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Results

Mechanisms of client protein activation, regulation and targeted destruction by the Hsp90 molecular chaperone system. 27 Jun 2006

The Hsp90 molecular chaperone system is involved in the activation of an important set of cell regulatory proteins, including many oncogenic protein kinases. Our understanding of the biochemistry of the Hsp90 and its co-chaperones has improved greatly in the last few years, but the means by which it's essential ATPase cycle is coupled to changes in state of a client proteins remains unclear. We propose to determine the mechanism of client protein activation by Hsp90 and its co-chaperone complexes using a combinationof biochemical and structural techniques. We will focus in particular on the mechanism of Hsp90-dependent activation of protein kinases, which form the largest coherent class of Hsp90 client proteins and give Hsp90 such a key rolein the regulation and maintenance of the eukaryotic cell. Additionally, we propose to determine the functional roles of several of the co-chaperones thatregulate Hsp90 and couple it to other multi-protein cellular systems, and in particular understand how client proteins are transferred to the ubiquitin-mediated targeted protein destruction system, following pharmacological inhibition of Hsp90.

Amount: £1,504,955
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

A second generation genome-side-association study in breast cancer. 12 Jan 2008

At the current time, approximately 25% of the genetic risk of breast cancer is explained by a combination of rare, high or moderate penetrance genes and common, low penetrance variants. Existing evidence suggests that much of the residual risk is mediated by many, possibly hundreds, of common variants that each confers a small increase in risk. The key goal of this research is to conduct a genome-wide association study to identify such breast cancer susceptibility alleles. In the first stage, 4,000 genetically enriched breast cancer cases and matched controls will be typed for 550,000 SNPs using the Illumina Infinium Duo 550k array, and genotypes will be compared with existing data on the 550k array available from the 1958 birth cohort. Associations identified in this genome-wide experiment will then be followed up in further stages involving a large, international consortium of an additional 40,000 breast cancer cases and 40,000 controls. Power calculations indicate that this design will identify most common variants that each explain at least 0.2% of the familial risk of the disease. Together, these detectable variants may explain much of the genetic variance of breast cancer.

Amount: £329,750
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

A genome-wide screen of SNPs to identify susceptibility alleles for adult glioma. 12 Jan 2008

Specific aims of the research: To identify low-penetrance susceptibility alleles for glioma through a genome-wide scan of tagging SNPs. Outline plan of research: A staged design will be adopted. Genotypes for 317,000 SNPs will be determined in 2,000 glioma cases and 2,500 controls. SNPs displaying an association with risk at the 5% significance level will be evaluated in an additional series of >2,000 cases and 2,000 controls. Positive associations from a joint analysis of these stages will be confirmed in additional case-control series. Subsequent analyses will be directed towards identification of causal variants.

Amount: £457,150
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

New structural templates for kinase inhibition. 16 Sep 2008

New Structural templates for kinase inhibition

Amount: £148,911
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

Histone methyltransferase Prmt1 in normal development and cancer therapeutics. 16 Sep 2008

Prmtl has emerged as a critical factor for both transcriptIonal regulation and leukemogenesis, the objective of this project is to characterize the roles of Prmtl in hematopoietlc development. I reason that comprehensive analysis of the loss of function of Prmtl in hematopoietic stem cells (HSCs) and/or progenitors during different developmental stages will give important Insights into the normal functions of Prmtl, which will also provide crucial Information for development of strategies targeting Prmtl in human diseases.

Amount: £272,566
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

Integration, application and development of biophysical techniques in structure based drug discovery. 16 Sep 2008

Integration, application and development of biophysical techniques in structure based drug discovery.

Amount: £148,911
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

Targeted disruption of TPR-Domain recruitment to the Hsp90/Hsp70 molecular chaperone systems. 16 Sep 2008

Targeted Disruption of TPR-Dimain Recruitment to the Hsp90/Hsp70 Molecular Chaperone Systems

Amount: £148,911
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

Inhibitors of Lysyl Oxidase for the Prevention and Treatment of Invasive and Metastatic Cancer 30 Mar 2009

Inhibitors of Lysyl Oxidase for the Prevention and Treatment of Invasive and Metastatic CancerThe 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.See our video: BRAF and cancer: collaborative drug discovery

