NIHRDataInsights/HRCSData huggingface dataset:
Title: The inverse source problem arising in Photoacoustic Tomography
Funder: Engineering and Physical Sciences Research Council

Abstract: The project addresses fundamental analytical questions on the acoustic wave equation. The questions arise in, but are not limited to the context of Photoacoustic Tomography (PAT). PAT is a medical imaging technique that combines the high contrast in electromagnetic absorption, say between healthy and cancerous tissue, with the high resolution of ultrasound. The existing PAT image reconstruction methods based on time-reversal arguments do not work when photoacoustic measurements are obtained by using an array of detectors that reflects acoustic waves. However, the use of detector arrays significantly speeds up the data acquisition in practice. One of the main objectives of the project is to develop a comprehensive analytical theory for PAT in a reflecting cavity formed by detector arrays. The mathematical results to be obtained have applications beyond PAT in the fields of Control Theory for Partial Differential Equations and Inverse Problems These applications will be explored. In particular, the results allow us to understand better the stability properties of hyperbolic inverse boundary value problems These problems occur in a large number of applications including medical ultrasound tomography, seismology, oceanology, process monitoring and non-destructive testing. In terms of these applications, our focus is on seismic imaging.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Qualification of Predictive Biomarkers for Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy in Oesophagogastric Carcinoma (Translational Cancer Oesophagus Gefitinib Study- TRANSCOG)
Funder: Chief Scientist Office (Scotland)

Abstract: The Cancer Oesophagus Gefitinib(COG) trial is the first placebo controlled, randomised trial of an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR TKI) Gefitinib, in Oesophagogastric cancer and also the largest trial in this setting. Accordingly, COG provides an invaluable and unique opportunity for translational cancer research. Using specimens from COG enrolled patients(n=300), we seek funding for the first study in Oesophagogastric cancer to investigate whether presence of somatic mutations of Epidermal Growth Factor Receptor(EGFR) signalling pathway genes within the tumour can predict clinical benefit from Gefitinib. The therapy independent prognostic impact of these markers will also be investigated. The proposed translational biomarker study will complete alongside the clinical study and simultaneous unblinding of both clinical and biomarker data will allow assessment of the clinical benefit of treatment and the impact of biomarkers upon this, therefore facilitating an optimised clinical and cost effective biomarker stratified approach to treatment.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: INVESTIGATING THE POTENTIAL OF COMMD1 AS A NOVEL PROGNOSTIC MARKER OF SURVIVAL, AND PREDICTOR OF NSAID RESPONSE, IN PATEINTS WITH COLON CANCER.
Funder: Chief Scientist Office (Scotland)

Abstract: Aspirin has remarkable activity against colorectal cancer and we have shown that a main mechanism of this action in vitro involves induction of COMMD1. Reduced COMMD1 has also been linked with poor prognosis in other cancer types. This study aims to investigate the potential of COMMD1 as a biomarker for prognosis, survival and aspirin response in colorectal cancer, and validate this molecule as a novel drug target. Tissue arrays will be used to quantify COMMD1 levels in colorectal adenomas and carcinomas, which will be related to recurrence, staging and survival data. The relationship between basal COMMD1, aspirin induction and the anti-tumour activity of the agent will be examined in vivo, using material previously collected from studies of aspirin-treated patients and mouse models. Molecules involved in aspirin up-regulation of COMMD1 will also be identified. These studies will reveal crucial information that is highly relevant to colorectal cancer treatment and prevention and that has direct clinical application.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Intra-operative assessment of infiltrating edge and peri-tumoural brain; image analysis correlation with MR and CT
Funder: Chief Scientist Office (Scotland)

Abstract: Gliomas are the most common primary brain tumours with an incidence of six to eight in 100,000. Treatment is usually partial resection followed by radiotherapy to residual disease and regions where there is known to be tumour infiltration. Currently a post-operative computerised tomography scan is registered to a pre- and post-resection magnetic resonance scan to define the radiotherapy volume. However, targeting radiation to the significant tumour bed and an adequate margin that takes into account peri-tumoural infiltration is made difficult by often outdated image sequences and is highly subjective with marked intra-observer variability. To investigate the potential to reduce radiotherapy volumes and consequently reduce toxicity this project will use novel image analysis techniques to analyse image data acquired at the infiltrating edge and peri-tumoural brain by intra-operative ultrasound. This will be correlated with CT, MR and has the potential for improved radiotherapy targeting.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Investigations of very high energy electron tumour therapy based on laser-plasma wakefield accelerators
Funder: Chief Scientist Office (Scotland)

