NIHRDataInsights/HRCSData huggingface dataset:
Title: Computer enhancement of clinical imaging
Funder: Innovate UK

Abstract: Visual examination of patients is an important aspect of medical care. In order to examine internal structures such as the epithelial surfaces of the bladder or the digestive system, an endoscopic system is usually employed which allows detailed examination of the patient in a less-invasive way. Although endoscopes have brought great benefits, they are not without problems The optical characteristics of the light sources commonly used and the tissue illuminated, combined with the behaviour of the human visual system, can make certain abnormalities difficult to detect. Although various dyes and alternative illumination techniques have been investigated in attempts to overcome this problem few have demonstrated a clear advantage. In this project Biosignatures will take a different approach and apply the computational techniques they have developed for proteomic gel image analysis to endoscopic video data. This has the potential to greatly enhance detection of abnormalities.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Modulating intracellular oncology targets using Adhirons™ – a novel therapeutic approach
Funder: Innovate UK

Abstract: Protein therapeutics a major growth area, but limited to extracellular targets. We propose to exemplify inhibition of two intracellular oncology targets, the small GTPase KRas and prosurvival protein Bcl-xL, in human cells using high-affinity target-selected peptide aptamers, based-on Adhiron™ technology (U. Leeds). The Adhirons™ will be formulated for delivery using Nanocin™ nanoparticles (Tecrea Ltd). Ten independent Adhirons™ that tightly bind KRas and Bcl-xL will be identified by screening and then tested for their capacity to inhibit target activity. For both targets, we will advance at least one inhibitory Adhiron to nanoparticle formulation and cellular delivery optimisation. Finally, phenotypic effects on downstream signalling events and dose response relationships will be determined. The outcome should exemplify how any protein inside mammalian cells can be targeted using Adhiron™:Nanocin™ techology.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Novel therapeutic antibodies against nf-P2X7
Funder: Innovate UK

Abstract: In December 2013 the World Health Organization, released data showing that globally there were 14.1 million new cases of cancer and 8.2 million cancer deaths in 2012. Significant medical progress has been made, but patient outcomes remain poor, new cancer cases are increasing and for certain types of cancer, existing treatment options and those in development are clearly inadequate. Bioseptre, a company developing cancer therapeutics in the UK, has discovered nf-P2X7, a unique varient of P2X7, an important cell protein present in cancer cells, that can be used to target cancers in order to kill them. This project will build on existing data to confirm that it is possible to create an innovative biological therapeutic that can be used to treat patients. Because of its mechanism of action, this therapeutic will have the potential to treat multiple cancer types safely.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Feasibility of inhibiting desumoylating enzymes for treating platinum-resistant cancers
Funder: Innovate UK

Abstract: Through work funded by the TSB, MISSION Therapeutics identified SENP enzymes as new therapeutic targets for treating drug-resistant ovarian cancer. For drug discovery, SENPs pose a distinct challenge as they require specific substrates and assays and they are not well studied in terms of their biological role(s). For these reasons, SENPS are currently considered higher risk targets. We propose to use our proven expertise targeting related enzymes to test the feasibility of developing SENP inhibitors by developing appropriate biochemical and cell-based activity assays then screening a bespoke compound library to assess druggability. In addition, we will carry out additional target validation to further assess the utility of inhibiting SENPs for treating drug-resistant cancers.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Improved next generation sequencing to detect ultra-rare, cancer gene mutations in circulating cell-free DNA in blood
Funder: Innovate UK

Abstract: It has been well documented that the release of cell-free DNA into the bloodstream in patients with various types of cancer. There has been growing interest in trying to use such circulating tumour DNA as a non-invasive biomarker to detect the presence of malignancy, follow treatment response, gauge prognosis, or monitor for recurrence. However, current methods have significant limitations. Next Generation Sequencing (NGS) has revolutionised genomic exploration and analysis by making possible simultaneous sequencing of hundreds of billions of base pairs at a fraction of the time and cost of traditional methods. However, the sensitivity of this method is limited by the inherent error rate of the sequencer, as incorrectly read bases might be mistaken for true mutant copies. To overcome this limitation, GeneFirst has developed a method termed Targeted BiDirectional Sequencing technology. This is potentially suitable for detecting rare mutations in circulating cell-free DNA in blood.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Clinical Asssesment of Compact Gamma Camera: An advancement in cancer diagnosis
Funder: Innovate UK

