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Results

LifeLines 20 Apr 2016

This is the expansion of a project supporting volunteers aged 50 plus to run activities for vulnerable older people to improve health and well-being. These have previously included art classes, creative writing, yoga and computer club. The group will expand across the city, recruiting more volunteers, supporting more than 800 new people and establishing a Men’s Network to encourage older men to socialise regularly. It will also extend its HealthLink scheme to help older people get to medical appointments.

Kilkeel RBL - Saving Our Community Venue 22 Oct 2015

The group is a community and voluntary based organisation providing a range of services and activities to the local community. They received a grant of £10,000 to make improvements to their venue so that it can be used for more classes and activities.

Grant to Royal British Legion Tipton Branch 19 May 2016

Remembering Tipton's World War One Heroes

Grant awarded to The Royal British Legion (Forest Hall) Branch And Club (Tyne & Wear) 20 Nov 1998

Towards improving access and facilities for disabled people at the Forest Hall Ex-Servicemen's Institute.

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.

Wellcome Trust Joint Basic and Clinical PhD Programme at the Institute of Cancer Research: 'Study of biomarkers in solid tumours including malignant melanoma and colon carcinoma by LC-MS metabonomics'. 20 Oct 2009

Reversed-phased Ultra-Performance Liquid Chromatography (RP-UPLC)-Quadropole Time-of-Flight (QTOF) mass spectroscopy (MS) metabonomics offers high levels of resolution, sensitivity and speed as a novel and promising approach to study circulating biomarkers. A reproducible LC-MS metabonomic signature of a human melanoma cell line has been observed in-vitro and this has been further validated in vivo in the plasma of mice bearing human tumour xenografts (unpublished observation). The aim of the project is to discover novel metabonomic signatures of solid tumours with a particular focus on the correlation of these with particular malignancies (e.g. melanoma and colorectal cancers) and signal transduction aberrations (e.g. MAPK and PI3K pathways) by RP-UPLC-QTOF-MS using a combination of in vitro cell line models and in vivo human xenograft models, additionally examining the impact of the adminstration of specific inhibitors of target molecule(s) that mediate key signal transduction pathways. If robust LC-MS signatures are reliably identified and validated in pre-clinical models, correlations in clinical specimens will subsequently be pursued. Formal analytical methodologies, including functional group derivatisation and tandem MS, will also be employed to deconvolute the LC-MS signatures alongside the use of online databases (e.g. HMDB and METLIN) to better understand the underlying biological significance of our findings.

Amount: £254,047
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

The development of tankyrase inhibitors for use in breast cancer therapy. 06 Nov 2009

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: £1,465,153
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

Investigation of Tankyrase Inhibitors to Block Wnt Signalling as a TherapeuticStrategy for Sarcomas 25 Jun 2012

Sarcoma sensitivity to tankyrase inhibitors will be investigated by screening a panel of sarcoma cell lines covering diverse histologies with compounds fromthe lead series of ICR tankyrase inhibitors. Sensitivity will be compared to activity of the Wnt pathway to confirm if tankyrase inhibitors are more effective in cells with high Wnt pathway activity. Pathway activity will be measured using immunoblots for active ?-catenin, TOPFLASH reporter assays and Wnt target gene expression profiling. Sensitivity will also be compared to cell line dependence on the Wnt pathway using dominant negative TCF4 expression to block expression of Wnt target genes. Biomarkers that predict sensitivity will be found by correlating the data for drug sensitivity to mutation and gene expression profiles available from online databases, and potential biomarkers will be confirmed by RT-PCR and immunoblots. Further investigation of the involvement of validated biomarkers in determining sensitivity will be performed using RNAi knockdown and cDNA overexpression of the gene in question. Mechanisms of resistance will be investigated using combinations of clinically relevant drugs with tankyrase inhibitors to identify compounds that act synergistically to increase the effect of tankyrase inhibitors.

Amount: £159,847
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

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

ATP mimetics as inhibitors and probes of ATPases. 13 Jul 2010

The initial aim of this project is to synthesise a small library of ATP-mimetics and probe the heterogeneous ATP binding pockets of the 8 CCT subunits. The compounds will first be tested in steady state ATPase assays (Shimon et al; 2008) and an activity series assembled. Selected molecules would then be used in a chemical genetics screen against yeast CCT and ATP-site mutants in various of its subunits. Recent work in the Willison laboratory has led to an X-ray crystal structure for yeast CCT which is of sufficiently high resolution to guide the design of mutants. This will allow a level of understanding of this complex molecular machine which has not been achieved by any other approach. If time permits, the understanding gained of both the biology of CCT and the small molecules will be used to develop drug-like inhibitors of human CCT.

Amount: £153,466
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

Mechanism based drug descovery. 24 Jun 2013

Tankyrase recognises a peptide motif, with consensus RXX(P/G)XGXX, in substra tes through its ankyrin repeat clusters (ARCs). My aim is to develop tool compounds to disrupt the sankyrase : substrate protein-protein interaction (PPI). Targeting the ARCs is a novel method of inhibiting tankyrase function. Several approaches will be taken to develop non-peptidic inhibitors targeting the ARCs,by modification of a short peptide binding partner from the tankyrase substrate 3BP2. A peptidomimetic approach aims to find non-peptidic replacements for residues that mimic the peptide sidechain and backbone interactions. A fragment-based approached will also be taken to widen the chemical space sampled and if fragments are found that have binding affinity to ARCs, tha t can be detected crystallographically, then these can be incorporated into the peptide or grown chemically into more drug-like molecules. The peptidomimetic and fragment-based approaches will complement each other,and both ultimately have the same goal of designing potent tool compounds that are selective for TNKS and TNKS2 over other PARP family members,are cell permeable unlike the parent peptide,and have good aqueous solubility.

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

Core costs 18 Jan 2019

To support the work of the charity r.

Amount: £1,000
Funder: County Durham Community Foundation
Recipient: Royal British Legion

RBL Portstewart Branching Out 26 Apr 2018

The group, based in Portstewart, are using a grant of £6,500 to replace their hall’s heating system and improve its insulation, making it more usable for community events.

Grant to Royal British Legion, Greenhithe & Swanscombe 23 May 2014

The impact of WW1 on Dartford and its residents

Grant to Royal British Legion, Downs Branch 15 Jul 2014

First Day Commemoration of World War I