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Volunteering Matters
Institute of Cancer Research

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Results

Grant to Volunteering Matters 23 Mar 2015

The men go forth to Battle, the women wait and knit

Amount: £9,800
Funder: The National Lottery Heritage Fund
Recipient: Volunteering Matters
Region: North East
District: County Durham

Grant awarded to Community Service Volunteers (Training and Enterprise NE) (Tyne & Wear) 10 Mar 2009

To provide support and mentoring to people with mental health problems to help them volunteer in Newcastle.

Grant awarded to Community Service Volunteers (Training and Enterprise NE) (Tyne & Wear) 13 Jul 2004

To provide daycare services to older people living in high rise flats in Newcastle.

Positive Futures London 18 Nov 2015

This project, based on a established youth-led volunteering model is expanding as a result of self-referrals and is being delivered in Hackney, Haringey and Tower Hamlets. It will support young people aged 13 to 25 to deliver volunteering and social action projects which they have identified to be of benefit to the local community. The aim of project is that all of the young people who are participating in it will develop key skills and have positive experiences that will shape their personal development.

Amount: £387,576
Funder: The Big Lottery Fund
Recipient: Volunteering Matters
Region: London
District: Hackney London Boro

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

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

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

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

A facility for in-house analysis and X-ray data collection of crystals with large subunit cells. 22 May 2012

Studies in groups in the Division are aimed at determining structures of large protein complexes using a combination of EM and X-ray crystallography. In the Wigley lab work is focused on several large multi-subunit protein complexes involved in the DNA double-strand break repair process. These include systems that remodel chromatin (Ino80), exchange histones (Ino80 & Swr1) and label them (Tip60 & NuA4). The broken DNA ends are processed by RecBCD/AddAB complexes in bacteria or by interaction s between the Blm/Dna2/RPA, Top3/Rmi1/Rmi2 and Mre11/Rad50/Nbs1 complexes in humans. The Barford lab is studying protein complexes involved in regulation of the cell cycle. A particular interest is the anaphase-promoting complex (APC/C) that functions as an E3 ubiquitin ligase to regulate defined cell cycle transition by targeting specific cell cycle regulatory proteins such as cyclins for degradation through the ubiquitin-proteasome system. The APC/C-co-activator complex comprises 14 differ ent proteins with a molecular mass of 1.2 MDa. The Vannini lab (starting March 2012) will be focussing on RNA polymerase III using a combination of cryo-EM and X-ray crystallography. The Guettler lab (starting October 2012) will be focussing on mechanisms of poly-ADP ribosylation.

Amount: £394,250
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

Addiction to chaperones: Probing the role of HSP70 isoforms in cancer cells. 25 Jun 2012