Abstract: The project aims to address the recognised need for greater accuracy in Sentinel Lymph Node Biopsy (SLNB), the standard procedure for evaluating & diagnosing a range of cancers - notably breast cancer & melanoma, through the development & clinical testing of a unique Compact Gamma Camera (CGC). The device will not only improve SLNB accuracy (to ~99.5%) but also improve rates of healing (by tissue sparing & nerve damage prevention): this advancement in imaging for cancer diagnosis will be provided at a cost of 60% less than current best in class gamma cameras. The CGC has the potential to deliver healthcare savings of ~£650Mp.a. in the targeted EU & US markets. The project, led by Xstrahl (SME), will include clinical assessment of the CGC for SLN detection in both breast cancer & melanoma across 2 major centres where these cancers are treated & practice taught: University of Nottingham (UoN) & Netherlands Cancer Institute (NKI). Other activities incl. advanced prototyping & assembly (production mechanisms & economics).


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Development Grant - Developing chemical inhibitors of protein-protein interactions of oncoprotein gankyrin for the treatment of hepatocellular carcinoma and other cancers
Funder: CORE

Abstract: Hepatocellular carcinoma (HCC), the most common form of liver cancer, is the third leading cause of cancer mortality worldwide, accounting for 0.5 million deaths annually. Treatment options are very limited, and more than half of patients die within a year. Esophageal squamous cell carcinoma (ESCC), the sixth leading cause of cancer-related deaths worldwide, likewise has few treatment options and very low survival rates. The discovery of new drugs is therefore of vital importance to treat these diseases. To do so, we will need to identify and then target different cellular processes and key proteins therein in order to determine which will lead to the most effective treatments. Gankyrin is one such protein and an interesting potential new target for the treatment of both HCC and ESCC. Gankyrin’s function is to remove two pivotal proteins, called p53 and Rb, from the cell. p53 and pRb are known as the ‘gatekeepers’ of the cell, essential to keeping it healthy and preventing cancer from developing. There are abnormally high amounts of gankyrin in the early stages of HCC and ESCC, and consequently greatly reduced amounts of p53 and Rb gatekeeper proteins. Therefore, a potential treatment for HCC and ESCC could be a drug that prevents gankyrin from removing p53 and pRb from the cell so that their gatekeeper functions are maintained. Gankyrin acts on p53 and Rb by interacting with a number of proteins that are required for protein destruction. As the first step in our drug discovery program, we therefore propose to find drug-like molecules that inhibit gankyrin by disrupting its interactions with its partner proteins. Recently, we discovered a small molecule, named cjoc42, that binds to gankyrin very tightly, and preliminary experiments indicate that cjoc42 can counter the adverse effects that gankyrin has on the cellular levels of p53. We have also shown that cjoc42 is not generally toxic in cells and that it does not bind indiscriminately to lots of other proteins. With CORE funding our objectives are (i) to determine the effects of cjoc42 in cancer cells originating from the liver where gankyrin is naturally very abundant, (ii) to use cjoc42 as a starting point to generate a set of more potent small molelcules against gankyrin, and (iii) to set up and optimise experiments to identify further therapeutic small molecules that disrupt the binding of the different partner proteins to gankyrin.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Advancing sub-classification of prostate cancer populations for targeted molecular treatment
Funder: Prostate Cancer UK

Abstract: Aims & Objectives 1. To identify fusion rearrangements within divergent clusters of men identified within our CamCaP study (e.g. TMPRSS2-ERG) 2. To identify methylation patterns within these sample groups (e.g. transcription factors regulating Hes6) 3. To interrogate a historical cohort of clinically 'high risk' relapsing and non-relapsing prostatectomies with 10-15yrs follow up to validate proposed molecular features predictive of poor outcome. Why is it important? Disease stratification based on molecular signatures has delivered much ‘added value’ in treatment decisions for other epithelial cancers, breast cancer being a principal example.1 In contrast, prostate cancer treatment decisions are still based almost exclusively on histological architecture (Gleason score)2 3, serum biochemistry (PSA)4 and local disease progression, without attention to molecular characteristics. However, recent studies suggest that prostate cancer can be stratified according to molecular signatures.5-9 Genetic changes associated with aggressive disease, when present in early tumours, herald the onset of early biochemical relapse. Early treatment of prostate cancer is very effective, yet it is difficult to identify those patients who are likely to progress and to treat them appropriately.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Empty virus-like particles (eVLPs) as bio-compatible targeted drug-delivery vehicles
Funder: Biotechnology and Biological Sciences Research Council

