NIHRDataInsights/HRCSData huggingface dataset:
Title: The effect of the level and timing of folic acid supplementation during the lifecourse on the epigenetic regulation of cancer determining genes and implications for genome stability and tissue differentiation
Funder: World Cancer Research Fund

Abstract: Background: The relationship between folic acid and cancer is uncertain as although most studies have shown that in adults moderate folic acid intake reduces breast cancer risk, there is also evidence that folic acid at high levels can increase susceptib


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: CANCER AND NEOPLASMS
Title: Metabolomic Profiling and Colorectal Cancer Risk
Funder: World Cancer Research Fund

Abstract: Background: Metabolomics is a powerful, high-throughput approach to identifying metabolic signatures that are associated with disease development and several recent studies have leveraged metabolite profiling to provide new insights into disease processes


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: The detection, imaging and therapy of pancreatic cancer.
Funder: Pancreatic Cancer UK

Abstract: Background: We previously identified a novel cell surface transmembrane tumour endothelial marker, which is highly expressed on endothelium associated with pancreatic ductal adenocarcinoma (PDA) but not detected on vessels in healthy tissue. Further, the extracellular domain of the marker is cleaved by a specific protease and released into the bloodstream. Cleaved marker was detectable in peripheral blood serum samples from patients with pancreatic cancer but not in healthy individuals. As the marker is present intact on the endothelial surface within the tumour, this presents an excellent opportunity for targeted imaging of tumours in patients. Immuno-positron emission tomography (immuno-PET) is an emerging imaging technology where antibody conjugates are used to visualise disease areas through specific antigen-antibody interactions, providing improved specificity and resolution over existing methods. Aims: The project has three primary objectives: 1. Validation of serum ELISA assay for the marker and further data collection. 2. Validation of the use of monoclonal antibodies against the marker for immunohistochemistry on human and murine pancreatic cancer tissue sections. 3. Imaging of murine pancreatic tumours using monoclonal antibody conjugates (immuno-PET technology) and confirmation of the tumour localisation of systemically administered antibody. Methods: Standard protocols for ELISA assays and immuno-staining will be used to quantify marker levels in clinical samples. Validation of the biomarker ELISA assay will follow FDA guidelines. Immuno-PET antibody conjugates will be developed and used in vivo to visualise tumours of PDA bearing mice. Radioactive or colour labelled antibodies will be used to confirm localisation to the tumour vasculature. How the results of this research will be used The results from this study will be used to compete for funding from Cancer Research UK for a biomarker project grant and will form part of future project grant applications to the Pancreatic Cancer Research Fund. The serum ELISA assay of the marker will form the basis of a patent application for a diagnostic test for pancreatic cancer.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Myosteatosis and muscle wasting in pancreatic cancer: murderer, mediator or mirror?
Funder: Pancreatic Cancer UK

