NIHRDataInsights/HRCSData huggingface dataset:
Title: Magnetic resonance and matrix assisted laser desorption mass spectrometry imaging for progressing the development of tumour vascular targeted drugs
Funder: Cancer Research UK

Abstract: Vascular targeting of tumours is a proven complementary approach to conventional cancer therapy, with development of new drugs an on-going process. For clinical trials, non-invasive imaging techniques are required to determine tissue pharmacokinetics and biomarkers that can be used to measure disease progression and delineate drug efficacy. Measures of innate and induced tumour resistance to vascular targeting are also required for selecting cancer patients or modifying treatment, at an early stage. We will use experimental tumour models to develop novel magnetic resonance imaging (MRI) and spectroscopic imaging (MRSI) techniques, in combination with matrix assisted laser desorption mass spectrometry imaging (MALDI-MSI), for these purposes. We hypothesise that use of hyperpolarised 129Xe as an MR contrast agent will provide a practical method for quantifying tissue blood flow rate, oxygenation and tissue composition, more accurately than currently available MRI methods. By developing dynamic nuclear polarization (DNP) techniques, we will enable measurement of rapid drug metabolism in vivo, in relation to patho-physiological features of tumours, such as oxygenation, on a regional basis, and therefore progress the understanding of drug action. We propose that MALDI-MSI, which is being pioneered in Sheffield, will provide a validation platform for the MR imaging and, because of its extreme versatility, will also provide wide-ranging information on drug pharmacokinetics, drug-target interactions and protein profiling. Finally, we propose to investigate ways to use MRI to assess vascular maturity of tumours, which has been shown to strongly influence tumour response to a variety of vascular targeting agents. Experimental tumours in rodents will be imaged using a newly installed 7T animal MR imaging system, with associated facilities for optical imaging and full physiology back-up. Mathematical models will be applied to tissue uptake kinetics of MR contrast agents and drugs to extract relevant pharmacokinetic and pharmacodynamic parameters. Image registration techniques will be developed and applied for direct comparison of MR images and MALDI-MS images. Principle component analysis will be applied to MALDI-MSI profiling data. Optical imaging of oxy-/deoxy-haemoglobin levels will be used inside the MRI magnet, in order to validate MR measurements of tissue oxygenation. Optical imaging will also be used for initial development of pericyte imaging, using polymersome nano-particles to optimise signal strength from targeted antibodies. Incorporation of MR contrast agents into the nano-particle core will facilitate MR imaging. Success of this research programme will result in novel imaging technology for application to the clinical development of vascular-targeted treatment strategies in cancer.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Pharmacological Imaging in Cancer
Funder: Cancer Research UK

Abstract: A key objective of the Northern Institute for Cancer Research (NICR) at Newcastle University is to develop improved drug therapies for cancer, and biomarkers are pivotal in the discovery and development new drugs in order to: • Select patients most likely to benefit from treatment with a specific agent – predictive biomarkers • Define the pharmacokinetics and pharmacodynamics of a novel agent to optimize early phase development – pharmacological biomarkers • Enable the early evaluation of the ultimate clinical utility of a drug, and determine the likelihood of efficacy in individual patients – surrogate response biomarkers Imaging is a key biomarker methodology which, unlike other approaches, has the significant advantages of being: • non-invasive • potentially able to provide dynamic “real time” data on all body compartments • readily translatable from pre-clinical to clinical studies The vision of the proposed Programme of research is to develop a suite of imaging biomarkers – predictive, pharmacological and surrogate response – to expedite the rational development of novel drugs discovered and/or undergoing early phase clinical evaluation at the NICR. The competitive edge of the Programme is the focussed application of novel chemistry to contemporary challenges in imaging biomarker and cancer drug discovery and development, in the context of a single multidisciplinary grouping. An ambitious Programme is proposed; however, the existing strong collaboration and management structure will ensure appropriate prioritization and hence delivery of the research. The Programme addresses significant challenges in cancer imaging and drug development, and therefore has the potential to deliver step-changes in knowledge and knowledge exploitation. To realize this vision, pre-clinical and clinical PET and MR imaging will be employed using both established imaging agents and novel reagents synthesized as part of the Programme.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Cancer Prevention: Cervical Screening & HPV Control
Funder: Cancer Research UK