Abstract: This project is aimed at developing empty (RNA-free) virus-like particles (eVLPs) of cowpea mosaic virus (CPMV) as a targeted drug delivery system. CPMV particles have already been shown to be well tolerated in mice and have been investigated as imaging agents. However, despite these properties, the presence of RNA within particles isolated from infected plants has, to date, precluded the use of CPMV for drug delivery. The project will exploit the recent success at JIC in the production of empty capsids using the CPMV-HT transient expression system and the applicants' experience in the genetic and chemical modification of CPMV particles. Although the ultimate aim will be the development of a generic targeted drug delivery system, the project will focus on the delivery of the anti-cancer drug, gemcitabine, to cells expressing a cancer-specific integrin. This receptor is absent from most healthy adult tissues but is over-expressed in a range of tumours including oral squamous cell carcinomas and lung and breast carcinomas. Thus, it is a tumour-specific target which is of particular interest to our industrial partner Aura Biosciences Inc.. To produce eVLPs which target to this sequence, we will express either a peptide, A20FMDV2, with known integrin-binding properties or a single-chain antibody (scFv) on the eVLP surface using established chemical and genetic methods. To load the eVLPs with gemcitabine, we will make use of pores which occur at the 5-fold particle axes. These allow small molecules to enter the eVLPs in a pH-dependent manner and thus access to the interior of the VLPs can be controlled. We will optimise methods for loading the drug into the VLPs including mutagenesis of amino acids which surround the pore and line the interior of the capsid. The ability of the targeted particles to deliver the drug to cancer cells will be investigated by testing their ability to bind to and kill cells expressing the integrin in culture.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Ion transport by the human Breast Cancer Resistance Protein (ABCG2)
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The human Breast Cancer Resistance Protein (ABCG2) is an ATP-binding cassette transporter that affects the pharmacokinetic properties of drugs in our body due to its wide distribution at important pharmacological barriers. In addition, ABCG2 expression confers resistance on cancer cells by reducing the intracellular concentration of cytotoxic drugs to subtoxic levels. Although the clinical need for inhibitors that could modulate ABCG2 activity is emphasized in the literature, the rational development of such compounds will require further insights into the possible routes for modulation, and will require a greater understanding of the molecular mechanisms that underlie ABCG2 activity. ABCG2 has been characterized in the literature as an ATP-dependent transporter which couples ATP-binding and hydrolysis to the transmembrane efflux of drugs. Surprisingly, analogous to previous observations on the bacterial ABC transporter LmrA, we found that the membrane domain of human ABCG2 in the absence of the nucleotide-binding domain (termed ABCG2-MD) is active as a secondary-active multidrug efflux transporter that, in ABCG2-MD, couples drug efflux to the uptake of protons by an electrogenic drug-proton antiport mechanism. The hybrid use of primary and secondary forms of metabolic energy by membrane transport systems is an intriguing and important concept that has been described for a number of other ATP-dependent transporters. In this project we will explore this novel fundamental property of ABCG2-MD in more detail and extend our observations to full-length ABCG2. We aim to characterize proton transport and transport of other ions by ABCG2 in electrophysiological experiments and conventional transport assays using radioligands and fluorescence spectroscopy, and identify amino acid residues in ABCG2 important for ion transport. We will assess how ion transport is integrated in the transport cycle of ABCG2, and how ion transport is linked to multidrug transport.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Gene-expression connectivity mapping and its application in phenotypic targeting
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The project covers three aspects of research in connectivity mapping: 1) Methodological and algorithmic advancement, 2) Novel application, and 3) software development. We will investigate and develop a gene progression method in the construction of gene signatures, first by ranking and sorting genes based on their statistical and biological significance. By progressively incorporating more features, the length of a gene signature is optimised by observing and achieving the desired statistical stringency among the discovered connections. We will develop a gene-signature perturbation method to test the stabilities of discovered connections. Two approaches to gene-signature perturbation will be investigated and their performance compared. The first is a leave-one-gene-out approach to derive shorter signatures. The second is an add-one-gene-in approach by adding an extra randomly selected gene to the signature. The perturbation stability will be assessed by the proportion of persistent significance. This will help further analyse and narrow down these connections in an unbiased manner such that the success rate of any follow-up investigation can be maximised. We will develop two types of applications following 'the general principle of phenotypic targeting'. Using experimentally derived gene signatures, we will investigate phenotypes related cancers in two case studies. Using manually coded gene signatures, we will apply connectivity mapping to the search for agents that will down regulate a small number of selected genes. We will use RAN and c-FLIP down-regulation as case studies. Finally there is a software development component, in which we will implement a parallel computing model of connectivity mapping with the new methods and algorithms developed here. We will use C/C++ and OpenMP as a development platform to create tools that fully exploit the hardware capacities of the increasingly common multi-core desktop computers.