Abstract: 40% of cancer patients receive radiotherapy delivered as X-ray photons or high energy particles. While photon-based therapies are effective, they are limited by normal tissue toxicity. Until recently electron beams from clinical accelerators were low energy and poorly penetrated tissue. An alternative modality is very high energy electron (VHEE) therapy that uses 150-250 MeV electron beams Monte Carlo simulations suggest that VHEEs are suitable for treating deep tumours, but until recently VHEE accelerators were unavailable. Rapid progress in developing ultra-compact laser-plasma wakefield accelerators allows consideration of VHEE for radiotherapy. The "Advanced Laser-Plasma High-Energy Accelerators towards X-rays" (ALPHA-X) programme at Strathclyde University has developed systems which now routinely produce 80 – 200 MeV VHEE beams For future clinical application, the biological effect of VHEE on tumour and normal cells correlated with dosimetry must be interrogated. At Strathclyde we now have unique multidisciplinary technology, facilities and teams in place undertake these essential studies.


Research activity codes: 5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Extracellular signal-regulated kinase 5 (ERK5) and the regulation of neuroendocrine differentiation in prostate cancer
Funder: Chief Scientist Office (Scotland)

Abstract: After lung cancer, prostate cancer is the second largest cancer-related killer of men in the UK, accounting for approximately 10,000 deaths/year. Whilst traditional androgen deprivation treatment is initially effective, the emergence of androgen refractory status is associated with terminal disease progression. Emergence of a neuroendocrine population of cells in the prostate also correlates with poor prognosis but neuroendocrine cells in biopsies are terminally differentiated. However the early stages of this process are reversible. Our pilot data indicates that elevation of intracellular messenger “cyclic AMP” drives neuroendocrine differentiation through ERK1/2 and ERK5 signalling pathways. This project will dissect the relative contributions of ERK1/2 and ERK5 to neuroendocrine differentiation, and determine how novel ERK5 signalling complexes direct this process. Ultimately, this information will provide new insights into the poorly characterised regulation of ERK5 signalling in prostate cancer that will have important implications for patient selection for treatment and inform novel therapeutic options.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Impact of Androgen Receptor Point Mutations on Androgen Ablation Therapy
Funder: Chief Scientist Office (Scotland)

Abstract: Cancer of the prostate is the most commonly diagnosed cancer in men, with ~3,000 new cases reported in Scotland in 2009. The androgen receptor (AR) is required for both normal prostate and tumour growth and a front line therapy in metastatic disease involves blocking the AR signalling pathway. However, treatment invariable fails resulting in a poor prognosis. It is known that mutations in the AR occur in tumours, but there remains a paucity of information on the impact of receptor mutations on the effectiveness of antiandrogen drugs. Our previous studies showed that the functional outcome of mutations in the AR cannot simply be predicted based on where they occur in the protein. Significantly, we also found that some mutations can cause antiandrogen drugs to switch on receptor activity. The aim of this project is to determine the wider impact of point mutations in the AR on antiandrogen drugs used in prostate cancer treatment.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Targeting the soluble isoform of CTLA-4 - supporting a novel therapeutic strategy in malignant melanoma
Funder: Chief Scientist Office (Scotland)

Abstract: "Antibody therapies targeting the immune system inhibitor, CTLA-4, promise new options for treating cancers by boosting tumour-specific immunity. These CTLA-4 immunotherapies can generate productive anti-tumour responses but with unpredictable and inconsistent effects, and no reliable biomarker to manage responsive patients. Current CTLA-4 antibodies bind two CTLA-4 forms, one on T cells and another secretable molecule detectable in plasma (sCTLA-4). Our group has demonstrated that by selectively inhibiting sCTLA-4 we consistently boost antigen-specific immune responses capable of reducing tumour spread in malignant melanoma models. We used a monoclonal antibody specific for sCTLA-4, currently being humanised by our partners, MRC Technology (MRCT), as a novel therapeutic. Here, we want to demonstrate that blocking sCTLA-4 function boosts malignant melanoma patient-derived responses to a range of melanoma antigens in vitro. A comparative analysis with current anti-CTLA-4 antibodies will examine whether this sCTLA-4 selective blockade approach offers a better, consistent strategy for boosting patient responses. "


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: An examination of diagnostic and prognostic biomarkers in malignant pleural mesothelioma
Funder: Chief Scientist Office (Scotland)