Abstract: Background & Relevance: Cervical cancer remains a major cause of mortality globally. Despite the success of screening, there are still ~2750 cervical cancers annually in the UK: coverage is falling and the underlying risk of disease is increasing. HPV vaccination will have little impact for thirty years. HPV testing offers an interim solution both in the UK and in developing countries. Aims: To study 1. Self-sampling to improve coverage and reduce costs of cervical screening 2. HPV testing in primary screening 3. Control of cervical cancer in developing countries 4. Surveillance and modelling of cervical screening and HPV vaccination 5. Strategies for enhancing HPV clearance Outline: The clinical team will conduct trials of self-sampling and help evaluate new biomarkers via colposcopy. We will establish a mega-trial to rigorously evaluate HPV testing as the sole primary screening test. We will update our overview of HPV testing. We will analyse data from the Peruvian TATI trial and work with colleagues in Cervical Cancer Action to set up a study of mother-daughter screening-vaccination in a developing country. We will analyse the CRISP-1 trial of diindolylmethane in the prevention of cervical cancer and help to develop other protocols for cancer prevention.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.4 POPULATION SCREENING
Health categories: CANCER AND NEOPLASMS
Title: A molecular analysis of centriole and centrosome function and dysfunction
Funder: Cancer Research UK

Abstract: 1. Background Centrosomes are the major microtubule (MT) organising centres (MTOCs) in animal cells, and they have important roles in organising many cell processes, including cell division, intracellular transport and the establishment of cell polarity. Centrosomes consist of a pair of centrioles surrounded by an amorphous pericentriolar material (PCM). Centrioles have an additional role in animal cells in that they also organise cilia, which are found on most human cells and have important, but poorly understood, roles in development. Abnormalities in centrosomes and cilia have been linked to many human diseases. 2. Relevance to Cancer The vast majority of cancer cells have an abnormal complement of chromosomes, reflecting a form of genetic instability. Many cancer cells have also been recently shown to have an increased number of centrosomes, which is widely believed to be a major cause of genetic instability in these cells. Thus, understanding the basic biology of centrosomes and how centrosome amplification contributes to tumourigenesis are important challenges in cancer research. 3. Aims of the project Our research has two main aims First, we want to identify and study the individual components of centrioles and centrosomes to better understand how these organelles function. Many of the potent anti-cancer drugs used today work by interfering with MT organisation, so that our studies are likely to identify new targets for anti-cancer therapies. Second, we want to understand how centriole and centrosome dysfunction can contribute to human disease, especially cancer. We will focus on how centrosome amplification initiates tumour formation in flies. 4. Outline of research plan We and others have identified many protein components of centrioles and centrosomes. We will use the powerful genetic and biochemical tools available in Drosophila, together with sophisticated live-cell imaging techniques, to analyse how these proteins function and interact with one another. We have recently shown that centrosome amplification in flies can induce neural cell tumours, although, surprisingly, it does not cause large-scale genetic instability; it does, however, cause defects in asymmetric division in neural stem cells. We will use this model system to investigate why centrosome amplification predisposes these cells to form tumours: is it the small increase in genetic instability, the defects in asymmetrical division and the resulting increase in neural stem cells, or both?


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Trans EPOC - Investigating the molecular predictors of response in metastatic colorectal cancer
Funder: Cancer Research UK

Abstract: Background. Following the success of the EPOC (EORTC 40983) trial, the New EPOC trial reflects and develops current UK practice for colorectal cancer patients with resectable liver metastases. The current trial was designed to investigate whether the addition of cetuximab to oxaliplatin and fluoropyrimidine based chemotherapy improves the outcome in patients whose tumours are ras wild type. Relevance to cancer. This study provides a unique opportunity to collect cetuximab and chemotherapy treated fresh tissue resected during surgery. Combining clinical and translational data from New EPOC and the MRC COIN trial provides an opportunity to evaluate the overall benefit of modern multidisciplinary treatment in advanced colorectal cancer in both operable and inoperable groups. The collection of paraffin blocks, fresh frozen tissue and blood samples will enable us to characterise the effects and utility of chemotherapy +/- cetuximab in colorectal cancer patients with resectable liver metastases by analysing the molecular predictors of drug response. Aims The aim is to provide colorectal liver metastases (as well as adjacent normal liver and primary colorectal cancer) to feed into the already funded COIN translational programme and other funded CRUK programmes. Additional potential studies include:- (i) Early detection of endothelial damage after Oxaliplatin based chemotherapy, (ii) correlation between mutations in the EGF signalling pathways in primary and secondary colorectal cancer; (iii) to investigate the relationship between DNA repair capacity, chemotherapy response and side effects; (iv) to evaluate the presence of EGFR and other downstream markers in an attempt to define molecular correlates with response to cetuximab; (iv) to undertake cDNA microarray analysis and further analyses related to EGFR pathway functions and response to therapy. Outline. This is a category 3 TRICC grant application for sample collection only. For patients randomised into the New EPOC trial we propose to collect paraffin blocks (primary cancer, normal colorectal tissue, liver metastases and normal liver tissue), fresh frozen liver metastases and normal liver tissue, and 20 ml blood (taken at screening). Paraffin blocks will be collected from patients randomised into the EPOC (EORTC 40983) trial. These will be transferred to a central laboratory for storage.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: Optimisation of management in clinical oncology
Funder: Cancer Research UK