Molecular chaperones assist the efficient folding of proteins, aid the refolding of stress-denatured proteins and prevent the aggregation of damaged peptides. Through these functions molecular chaperones are essential for maintaining protein homeostasis (proteostasis) within the cell (Hartl et al., 2011). Cancer cells have been found to exhibit dependence upon molecular chaperones. Chaperones provide essential support for a malignant lifestyle through the management of stresses imposed on cancer cells as a result of overexpressed and mutated oncoproteins as well as by the adverse microenvironmental conditions present in solid tumours (Galluzzi et al., 2008). The dependence of cancer cells on molecular chaperones makes these proteins an attractive target for drug discovery, exploiting this addiction could aid the development of drugs that selectively target cancer but not healthy cells. Small molecule inhibitors have successfully been developed for the molecular chaperone, Heat Shock Protein 90 (HSP90), which are currently in clinical trials (Neckers and Workman, 2012; Travers et al., 2012). Although the major focus has previously been on HSP90, evidence is now accumulating that the HSP70 family of molecular chaperones is also critical in cancer. HSP70 is antiapoptotic in addition to its role in protein folding and has been found tobe overexpressed in various tumour types including gastric adenocarcinomas (Yoshihara et al., 2006), hepatocarcinomas (Lee et al., 2005) and esophageal cancer (Jazii et al., 2006). Correlations have been described between over-expression of HSP70 and the aggressiveness of several types of cancer. Inaddition HSP70 over-expression in tumours has been linked with therapeutic resistance (Khalil et al, 2011). Previously published work carried out in the laboratory demonstrated that the dual silencing of the HSP70 isoforms, HSP72 and HSC70 causes tumour selective apoptosis and sensitizes malignant cells to HSP90 inhibitors (Powers et al., 2008). It has become clear that a limitation of inhibiting HSP90 is that it causes a mechanism-based activation of the heat shock response leading to the induction of various protective genes including HSP72 and HSC70 (Maloney et al., 2007). HSP70 inhibitors could therefore be valuable as single agents in their own right or extremely effective in combination with HSP90 inhibitors (Powers et al., 2009). The current understanding is that HSP70 plays a key role in the molecular pathogenesis and progression of cancer and is a potential therapeutic target. However, there is much which is not understood about this target. The HSP70 family of molecular chaperones consists of a number of genes which vary in amino acid sequence, cell and tissue localisation and pathology (Daugaard et al., 2007). It is difficult to state the exact number of genes which have been identified within this family as an array of nomenclature is used in the literature. However, a study in which extensive bioinformatic queries were carried out identified 17 genes belonging to the extended HSP70 family in the human genome (Brocchieri et al. 2008). The role and effect of inhibiting each of these targets alone is not well understood. Therefore, the aim of this project is to increase our comprehension of both the basic and translational aspects of HSP70 in cancer, in particular through understanding the role of the different HSP70 isoforms. An improved understanding of the different isoforms of HSP70 will aid in the discovery and development of drugswhich inhibit HSP70.

Amount: £159,847
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

Identification of genes involved in the differentiation of liposarcomas as novel therapeutic targets. 16 Apr 2012

Liposarcomas (LPS) are a heterogeneous group of tumours that show features of adipocyte differentiation. Well differentiated (WD) LPS and de-differentiated(DD) LPS represent a continuum of disease and together comprise the most frequent subtype of LPS in adults. WDLPS tend to have a goodoutcome whereas DDLPS reoccur and metastasize with an associated poor outcome for patients. The aim of the project is to identify novel therapeutic targets for the treatment of liposarcomas. Our working hypothesis is that gene products involved in maintaining the undifferentiated adipocyte phenotype of liposarcomas are a potential therapeutic target for 'differentiation therapy' of these tumours. Gene expression profiling of LPS with different histologicalcomponents, cell lines and normal tissues as well as mining of publically available data will identify differentially expressed genes linked to the differentiation process. These will be investigated in vitro and in vivo as new molecular targets for therapy.

Amount: £257,577
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

Open access publishing costs 2014/15. 15 Sep 2014

Not available

Amount: £63,573
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

Mechanism-based Drug Discovery. 24 Jun 2013

The first aim of the project is determine those cancer types that are sensitive to single agent CHK1 inhibition and identify potential biomarkers of this phenotype,such as replication stress (RS). CHK1i have shown single agent activity in certain cancer types, including neuroblastoma and B cell lymphoma, the literature suggests this may be due to increased replication stress. Which leads on to the second aim of the project,which is to establish models of RS to determine if it enhances single agent CHK1 sensitivity. This will be done looking a t foci indicative of replication stress. Finally, the Iast aim of the project is toidentify those gene products whose loss is synthetically lethal with CHK1 inhibition in cancer cells, which could allow the therapeutic activity of CHK1 inhibitors to be broadened through use with appropriate molecularly targeted agents. This will be done by screening 2 CHK1i resistant cell lines, with and without CHK1i,aqainst the Dharmacon druqqable qenome siRNA library.