Abstract: "Malignant Pleural Mesothelioma (MPM) is an invasive, asbestos-related malignancy with median survival of 9-10 months. There are few areas of the world with a higher incidence of MPM than the West of Scotland, reflecting the historical use of asbestos in Clydeside shipyards. The diagnosis and monitoring of MPM is extremely difficult due its non-specific presentation with pleural effusion, the lack of an effective staging system and unusual growth pattern. As a result, diagnostic delays are common and it is difficult to select patients for exciting clinical trials and palliative chemotherapy, which improves survival in appropriate patients. We plan to prospectively assess the diagnostic and prognostic performance of two novel blood biomarkers of MPM (SOMAscan and Fibulin-3). To deliver this study, we have developed a collaborative relationship with the developers of SOMAscan and convened a multi-centre clinical trial group, comprised of leading centres in the UK and Ireland, coordinated in Scotland."


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Detection of hypoxc regions in Oesophagogastric Carcinomas with 1F-fluoroazomycin-arabinofuranoside (FAZA) Positron Emission Tomography (PET) Imaging
Funder: Chief Scientist Office (Scotland)

Abstract: The rising incidence and poor clinical outcomes for Oesophagogastric Adenocarcinoma (OGC) indicate the need for improved treatements, and the optimised use of current therapies to avoid ineffective treatments. Hypoxic tumours have a poor prognosis and respond poorly to chemo- and radiotherapy.Stratifying OGC patients into hypoxic and non-hypoxic groups would optimise therapy selection, but urrent mathods for hypoxia detection are invasive, techically chalenging and not suitable for routine clinical use. As the only Scottish centre that can manufacture a hypoxia radiotracer for clinical use, we propose a study to validate FAZA PET as a non invasive imaging tool for hypoxia in PGC and investigate the realtionship between tumour hypoxia and response to chemotherapy. Parallel studies will characterise FAZA uptake in OGC cell lines and identify novel markers and mechanisms for tumour hypoxia. this study will validate FAZA-PET for use in multicenter clinical studies assessing its utility as a predicitive biomarker and as a tool investigating mechanisms of tumour hypoxia to aid novel target identification.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Characterisation of the role of ERCC1 induction following platinum-based chemotherapy in ovarian cancer resistance in vivo and investigation of therapeutic strategies to inhibit this process
Funder: Chief Scientist Office (Scotland)

Abstract: Epithelial ovarian cancer is a major cause of female cancer death. Although initially chemo-sensitive, ultimately resistance develops, leading to death. Methods of predicting and overcoming resistance are urgently required. We have shown that expression of DNA repair gene ERCC1 is induced following platinum exposure in cancer cell lines and that this induction can be abrogated by inhibition of the mitogen activated protein kinase (MAPK) pathway. We will study the effect of modulating ERCC1 expression on platinum resistance in ovarian cancer cell lines. ERCC1 induction will be measured in ovarian cancer cells isolated from ascites before and after platinum chemotherapy to investigate the relationship with clinical outcome. Cancer cells will also be used to characterise the role of the MAPK pathway in ERCC1 induction and platinum resistance in ovarian cancer. We hope to demonstrate that ERCC1 modulation is a strategy to overcome platinum resistance which should be tested in clinical trials.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Myeloma IX Trial
Funder: Medical Research Council

Abstract: This randomised controlled trial aims to evaluate whether thalidomide, together with induction therapy prolongs remission and overall survival, whether thalidomide in the maintenance setting prolongs remission and overall survival, whether the oral Z-Dex regimen is as effective an induction regimen as i.v. VAD with respect to survival and QOL, in younger/fitter patients, whether Z-Dex-C-weekly is as effective an induction/consolidation treatment as ?standard? chemotherapy (MP) with respect to survival and QOL, in older/less fit patients, and whether a second generation bisphosphonate (zoledronate) is superior to clodronate in inhibiting the bone changes in myeloma. In addition, the trial aims to assess whether the bisphosphonate exerts an antitumour effect in vivo, which translates into a survival benefit. 1600 patients will be randomised. The trial will comprise two groups of patients: younger/fitter and older/less fit. With the exception of the analysis of induction chemotherapy, the two groups will be combined for the primary comparisons. The primary end-points are remission rate, progression-free survival, relapse, survival. The secondary outcomes are quality of life and resource use. Protein studies, to include measurement of paraprotein (with immunofixation, as appropriate), and free light chains as objective measures of response, will be carried out centrally. Peripheral blood and bone marrow samples will be analysed centrally at presentation and at key specified time points, with in-depth assessment of responses using flow cytometry and PCR techniques. Patients will be followed up for five years, and then annually to death.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Hybrid prokaryotic-eukaryotic vectors for targeted gene delivery to brain tumours in animal models
Funder: Medical Research Council