Abstract: Background: Virtually all patients with pancreatic cancer develop cachexia whilst more than a third are either overweight/obese or have clinical/sub-clinical diabetes. Cachexia is associated with reduced treatment tolerance, quality of life and survival. Cachexia is thought to be mediated in part by systemic inflammation which in turn drives a variety of metabolic changes including peripheral insulin resistance. The key feature of cachexia is progressive muscle loss which may be obscured/ compounded by obesity. Myosteatosis is both a feature of obesity and diabetes and has recently been associated with adverse survival in cancer patients. It is not known whether such myosteatosis may play a primary role in the development of muscle wasting? Aims: to improve the supportive care of patients with pancreatic cancer, the present project aims to explore the relationship between myosteatosis, systemic inflammation, insulin resistance, myocellular protein synthesis and muscle wasting in overweight/obese cachectic pancreatic cancer patients. Methods: 20 overweight/obese patients with advanced pancreatic cancer and cachexia will be selected for the presence or absence of myosteatosis (on the basis of attenuation of skeletal muscle Hounsfield Units from their routine diagnostic CT scan). Patients’ level of muscularity will be assessed from image analysis of the same abdominal CT-scans. Patients will undergo a glucose tolerance test. Patients will then receive an oral dose of deuterated water (Robinson et al., 2011) and after 14 days will undergo a muscle biopsy at the time of surgery for estimation of skeletal muscle protein synthesis rate. Systemic inflammation will be assessed using plasma C-reactive protein concentration. Data will then be explored for the potential relationship between myosteatosis, glucose intolerance and suppression of myocellular protein synthesis. How results will be used: Rates of MPS from the cancer patients in this study will be compared with our existent data on healthy controls. If MPS is suppressed in cancer cachexia and is further reduced in the presence of myosteatosis, this would provide a scientific rationale for tailored/targeted management of the obese patient with cancer cachexia based on the presence or absence of myosteatosis. The nature of any therapeutic intervention would be influenced by finding a significant association between myosteatosis with either systemic inflammation and/or glucose intolerance. We would suggest a pilot study that used the minimal-burden stable isotope method for measurement of MPS as the primary end-point, stratified the patients for myosteatosis by CT and randomised to metformin/eccentric exercise.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Can protein profiling enable future screening of newly diagnosed diabetics for pancreatic cancer?
Funder: Pancreatic Cancer UK

Abstract: Background: Approximately 1% of newly-diagnosed diabetics are diagnosed with pancreatic ductal adenocarcinoma (PDAC) within three years of the diagnosis of diabetes. For these individuals, PDAC is believed to have caused diabetes and the latter is, in effect, an early warning sign of the presence of cancer. It has been recommended that patients with newly diagnosed diabetes mellitus or hyperglycemia should undergo screening for PDAC. However given the high numbers of newly diagnosed type 2 diabetics and the low incidence of PDAC amongst this group (~ 1%), screening would be prohibitively costly and the rate of misdiagnosis (with current screening modalities) unacceptably high. Cancer-associated diabetes is different from common type II diabetes, suggesting that diabetes related factors found in the blood of pancreatic cancer patients may differ from those found in other type II diabetics. Therefore, it may be possible to select for the newly diagnosed diabetics most likely to have cancer (making screening of this much smaller group feasible). We have undertaken serum proteomic analysis from patients with PDAC, benign pancreatic diseases, healthy subjects and a unique set of samples taken up to 4 years prior to diagnosis of PDAC (from UKCTOCS; www.ukctocs.org.uk/). Of 141 proteins differentially expressed in pre-/post-cancer diagnosis samples versus controls, 25 proteins were diabetes-related (Ingenuity Pathway Analysis; Fishers exact 7.69x10-17). One of these, Chemerin, known to be upregulated in diabetes was also upregulated in PDAC. Another, SPARC, reported to be increased in newly-diagnosed diabetics was decreased in PDAC patients. This suggests that the serum proteome of PDAC-related diabetes may be distinct from type 2 diabetes. Aim: To determine whether asymptomatic pancreatic cancer patients, newly-diagnosed with diabetes can be distinguished (using diabetes-related proteins) from individuals newly diagnosed with common type II diabetes (enabling entry of the former into screening for the detection and treatment of their cancer. Methods: We will perform assays of serum from PDAC patients with (n=50) and without glucose intolerance (n=50), comparing the results with assays of serum from patients with known diabetes mellitus and no diagnosed cancer (n=100). ELISA/Multiple Reaction Monitoring assays will be undertaken for diabetes-related proteins identified in our proteomic studies. LUMINEX assays will be performed for classical protein markers of diabetes. How results will be used: Our results will inform future proposals for PDAC screening using patients with new-onset diabetes, some of whom will come from the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC; regularly tested for glucose intolerance).


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Modelling heterotypic cell-cell interactions in vivo at the initial stages of pancreatic cancer
Funder: Pancreatic Cancer UK

Abstract: Pancreatic ductal adenocarcinoma (PDAC) arises from precursor lesions called pancreatic intraepithelial neoplasms (PanINs). Mutations that result in constitutively active KRas (KRasD12) occur as an initiating event in PanIN formation and are detected in more than 90% of human PDAC. Recent studies describe how pancreatic ductal epithelial cells expressing GFP-tagged oncogenic KRasD12 are out-grown by wild-type cells in vivo, whereas cells expressing GFP-tagged wild-type KRas are retained in the tissue. This suggests that KRasD12 cells are selectively lost from the normal tissue. Yet, 99% of stage 1 PanINs contain activating mutations in KRas, suggesting that in order for PanINs to develop KRas-transformed cells must adopt a strategy to overcome the suppressive barrier imposed by the normal cells. What remains unclear is the fate of the eliminated KRasD12 cells and the process by which they are removed from the normal tissue. I have examined and characterised the effect of expressing constitutively active oncogenic RasV12 in single cells within normal epithelial cell sheets. This revealed several significant and novel outcomes; RasV12 cells alter cell shape, cluster and self-aggregate, and are eventually extruded from the normal epithelium in a process that is dependent on direct cellcell interaction with the normal cells. During development, extrusion removes excess or dying cells in order to maintain epithelial integrity, suggesting that this process may act as a tumour suppressive mechanism. Conversely, extrusion may provide transformed cells with a route to escape homeostatic control within a tissue, and therefore may promote tumour formation and metastatic behaviours. The signals that trigger extrusion of transformed cells from normal tissues remain undefined. The main goal of this proposal is to investigate the fate of oncogenic KRasD12-transformed ductal epithelial cells in ductal epithelial tissues in vivo, and determine whether KRasD12 cells are eliminated from the normal tissue by a process that depends on the direct cell-cell interaction with the normal neighbouring cells. By investigating the cellular processes that arise following KRasD12 expression, we will generate for the first time, kinetic and real time analyses of PanIN initiation. This will lead us to identify the mechanisms controlling this process, thus advancing the development of new methods to detect PanINs at the earliest time points and prevent disease progression.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Immunotherapy of pancreatic cancer using chimeric antigen receptor engrafted T-cells targeted against the avBeta6 integrin
Funder: Pancreatic Cancer UK

Abstract: Ductal adenocarcinoma is the commonest form of pancreatic cancer (PDAC) and carries a dire prognosis, mandating the development of novel therapeutic approaches. A highly attractive target that could be exploited for this purpose is the alpha-v-beta 6 integrin, which is found in every tested case of PDAC. This integrin promotes cell migration, proliferation, suppression of apoptosis/ anoikis and activates the immunosuppressive cytokine, TGF-beta. Importantly, healthy adult tissues do not express this integrin, other than at low-levels in the gastrointestinal tract. Expression is also upregulated during wound healing. The goal of this application is to develop an immunotherapeutic approach to target the alpha-v-beta 6 integrin in PDAC using chimeric antigen receptor (CAR) technology. CARs are bespoke fusion molecules that couple the binding of a selected (tumour-associated) target to the delivery of a T-cell activating signal. In preliminary studies, the applicants have developed a CAR that recognises both human and murine alpha-v-beta 6. Targeting is achieved using a 20mer peptide derived from the foot and mouth disease virus VP1 protein that binds this integrin with high affinity and specificity, both in human and mouse cells. The latter is important since it will facilitate subsequent toxicity studies. CAR signalling was provided by a fused CD28+CD3zeta endodomain, which promoted PDAC cell cytotoxicity and transient proliferation/ cytokine production in a strictly alpha-v-beta 6-dependent manner. Here, we propose to achieve two aims to advance alpha-v-beta 6-targeted CAR-based immunotherapy of PDAC. First, we will demonstrate proof of concept for the in-vivo efficacy of this approach. To achieve this, we will generate two additional alpha-v-beta 6-specific CARs that signal via CD3zeta and deliver co-stimulation using 4-1BB, either alone or together with CD28. Comparison will be made with the existing CD28-CD3zeta CAR in addition to an endodomain truncated negative control. Efficacy of all CARs will be tested in SCID Beige mice bearing established orthotopic PDAC xenografts. Tumour status will be monitored using bioluminescence imaging since tumour cells will express firefly luciferase, rendering them amenable to real time imaging after administration of d-luciferin. Second, we will use bioluminescence imaging to track human T-cell longevity and migration in-vivo. Such studies will indicate whether intratumoral T-cell homing occurs, in addition to providing information on T-cell longevity in-vivo. The latter is required for subsequent design of GLP toxicity studies since MHRA require that animals are culled at the point where infused human gene-modified T-cells are no longer present.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: PanORAMA project: Pancreatic Cancer Predisposition, Obesity-Related Deposition Assessment using Magnetic Resonance ImAging: a development and discovery study to evaluate the assessment of pancreatic fat deposition using MR imaging as a predisposition biom
Funder: Pancreatic Cancer UK

Abstract: The problem: Patients with pancreatic cancer (PC) generally present with advanced stage disease and prognosis is dismal. Thus, there is a priority to develop predisposition biomarkers (BM) to identify high-risk individuals as a basis for early detection. Hypothesis: Body mass index (BMI), as an approximation of total body adiposity, is associated with an increased risk of PC, but is too crude an indicator of the pancreatic local adipose tissue. We postulate that pancreatic fat deposition is a more enriched indicator of the micro-environment relevant to PC predisposition. Novelty: To-date, there are no human studies evaluating the role of pancreatic „steatosis‟ relevant to the development of PC. Overall aim: PanORAMA is a proposed two phase research programme to evaluate the assessment of pancreatic fat deposition using MR imaging as a predisposition BM for PC. Study design: This proposal is phase one: a mixed set of development and discovery BM studies (CRUK roadmap stage 1). Imaging BMs: Phased „chemical shift‟ magnetic resonance imaging (CS-MRI) and proton MR spectroscopy (MRS). The readouts will be quantitative (e.g. pancreatic fat fraction, PFF) and descriptive assessment (e.g. major lipid metabolites) of pancreatic fat. Objectives: To (i) assess accuracy and reproducibility of CS-MRI and MRS; (ii) correlate the MR readouts of pancreatic fat deposition with known obesity-related risk factors for PC; and (iii) test the proof of principle that pancreatic fat changes in response to weight reduction, and thus, is a modifiable risk factor. Target population: Patients undergoing pancreatic resection; patients undergoing standardof-care MR imaging with non-diseased pancreas; healthy individuals in weight reduction intervention trial. Sample sizes: Three discovery studies of pragmatic sample sizes 8, 8 and 12 (before and after 4 week intervention). Pilot data: We have piloted the above methodologies in the context of hepatic steatosis: developing a method of digital quantification of histological fat; validated the use of CS-MRI and MRS; and developed a novel CT-derived measure of abdominal fat compartment (e.g. subcutaneous and visceral adipose fat; SAT and VAT) volumes. Next step: The outputs will be a „fit for purpose‟ imaging BM set that will inform the prospective evaluation of the clinical utility of MR imaging to enhance the identification of individuals at high-risk of PC. Clinical utility: It is unlikely that these imaging modalities will be a stand-alone predisposition BM, but rather will contribute as „add-on‟ markers to other risk models currently in worldwide consortia development.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Can multiplex deep sequencing of circulating free DNA detect pancreatic cancer at an early stage?
Funder: Pancreatic Cancer UK