Abstract: Radiotherapy is used widely in the curative treatment of localised cancers, a goal which becomes increasingly important as advances in chemotherapy improve the control of micro-metastases. The new techniques of intensity modulated radiotherapy coupled with functional imaging permit radiation dose boosting to resistant sub-targets within a tumour, such as areas of hypoxia or rapid proliferation. One limitation of these approaches is target mobility due to respiratory, cardiac, bowel and bladder movement. Methods to identify and treat sub-targets and to measure and account for these movements - image guided radiotherapy (IGRT) - need to be developed and applied in clinical practice. Precise radiation targeting also provides the opportunity to intensify treatment with concomitant relevant biologically-targeted agents. The proposals in this application continue the close collaboration between academic radiotherapy and research physics, and exploit our links with other research groups on-site, including Cancer Research UK Centres (Molecular Biology, Cancer Therapeutics and Imaging). They extend from conceptual and laboratory developments to translational pre-clinical studies and clinical trials and include analyses of physics and outcome data as well as tissue from these trials. The overarching aim is to increase cancer control and cure whilst moderating treatment related side effects. Last updated 21/07/2010


Research activity codes: 5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: A multi-level study of peptide editing in the MHC class I antigen processing pathway and its immunological consequences
Funder: Cancer Research UK

Abstract: When our immune system encounters a cancer or a cancer vaccine, it is faced with a choice thousands of different molecules to recognise but ends up focussing on just one or two of these: thereby putting all its combative eggs in one basket. This research will determine how this choice is made and what we can do to influence the choice in order to gain more control over anti-cancer immune responses. Background: We have identified the molecule tapasin as the primary intracellular cofactor responsible for the editing of the peptide repertoire presented by MHC I and have shown that tapasin mediated editing can dictate the hierarchy of CTL responses to a model antigen in vivo. Relevance to cancer: Mutations and alterations in gene expression in tumour cells can be monitored by MHC class I restricted CTL and can lead to the destruction of tumours. Understanding which epitopes are likely to lead to good tumour killing and how selection of these epitopes is favoured is essential for the rational design of cancer vaccines. Aim: To adopt an interdisciplinary approach to determine the precise mechanism of peptide editing for MHC I at the atomic, molecular and cellular level; evaluate its immunological consequences in vivo; and to identify ways of manipulating the process with a view to improving vaccines. Plan: The research programme comprises four linked workflows 1. The molecular mechanism of MHC class I peptide loading and its relevance to cargo editing. 2. The cell biology of peptide optimisation. 3. Modulating MHC class I peptide loading and cargo editing with small molecules. 4. The Physiological consequences of peptide editing. Last updated 21/07/2010


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Antibodies targeting the tumour vasculature and MHC class I presented peptides
Funder: Cancer Research UK

Abstract: We aim to develop novel monoclonal antibodies for cancer therapy by using new approaches to target proteins essential for tumour cell growth and survival, tumour blood supply and a type of regulatory T-cell that allows tumour cells to evade the patientÆs immune system. Therapeutic antibodies represent a rapidly expanding class of anti-cancer drugs that have revolutionised the treatment of several malignancies. Examples are the anti-CD20 antibody, rituximab, for the therapy of non-Hodgkin's lymphoma and Herceptin (Trastuzumab) for treating breast cancer. The aims of this Programme are to generate and pre-clinically test novel therapeutic monoclonal antibodies that have widespread application for cancer therapy. We have selected two complimentary groups of targets that enable; 1) targeting the tumour vasculature by blocking signalling mediated by the Notch1 receptor and its ligand Jagged-1; 2) targeting intracellular proteins through the production of TCR mimic (TCRm) antibodies that recognise peptides derived from intracellular tumour antigens that are presented on the cell surface in the context of the HLA-A*0201 MHC class I molecule. The intracellular tumour antigens p53 and survivin have been selected not only on the basis of their high level expression in a wide range of tumour types but also their continued expression throughout the disease process, including advanced cancers that are most likely to be used for testing experimental therapies. These antigens also have a proven role in disease pathogenesis to eliminate tumour escape variants. TCRm antibodies will also be raised to the FOXP3 transcription factor, to target regulatory T cells in the tumour microenvironment and thus improve tumour cell immunosurveillance by the patients' immune response. Murine monoclonal antibodies will be generated using classical hybridoma technology and tested for reactivity and specificity for the target antigens. Immunogenic peptides will be specifically defined for FOXP3 for this purpose, as tetramers containing the target peptides complexed with HLA-A*0201 MHC class I will be used as the immunogen for raising TCRm antibodies. Antibodies with the appropriate specificity and isotypes will be further tested for biological activity in vitro, including their ability to mediate antibody-dependent killing and for their ability to modulate tumour growth and angiogenesis in vivo in mouse models. Selected antibodies will be humanised and their specificity for the target antigens and ability to mediate antibody-dependent killing will again be confirmed using in vitro assays for antibody-dependent cell killing. We aim to have lead reagents with proven specificity ready for commercial development and GMP production by the end of the funding period. Last updated 21/07/2010