Abstract: Human malignant gliomas are highly-aggressive central nervous system tumors. The effect of current therapies is limited, and novel therapeutic approaches are required to improve the treatment of brain tumors. Gene therapy has shown early promise and presents an interesting approach for intervention; however, in brain tumor patients, efficacy has been hindered by low tumor transduction rates. We have reported (Hajitou et al. Cell 2006) the generation of targeted hybrid prokaryotic-eukaryotic vectors, which are chimeras between two single-stranded DNA viruses, an adeno-associated virus (AAV) and targeted bacteriophage (termed AAV phage; AAVP). In our prototype, the AAV transgene cassette is inserted in an intergenomic region of the bacteriophage (phage) genome and is packaged with the phage DNA into the capsid. In addition, the vector displays the RGD 4C ligand on the phage capsid to specifically target alpha v integrin receptors overexpressed in many tumors. The combination showed improved systemic delivery and transduction for imaging and therapy. In this application, we propose to develop a new chimeric phage-based vector for targeted delivery of therapeutic/imaging genes to angiogenic vasculature and tumor cells in brain tumors. Specifically, we will increase vector transport through the blood-brain barrier by displaying on the bacteriophage capsid ligands for transcytosis such as transferrin. Moreover, we will combine attributes of prokaryotic and eukaryotic viruses to improve endosomal escape so as to achieve superior tumor transduction. Thus, these approaches could result in the derivation of an improved targeted vector system which would represent a major advance in the management of brain tumors and the development of gene therapy systems for patient use.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Overcoming treatment resistance in glioblastoma multiforme by tumour specific inhibition of DNA repair.
Funder: Medical Research Council

Abstract: Aims To identify and characterise novel, effective therapies for treating glioblastoma multiforme (GBM) by tumour-specific inhibition of DNA repair. Objectives (1) Demonstrate whether inhibitors of DNA repair proteins increase radiosensitivity of human glioma stem cells. (2) In vivo analysis of the effects of PARP inhibitors on DNA repair in GBM and normal tissues, alone and in combination with radiation and/or chemotherapy. Identification of biomarkers predictive of response to PARP inhibitors. (3) Establish whether tumour-specific downregulation of O6-methylguanine methyltransferase (MGMT) by modulation of PI3kinase/mTOR signalling overcomes temozolomide resistance of human glioma cells with unmethylated MGMT gene promoters. Design and methodology (1) Analysis of effects of inhibitors of PARP, DNA-PKcs, ATM, Chk1 and Chk2 on radiation responses of human glioma stem cells, measured by clonogenic survival, induction and repair of DNA damage (immunofluorescence and comet assays) and cell cycle parameters. Active agents will be tested in vivo by quantifying effects on tumorigenicity of irradiated glioma stem cells implanted into the forebrains of SCID mice. (2) Immunohistochemical analysis of induction and repair of DNA double strand breaks, measured by H2AX, 53BP1 and Rad51 foci, in tumour specimens and hair follicles of patients in early phase clinical trials of the PARP inhibitor AZD2281 +/- radiotherapy and/or temozolomide. Dual staining will address cell cycle phase specificity. Repair parameters will be correlated with progression-free and overall survival. (3) Measurement of effects of inhibitors of p38MAPkinase, mTOR or ERK signalling on MGMT gene and protein expression and temozolomide sensitivity of human glioma cells and glioma stem cells. Scientific opportunities Studies on glioma stem cells will verify or refute previous observations that they are radioresistant, and elucidate mechanisms underlying this phenotype. Translational studies using tumour resection specimens will interrogate in vivo effects of PARP inhibitors on DNA repair processes in GBM and normal tissues treated with radiotherapy and chemotherapy. Understanding the mechanisms underlying effects of PI3kinase/mTOR inhibition on MGMT expression will provide novel insights into interactions between oncogenic signalling pathways and protein translation, and elucidate the key factors regulating activity of this DNA repair protein. Medical opportunities All aspects of this proposal are aimed at improving treatment of GBM. Overcoming radioresistance of glioma stem cells is likely to be necessary to achieve tumour cure; elucidating mechanisms of sensitisation by PARP inhibitors in vivo and identifying predictive biomarkers will define their therapeutic role; and tumour-specific downregulation of MGMT may improve outcomes in GBM that are resistant to existing therapies.


Research activity codes: 5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS