continuation as an invaluable public resource; and implement a sustainability plan for future independence. The Portal is a public online resource created to provide biomedical researchers with expert advice to identify the most appropriate chemical probes for their experiments. Experts rank probes using a star rating and provide advice on their properties and use. It is an innovative, open science solution with a clear aim – to reduce the use of poor quality probes in the literature, and thus increase the quality and reproducibility of scientific research. The Portal is currently supported by small donations from companies and in-kind contributions from a founding set of 146 advisors from academia and industry. We are seeking complementary funding from The Wellcome Trust to enhance, extend and maintain the core infrastructure, to expand the number of probes, and to better communicate the Portal’s offering to funders, scientists and publishers.

Amount: £1,530,473
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

Investigating how actomyosin contractility damages DNA 31 May 2018

DNA damage can lead to deleterious mutations, cell death, and is a driver of diseases such as cancer. Although exogenous sources, such as radiation, have long been characterized as DNA damaging agents, we have recently discovered that in normal cells, DNA is also damaged during normal DNA synthesis; leading to cell cycle arrest mediated by the Cyclin Dependent Kinase Inhibitor p21 (p21WAF1/CIP1, CDKN1A) (Barr et al., Nature Communications 2017; Heldt et al., PNAS 2018). The mechanism behind this damage is not clear, but a number of recent studies suggest that mechanical forces, including those generated by the cell's own actomyosin contractile machinery, can damage DNA. Actomyosin contractility is a key regulator of cell shape, and is particularly high when cells are attached to stiff matrices such as in bone or fibrotic tissue, or when cultured on stiff tissue culture plastic. We will determine if actomyosin contractility, generated by the cell’s own cytoskeleton, causes DNA damage during S-phase during proliferation. The student will monitor DNA damage in living single cells during by imaging the dynamics of endogenously tagged p21 after manipulating actomyosin contractility using chemical or bioengineering approaches. This work will provide new insights into the source of endogenous DNA damage.

Amount: £0
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

Exploiting 3D molecular and cellular models of endocrine resistant breast cancer to identify new therapeutic strategies 30 Sep 2018

Breast cancer is one of the most common cancers in the world. One of the treatments is the use of drugs that block the action of hormones that can help the cancer grow. However, while 80% of breast cancers can initially be treated this way, half of these will develop resistance to these drugs, and start to grow and spread again. There has been a lot of research thus far into how the cancer changes to circumvent these drugs using 2D models, by mimicking the treatment conditions and examining how breast cancer cells adapt on a molecular level, but the answer still eludes us. This project aims to develop 3D models of breast cancer – so that the experiments more accurately reflect how the cells exist in the patient – and then subject these models to different genetic interferences and drug conditions, to see if we can find the key drivers in the cells that confer resistance to endocrine therapy. We then hope to identify drugs that can block these drivers, to find new therapeutic strategies for treating endocrine resistant breast cancer.

Amount: £0
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

Improving oncolytic virus immunotherapy for the treatment of cancer 30 Sep 2018

The aims of the project are to develop and select the most effective maraba oncolytic viruses (OV), encoding genes into the maraba virus in order to enhance an anti-tumour response through immune priming, to be taken forward into clinical testing for the treatment of advanced melanoma.

Amount: £0
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

Clinical PhD Programme in Cancer Research 30 Nov 2016

The Institute of Cancer Research (ICR), a degree-awarding, independent college of the University of London, proposes to host a Clinical PhD Programme in Cancer Research. The Clinical Fellows appointed to this Programme will be embedded in the highly successful translational research culture of the ICR, and our hospital partner the Royal Marsden Hospital (RM). Clinical Fellows will directly contribute to delivering practice-changing research and will be an integral part of the flow of ideas in both directions between the laboratory and the clinic. The Clinical Fellows will participate in, and learn from, research teams working as parts of global consortia on projects as diverse as understanding cell division, MR-guided radiotherapy, novel drug discovery and development; genome damage and stability and big data approaches. We will continue to maximise opportunities to support the career development of Clinical Fellows on this Programme; build on existing good practice in supporting clinical academics, strengthen the provision of training tools, workshops and mentorship opportunities; and facilitate communication and the establishment of collaborative relationships between ICR and RM clinical researchers at different career stages. The ultimate goal of the Programme is to train, develop and support future international leaders in clinical cancer research.