Amount: £1,119,130
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

A systems genetics analysis of Rho-family GTPase signalling. 23 Jun 2009

To study condition-specific Rho signaling I am performing image-based sensitized screens in order to identify genes which act to enhance or suppress signaling by different Rho components. I will identify genes that when inhibited quantiatively alter the morphology of cells already deficient in particular Rho components. Moreover, I will isolate genes that when inhibited enhance or suppress JNK, ERK, and GSK3 activity in cells deficient in particular Rho components. These screens will: (1) Ide ntify genes that act as regulators of individual RhoGEFs, RhoGAPs, and Rho-family GTPases (2) Provide datasets for computational methods which aim to model the archiecture of Rho signaling networks. I will use two models of metastasis in order to validate in vivo the function of Rho signaling regulators identified in cell-based screens. The necessity of newly identified Rho regulators for cell migration and invasion will be tested in Drosophila model of invasion in which cells over-express ing activated RasG12V are also deficient in dlg1. Additionally I aim to establish a second model of metastasis where migration and invasion are driven by overexpression of RasG12V and oncogenic RhoGEFs or overexpression of RasG12V in RhoGAP deficient backgrounds.

Amount: £903,049
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

Development of mass spectrometry tools to study signaling networks in vivo. 27 May 2009

I propose to develop and refine state-of-the-art mass spectrometry-based phosphoproteomic tools to assess in vivo signaling networks. The first aim will be to develop a suite of mass spectrometry-based tools to understand how the microenvironment influences receptor tyrosine kinase (RTK)-mediated signaling and glioblastoma cellular responses in the context of a 3-dimensional (3D) extracellular matrix (ECM) in vitro model. In the second aim, I will extend and validate these in vitro mass spectr ometry approaches in an in vivo mouse xenograft system. Through the manipulation of RTK expression levels in glioblastoma xenografts, I will establish how RTK signaling networks regulate tumor responses in the brain. In collaboration with computational biologists (Dr Rune Linding, ICR), novel biological insights into the complex program by which the tumor microenvironment modulates intracellular signaling networks and biological responses will be gained by the implementation of phosphoproteomic data-driven computational models. Leads generated by these in silico approaches will ultimately be subjected to in vitro and in vivo experimental validation.

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

Synthesis of cancer targeting compounds derived from a fragment-based approach. 08 Jun 2009

In the initial phase of this project, the PhD student will synthesise selected fragment type molecules, which mimic the observed5 interaction of TLE1 with the small peptide sequences. These specific fragments will supplement the fragment library, which is routinely used at the I CR. Within the structure based drug design team (SBDD} and the section of structure biology these specific fragments as well as the ICR fragment collection will be screened for binding to TLE1. Fragments with sufficient affinity for TLE1 will be co-crystalized. The PhD student will use these co-crystal structures to design and synthesise more complex and potent inhibitors of TLE1 binding thus completing the first round of testing, crystallography and synthesis. Additional iterative rounds will lead to inhibitors with further improved properties. The overall goal is to obtain inhibitors suitable for investigating the role of TLE1 in a cellular setting and potentially in in vivo models.

Amount: £152,502
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

Structural & functional investigation of potential drug targets in metastatic melanoma. 08 Jun 2009

The aims of this project are to investigate which scaffolding proteins are crucial for the invasive phenotype of metastatic melanoma cells, determine crystal structures of scaffolding protein complexes and evaluate the potential of the protein-protein interactions as targets for drug discovery. There are two parts to the project, and the student will spend time in two laboratories: First, the student will carry out structural studies in the laboratory of Richard Bayliss; Second, the student will conduct cell and molecular biology studies in the laboratory of Richard Marais. The student will learn how to determine protein complex structures using X-ray crystallography, how to design structure-based mutations that disrupt protein-protein interactions, and how to conduct studies into the cellular effects of targeted disruption by RNAi. The student will also gain insights into target selection and assessment for drug discovery.

Amount: £152,502
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

Structural & functional studies of DOCK-family guanine nucleotide exchange factors. 08 Jun 2009

The aims of this PhD project are: (i) to provide a molecular understanding of the mechanism of GTPase guanine nucleotide exchange by the DHR2 domain of DOCK3 and DOCK180, (ii) to define the molecular basis for their specificity for Rae members of the Rho-family of GTPases, (iii) to investigate the possibility of developing small molecules that inhibit the GEF activity of DOCK180/3 and (iv) to apply information obtained from the X-ray structure of DOCK180/3-Rac complexes to generate mutations that affect GEF activity to delineate functions of DOCK180/3 in cell-based experiments. The structure of the DHR2 domains of DOCK180 and DOCK3 will be determined by X-ray protein crystallography in isolation and in complex with Rae. A high throughput structure-based screen (Jhoti et al., 2007) will be developed to identify agonists and antagonists of the DHR2 domain-Rae interaction. Finally the cellular consequences of disrupting the GEF activity of DOCK180/3 will be analysed by monitoring the consequences of Rae activation in vivo.