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Effect of the co-chaperone CDC37 and the phosphatase PP5 on the molecular pharmacology of HSP90 inhibition
Funder: Cancer Research UK

Abstract: The molecular chaperone HSP90 is overexpressed in many cancers and is associated with poor clinical outcome. HSP90 is responsible for regulating the conformation, activation and stability of many important oncogenic 'client' proteins. Inhibition of HSP90 results in degradation of these clients by the ubiquitin-proteasome pathway. Thus HSP90 inhibitors deliver a one-step combinatorial attack on multiple oncogenic pathways. Therapeutic cancer selectivity is due to factors such as oncogene addiction, greater dependence upon HSP90 of mutant or overexpressed oncoproteins, and the hypersensitivity of the HSP90 super-chaperone complex in malignant versus normal cells. We and others have demonstrated promising clinical activity with the first-in-class natural product HSP90 inhibitor 17-AAG in melanoma, multiple myeloma, breast and prostate cancer. We discovered a novel pyrazole/isoxazole resorcinol series of HSP90 inhibitors, optimised these (in collaboration with Vernalis) and the first drug arising from this programme, NVP-AUY922, has been taken into the clinic by Novartis. As an alternative approach we have previously shown that genetic modulation of HSP90 cochaperones can have therapeutic effects. Here, our aim is to investigate the role of the kinase cochaperone CDC37 and its dephosphorylating enzyme PP5 on the activity of HSP90 in cancer cells and also on the sensitivity to HSP90 inhibitors. To do this we will use both overexpression and RNA interference models. The results will help us to understand the role of the CDC37 and PP5 in cancer cells and could provide biomarkers for predicting sensitivity to HSP90 inhibitors in patients, as well as new targets for therapy.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Structural Biology
Funder: Cancer Research UK

Abstract: Research in the laboratory is focused on molecular mechanisms that control the assembly and activation of growth factor signalling complexes and their associated catalytic functions. Our current group interests are concentrated in three areas: (1) defining the architecture and regulation of RET receptor tyrosine kinase (2) uncovering regulatory mechanisms controlling atypical protein kinase C serine/threonine kinases and (3) investigating actin-dependent regulation of RPEL domain-containing proteins


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Biomolecular Modelling
Funder: Cancer Research UK

Abstract: In this laboratory we are motivated by fundamental and challenging problems in both structural and systems biology: in particular, how proteins interact at the atomic level to facilitate higher order cellular events. Much of our work involves applying the principles of physics and evolution to the design of novel computer-based algorithms Specific areas so far concentrated on are: generating putative protein-protein interaction maps; improving protein structure modelling algorithms; developing algorithms and protocols to predict flexible protein-ligand complex formation; predict binding affinities; modelling of protein networks coupled to cell patterning such as found in early angiogenesis - new blood vessel formation - and cancer cell motility; modelling system level dynamic effects of nonsynonymous single nucleotide polymorphisms (SNPs) within key cellular pathways.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS
Title: Urological Research Group
Funder: Cancer Research UK

Abstract: Previous and current research How do endocytic adaptor proteins (e.g. HIP1) interact with the androgen receptor and androgen response elements to modulate transcription? To study the effects of a novel protein (LYRIC) on androgen function. Evaluation of MCM5 as a biomarker in bladder and prostate cancer. Cambridge is coordinating one of the two UK Specialised Programmes of Research Excellence (SPOREs) on translational prostate cancer (National Cancer Research Institute: £5.5m), which involve studies of the molecular pathology of advanced prostate cancer. To determine the most effective treatment for early prostate cancer: the Prostate testing for cancer and Treatment (ProtecT) trial of case finding, funded through a £21m National Health Service Health Technology Assessment Programme (NHS HTA); 250,000 men are invited to be screened. Men with prostate cancer are invited to enter a three-arm randomised clinical trial (RCT) of treatment and will be followed for 10 to 15 years. Tissue, blood and DNA are stored for studies of genetic epidemiology and proteomics. Future projects To study the effects of adaptor proteins on AR signalling. To identify novel androgen response elements. Translational uro-oncology studies on tissue samples of novel proteins to determine use as bio-markers. High throughput genetic epidemiology studies using the ProtecT biorepository. To complete the ProtecT Trial. To extend the bio-repository


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.4 POPULATION SCREENING
Health categories: CANCER AND NEOPLASMS