Amount: £2,565,000
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

Inhibitors of Lysyl Oxidase for the Prevention and Treatment of Invasive and Metastatic Cancer 02 Oct 2016

The enzyme lysyl oxidase (LOX) regulates cross-linking of structural proteins in the extracellular matrix. LOX also plays a role in stimulating the metastatic spread of cancer through the body. Its expression is increased in hypoxic cancers and is correlated with tumour metastasis and decreased patient survival. In model systems its inhibition significantly decreases cancer metastasis and increases survival. Since metastasis is responsible for over 90 per cent of cancer deaths these data validate LOX as an important therapeutic target in cancer. Professor Caroline Springer and Professor Richard Marais from the Institute of Cancer Research have been awarded Seeding Drug Discovery funding to develop drugs that target LOX. They are applying a medicinal chemistry drug discovery approach underpinned by a strong programme in LOX biology with the aim of producing orally available, small molecular weight drugs that inhibit LOX activity for cancer treatment.

Amount: £402,800
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

Harnessing polypharmacology in precision oncology 09 Nov 2016

The serendipitous discovery of new targets of drugs questions the prevalent view of drugs as selective inhibitors of a single protein. However, how the binding to several proteins – termed polypharmacology – influences clinical safety and efficacy is poorly understood. During this project, I will analyse clinical, omics and chemical data to uncover the impact of polypharmacology in precision oncology. Firstly, I will analyse data from clinical trials performed at the Royal Marsden Hospital to identify the drugs taken by patient super-responders or those drugs that produced unexplained side-effects. This clinical data will be integrated with chemical data available via the knowledgebase canSAR and used to predict polypharmacology using recently developed chemoinformatic methods. Predicted off-tragets will then be experimentally validated. Finally, I will use available clinical and omics data to identify predictive biomarkers of the newly identified off-targets. Overall, I propose a unique project that has not been attempted before due to the combination of multidisciplinary skills, data and environment required. This project has the potential to transform our understanding of drug action and to yield new biomarkers that can quickly be translated to extend the use of existing cancer drugs in the clinic for the benefit of cancer patients.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

Vacation Scholarships 2017 - Institute of Cancer Research 16 Jun 2017

Vacation Scholarships 2017 - Institute of Cancer Research

Amount: £6,000
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

Deciphering copy number variation in susceptibility to testicular germ cell tumour 27 Apr 2017

Testicular germ cell tumour (TGCT) has a strong inherited basis with brothers of cases having a 6—10 fold increased risk of disease and heritability of >45%. Whilst GWAS studies have identified >25 loci associated with disease, the underlying causative variants and mechanisms for conferring susceptibility to the disease are poorly understood. Furthermore, whilst recent whole exome analysis had implicated rare variants in genes related to microtubule and ciliary function in familial TGCT, these rare variants only account for a modest proportion of disease heritability. To date there has been no exposition of the role of copy number variation in susceptibility to TGCT and it is plausible that copy number variants may contribute to the "missing heritability" of TGCT. Furthermore, identification of copy number variants implicated in TGCT susceptibility may be informative with regard to highlighting novel TGCT susceptibility genes located within the regions of copy number variation. In this project I shall deploy copy number-calling algorithms on (i) SNP array data on 7319 TGCT cases and 23082 controls and (ii) whole exome sequencing data on an overlapping set of 962 TGCT cases and 1644 controls.

Amount: £0
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

Characterisation of glioma risk loci 27 Apr 2017

While few environmental exposures have been identified to affect glioma risk, 13 genetic loci that influence the risk of this disease have been identified in genome-wide association studies (GWAS). Many of these loci lie in non-coding regions of the genome and therefore have no direct effect on protein sequence. It is therefore believed that these loci may affect glioma risk by modulating the expression of cancer genes. The key aim of this project is to characterise previously identified glioma risk loci by measuring the enrichment of transcription factor binding in these regions. This will be done through the adaptation and application of previously developed methods, including the variant set enrichment method proposed by Cowper-Sal Lari et al. and the credible set method proposed by Gaulton et al. ChIP-seq data from relevant cell lines will be incorporated to aid in the identification of transcription factors that bind at these sites. Time permitting, chromatin interaction data from promoter-capture Hi-C experiments completed by the group will be used to determine the genes most likely to be influenced by the disease loci.