Amount: £160,623
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

Mitigating late adverse effects in free flaps following radiotherapy: an immunomodulatory gene therapy strategy 19 Nov 2015

Mastectomy and immediate, autologous breast reconstruction, using a free flap, is now standard-of-care in breast cancer. Approximately half of these, high-risk, patients will require adjuvant radiotherapy to the chest wall resulting in irradiation of the free flap. This is detrimental to flaps and leads to late adverse effects (LAEs) within flap tissues resulting in wound breakdown, fat necrosis, fibrosis and distortion. Up to 25% of these patients will require salvage reconstruction and, in extreme cases, a further free flap. The over-arching goal of this proposal is to combine radioprotective gene therapies with microvascular surgical techniques to give cancer patients a more durable reconstruction. Gene therapies can be delivered into flaps using viral vectors, administered ex vivo, during the flaps ischaemic interval. We have identified the CXCL12-CXCR4 axis as an immunological link between radiation damage and LAEs, and in particular fibrosis. This proposal aims to investigate the involvement of the innate immune system in the development of LAEs within irradiated flap tissues. Using a small animal model of free flap irradiation, I aim to manipulate therapeutically the LAE phenotype using a lentivirally-delivered, RNA-interference strategy to silence CXCL12 expression. Finally, this work will evaluate the oncological safety of the proposed therapeutic strategy.

Amount: £225,769
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

Inhibitors of Lysyl Oxidase for the Prevention and Treatment of Invasive and Metastatic Cancer 30 Jul 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: £183,502
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

The radioprotection of composite tissue free flaps using ex vivo gene therapy. 27 Jun 2012

Radiotherapy forms a vital component of the adjuvant management of cancer following ablative surgery and has been shown to confer a survival benefit by controlling local disease. When reconstruction is required after radical excision this is usually in the form of a free flap, where a flap (composite block of tissue supplied by a named blood vessel) is moved with its vascular pedicle from a donor site to a recipient bed. Irradiation of free flaps results in fibrosis, fat necrosis and flap contra cture, leading to anatomical distortion, wound breakdown and often necessitates surgical debridement and salvage reconstruction. A delayed reconstruction may be performed after radiotherapy but means more operative procedures, worse aesthetic outcomes and can be psychologically deleterious to the disfigured patient. Radioprotecting a free flap offers patients requiring reconstruction the opportunity to have an earlier and more durable reconstruction by selectively abrogating the deleterious effects of radiotherapy on flap tissues only. We propose to achieve this by modulating two pathways (SOD2 and connective tissue growth factor (CTGF)) that have already shown promise in ameliorating the cellular damage caused by radiotherapy. We aim to achieve this using a lentiviral vector to produce longer lasting expression of transgene products in vivo.

Amount: £168,900
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

The development of tankyrase inhibitors for use in breast cancer therapy. 17 Sep 2012

We propose to develop orally-bioavailable small molecule drugs that inhibit tankyrase 1 - a novel target for breast cancer therapy. Our data indicate that such drugs could be used in a synthetic lethality approach to treat cancer. A tankyrase 1 inhibitor would confront several tumour-specific characteristics and would be useful for treatment of specific breast cancer subtypes with a poor prognosis, where few treatment options exist. As part of this drug research programme, we will build on our existing in-house and proprietary knowledge to generate novel, patented candidate drugs that will be used in first in class Phase 1 clinical trials at The Royal Marsden Hospital. The programme we propose will include: 1) the further development of our existing prototype tankyrase 1 inhibitors, which we have identified following pre-selection of a compound set using an in silico based screen, 2) the delineation of a proprietary crystal structure of the active form of tankyrase 1 to guide the design of inhibitors, 3) a comprehensive medicinal chemistry programme, 4) the use of cellular assay systems and in vivo therapeutic efficacy assessments to aid the development of inhibitors and companion biomarkers and 5) high-throughput genetic and drug synergy screens that will identify companion biomarkers and direct the design of clinical trials. This programme will be underpinned by: (i) the unique in-depth knowledge of breast cancer, synthetic lethality and tankyrase 1 biology of the research team led by the Principal Applicant, (ii) the strong track-record of key members of the project team in drug research, and (iii) the strengths in structural biology and drug development available within the host Institute.

Amount: £155,638
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research