Amount: £152,502
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

Developing selective inhibitors of P70S6K from an understanding of the molecular determinants of intra-family AGC kinase inhibitor selectivity using PKA chimeric protein. 08 Jun 2009

The aim of the project is to construct, crystallise and determine the structures of a suite of PKAbased chimeric proteins: PKA, P70S6K-PKA, PKB-PKA, ROCKII-PKA with minimal changes to the PKA sequence in the ATP-binding site (3-5 residue) to make the chimeras representative of the non-PKA component, a strategy already proved successful for PKB-PKA [4,5] and ROCKPKA [6]. We will particularly focus on establishing a novel P70S6K-PKA chimera. We will establish back-soaking protocols for ligand binding to enable high-throughput determination of ligand-protein crystal structures. We will select a representative set of potential P70S6K inhibitors with varying chemotypes and kinase selectivities based on compounds from our own in-house projects, and from published compounds with AGC kinase activity, and will characterise the selectivity profiles using Caliper ProfilerPro assays recently established in the Centre. The crystallographic binding modes of suitable inhibitors in the different AGC chimeras, and wild type protein where available, will be determined and compared. Correlation of the key interactions and binding poses will establish the molecular determinants of small molecule selectivity for P70S6K against other AGC kinases.

Amount: £152,502
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

Biomedical Vacation Scholarship 14 Jun 2010

Not available

Amount: £1,520
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

A Genome-wide association study in childhood kidney cancer (Wilms tumor) . 01 Apr 2009

At the current time, only a small proportion of the genetic risk of Wilms tumor is explained by known factors. It is likely that much of the residual risk is mediated by common variants that each confers a modest increase in risk. Our key goal is to conduct a genome-wide association scan to identify such Wilms tumor susceptibility alleles. In the GWAS, 2000 Wilms tumor cases will be genotyped for 660000 SNPs and genotypes will be compared with existing data on 6500 geographically-matched con trols. Any loci showing strong evidence of association after the GWAS will be fast-tracked for immediate verification by Taqman. Additionally, we will test 1536 SNPs from the ~1000 regions showing the strongest associations in 2000 additional cases using a custom assay. These genotypes will be compared to data available on an additional 6500 geographically-matched controls. Power calculations indicate we have at least 80% power to identify any locus conferring a per-allele risk of 1.25, pro viding the allele frequency is at least 20%. By additionally genotyping DNA from both parents of 1000 cases, we will investigate parent-of-origin effects for all confirmed loci and the 150kb critical region involved in control of IGF2 imprinting.

Amount: £716,043
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 2010

Inhibitors of Lysyl Oxidase for the Prevention and Treatment of Invasive and Metastatic CancerThe 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.See our video: BRAF and cancer: collaborative drug discovery

Amount: £818,674
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

Evaluation and Qualification of Non-Invasive MRI Biomarkers Associated with Platelet-Derived Growth Factor (PDGF) Signalling In Vivo. 06 Jul 2010

This proposal is specifically concerned with investigating the use of both established (DCE-MRI) and emerging (susceptibility contrast, contrast enhanced T1-weighted MRI with slow infusion of Gd-DTPA) non-invasive MRI methods to interrogate the effects of PDGF expression and pericyte recruitment on vascular re-modelling, pharmacological vasoreactivity and therapeutic response in vivo. Given the dependence of solid tumour progression on angiogenesis, a murine B16 tumour model in which pericyte r ecruitment and maturation is increased through the expression of PDGF (B16/PDGF) will be utilised, and the data compared to that derived from control (B16/ctr) tumours. Initially, B16/ctr and B16/PDGF tumours will be characterised by DCE-MRI to establish the effect of increased pericyte coverage on vascular permeability. Subsequently, the ability of T1-weighted MRI with slow infusion of Gd-DTPA, a recently described approach to measure the spatial distribution and quantify tumour IFP, will be fully evaluated in this highly relevant and appropriate model system. Importantly, invasive wick-in-needle measurements will also be made to corroborate any differences in IFP. Subsequently, the response of B16/ctr and B16/PDGF tumours to a PDGF antagonist (CP-868596), an endothelin-1 antagonist (BQ123), and a vascular disrupting agent (ZD6126), all predicted to have a differential sensitivity against mature vasculature, will be investigated by MRI.

Amount: £188,220
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research