Amount: £0
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

Investigating functional pathway dependencies in mutation EGFR lung cancer 27 Apr 2017

EGFR inhibitors (EGFRi) are successfully used to treat non-small cell lung cancer (NSCLC), however, 10-20% of patients with EGFR mutations initially fail to respond to first-line EGFRi treatment. The mechanisms underlying intrinsic resistance to EGFRi in NSCLC patients are unclear. This project will investigate the signalling pathways essential for the survival of EGFRi-resistant NSCLC. Targeted siRNA screens have been performed in the laboratory using unique established and patient-derived cell line models which model intrinsic EGFRi resistance. The key goals of this 8 week project will be to validate preliminary RNAi screening data using an orthogonal approach. An inducible CRISPR interference (CRISPRi) system will be developed to validate the cytotoxic response observed upon knockdown of specific genes in combination with EGFRi treatment. An advantage of CRISPRi is that it is scalable, providing flexibility to examine the global signalling alterations arising from lethal interactions. CRISPRi will facilitate large-scale molecular profiling techniques including RNA-Seq and mass spectrometry based proteomics. This will provide the groundwork to ultimately define the bypass signalling pathways driving intrinsic resistance in mutant EGFR lung cancer. With this knowledge, novel therapeutic strategies can be developed as effective salvage treatments for lung cancer patients who do not respond to EGFRi treatment.

Amount: £0
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

Evolutionary Predictions In Colorectal Cancer (EPICC) 05 Jul 2016

We aim to make prognosticating cancer like forecasting the weather. Weather forecasting combines detailed measurement of the current atmospheric state with a mechanistic understanding of atmospheric evolution that can be ‘played forward’ using a mathematical model to give accurate predictions. In oncology, we have the capability to make detailed measurements of the current state of a cancer, but critically lack a mechanistic understanding about how tumours will evolve over time. The shortfall in knowledge presents a major hurdle to accurate prognostication and is the focus of our proposal. We will perform a uniquely high-resolution molecular analysis of human colorectal cancers, and via mathematical modelling of these data, derive an unprecedented quantitative understanding of the ‘evolutionary laws’ that underpin colorectal carcinogenesis. We will evaluate the prognostic value of these laws, and then use them to construct and test models that mechanistically forecast disease evolution. The proposal builds upon our previous work demonstrating the predictability of cancer genomic alterations (Williams et al., Nature Genetics, 2016) as a direct consequence of physical constraints on tumour evolution (Sottoriva et al., Nature Genetics, 2015). This research will represent a major step towards the replacement of correlation-based prognostication with a new paradigm of accurate mechanistic forecasting.

Amount: £1,176,028
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

Architectural Role of RNA Polymerase III Promoters and Associated Factors in Shaping and Organising the Human Genome 05 Apr 2016

In higher eukaryotes chromosomes are subdivided in defined globular units, named topological associated domains (TADs). TADs borders have been found enriched with tRNA genes and short interspersed element retrotransposons, both RNA Polymerase (Pol) III transcriptional units. In order to obtain a mechanistical understanding of how RNA Pol III loci contribute to the spatial organization of the human genome, we will exploit a "library" of recombinant human RNA Pol III factors generated in my laboratory in order to reconstitute genomic architectural binding sites and to understand the molecular basis of the specific recruitment of complexes involved in structural maintenance of chromosomes (condensins and cohesin) and architectural DNA-binding factors (CTCF and ZNF143). Combining cryo-electron microscopy and x-ray crystallography will enable us to unravel the structures and functions of these complexes and to understand how they cooperate at a molecular level. Integrating structural data with biochemical and functional analysis in vitro and in living cells will allow us to obtain mechanistic models. The output of this research will shed light on how eukaryotic chromosomes are structurally organized and how the spatial organization of the genome impact on fundamental nuclear processes, such as gene transcription.

Amount: £1,505,199
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

Open access block grant 2016/17 30 Sep 2016

Not available

Amount: £63,600
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research