Abstract: Pancreatic ductal adenocarcinoma (PDAC) comprises 80% of pancreatic cancers. The majority of patients with PDAC present with advanced disease, which is unsuitable for curative resection. However, earlier detection would increase the likelihood of successful treatment, resulting in improved prognosis. The detection of circulating tumour-derived biomarkers in blood could provide a relatively non-invasive approach to earlier detection of cancer. PDACs harbour specific somatic mutations, and we have shown in this and other tumour types that such alterations can be detected in circulating free DNA (cfDNA) isolated from plasma by targeted next generation sequencing (NGS). In the last few years knowledge of the molecular changes in PDAC has increased greatly. The most frequently mutated genes are KRas (95%), TP53 (~75%), CDKN2A (90%), and SMAD4 (~55%). P53, SMAD4 and CDKN2A are known to drive PDAC, but an additional 15 driver mutations have recently been identified. However, to date there have been no comprehensive multi-gene studies in cfDNA of PDAC patients or individuals at risk. The aim of this study is to provide proof of principle that mutations in key cancer genes of relevance to PDAC can be identified by targeted next generation sequencing (NGS) of this cfDNA, which, with appropriate validation, would detect a significant number of early PDACs or predisposing conditions and help target effective treatment. We have chosen to use the Ion AmpliSeq™ Cancer Hotspot Panel v2 for our studies. This is designed to amplify 207 amplicons covering approximately 2,800 COSMIC mutations from 50 oncogenes and tumor suppressor genes (including the common PDAC mutations) from as little as 10ng of cfDNA. This opens up the possibility of using NGS of cfDNA for earlier detection of this cancer.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Q-CANCER: development of a sample to result device for low cost, rapid tumour profiling
Funder: Innovate UK

Abstract: This project is concerned with the development of a fully integrated, low test cost, sample to result medical device that will enable a histopathologist (or a technician) to perform multiplex genotyping and tumour staging & profiling, within minutes, from formalin fixed &/or fresh tissue samples, providing a molecular adjunct to a histopathologist's standard practice. The device will automate sample prep & DNA sequencing at the press of a single button, following the introduction of a sample. The tissue sample is processed using a number of novel & innovative but proven microfluidic and nanotechnologies that allow for massive multiplexing potential. The device will enable fast turnaround of high quality genotyping that integrates with established clinical practice . Furthermore, the ability to rapidly profile & stage a tumour or identify genetic mutations will lead to improvements in patient outcomes, reduce patient anxiety & result in cost savings in treatment programmes.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: OCTAVE - Ovarian Cancer Trial with an Enhanced Group B Oncolytic Adenovirus
Funder: Innovate UK

Abstract: ColoAd1 is a chimeric adenovirus serotype 3/11p, with a number of key characteristics that may make it a suitable oncolytic agent for the potential treatment of metastatic carcinomas. This is a phase I/IIa study designed to determine the safety, toxicity and tolerability of ColoAd1 and the clinical benefit and potential efficacy of ColoAd1 as a single agent and in combination with chemotherapy in women with recurrent platinum resistant ovarian cancer when administered intraperitoneally. Safety evaluations will be will be assessed using NCI CTCAE v4 and efficacy evaluations will be assessed using CT and [18F]-FDG PET/CT scans. A number of pharmacogenomics and biomarker assessments will also be performed.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Enhancement and Mapping of Oncological drug Delivery by Ultrasound
Funder: Innovate UK

Abstract: The TSB Biomedical Catalyst Fund will be instrumental in enabling OxSonics Limited to develop a prototype of its first product, “SonoTran”, a low-cost therapeutic ultrasound device and associated consumables for the non-invasive targeted and enhanced delivery of cancer drugs to solid tumours. SonoTran has the capability to overcome the greatest challenge facing solid tumour drug delivery: poor penetration of even the smartest drugs deep into solid tumours. A key feature of OxSonics core technology is the ability to map and intra-operatively monitor treatment in real-time and in 3D – a feature that has the potential to transform healthcare practice. The platform technology can also be applied to a range of surgical applications including the repair of intervertebral discs for the treatment of chronic low back pain. TSB funding will initially enable the creation of 4 new UK jobs, rising to 24 new UK jobs by 2019.


Research activity codes: 6.3 MEDICAL DEVICES;5.3 MEDICAL DEVICES
Health categories: CANCER AND NEOPLASMS