Research activity codes: 5.1 PHARMACEUTICALS;8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: CANCER AND NEOPLASMS
Title: Understanding the regulation of alkaloid biosynthesis in opium poppy and breeding new varieties
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Papaver somniferum (opium poppy) remains one of the richest sources of natural products for the pharmaceutical industry. We recently reported that opium poppy contains a cluster of ten genes encoding five different enzyme classes responsible for the biosynthesis of noscapine (Winzer et al, Science 2012, 336:1704-8), an antitumour alkaloid that is currently in clinical trials in the USA. Our discovery of the ten gene cluster in opium poppy allowed us to rapidly elucidate the main steps in the previously unknown noscapine biosynthetic pathway. In the current proposal we will use a combination of metabolite profiling and next generation sequencing to establish if related species that also produce noscapine have an equivalent gene cluster, allowing us to gain new understanding about the evolution of gene clusters in higher plants. We will also characterise those remaining steps in the biochemical pathway which are not fully understood using a combination of in-planta based Virus Induced Gene Silencing (VIGS) and in-vitro characterisation of enzymes obtained by heterologous expression. Major questions remain about the regulation of flux into the noscapine branch versus the morphinan branch of alkaloid biosynthesis and to address these we will use a combination of RNA sequencing, quantitative proteomics and isotope labelling followed by deep metabolite profiling to pinpoint the regulatory steps. In order to learn more about the control of flux and to develop new poppy varieties we will cross noscapine producing poppies into a number of mutant backgrounds that produce altered levels of morphinan alkaloids including morphine, codeine, thebaine and oripavine. This will result in new varieties producing novel combinations of opiate alkaloids that are required by the pharmaceutical industry. The research programme will therefore contribute both fundamental knowledge and improved sustainable feedstocks for the pharmaceutical industry.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: A translational science approach to prevent prostate cancer incidence and progression through diet
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Ageing prostate tissue becomes at risk from the emergence of cancerous clones. These emerge due to genetic changes within individual cells which, in many cases, are likely to be due to reactive oxygen species inducing mutation. Metabolic deregulation of lipid metabolism in ageing tissue is both a cause and marker of oxidative stress. While certain dietary factors, such as red meat and dairy products, can enhance oxidative stress, other dietary factors, such as sulforaphane (SF), obtained from broccoli, can reduce oxidative stress through induction of nrf2-regulated gene expression and in so doing prevent or reverse metabolic deregulation. We propose to undertake a human intervention study to test the hypothesis that a diet rich in SF delivered either through Beneforte broccoli can alter the metabolism and gene expression of ‘at risk’ non cancerous tissue of men under active surveillance in a manner that would reduce the probability of the emergence of aggressive cancerous clones. We will obtain global gene expression and metabolite profile from prostate biopsy tissue before and after a 12 month intervention, combined with analyses of plasma and urine. The study will provide for the first time evidence in humans for the critical role of SF in regulating metabolism and will identify the underlying mechanisms by which SF can reduce the risk of aggressive prostate cancer. Although it is not designed or powered to assess clinical endpoints, it can inform such studies.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: CANCER AND NEOPLASMS
Title: UK IND-ISPG Studentship: How does vitamin D maintain gut health
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Convincing evidence exists for the preventive effect of increased vitamin D status on colon cancer risk. However, since a significant proportion of the UK population is vitamin D deficient, particularly during the winter months, this represents a significant public health concern. Colon carcinogenesis is associated with altered epigenetic modifications, such as DNA methylation, which modulate the expression of genes important for controlling cancer development. We have recently demonstrated that the abnormal DNA methylation of these genes in the healthy human colon is induced during ageing but the rate of its acquisition is significantly influenced by vitamin D status. Vitamin D has previously been suggested to affect cancer risk via postulated mechanisms that include effects on cell signalling pathways, modulation of innate immune responses and promoting epithelial barrier integrity. This project will therefore explore the hypothesis that vitamin D influences colon cancer risk by modifying the epigenetic regulation of genes involved in these processes. The project will utilise a recently developed colonic epithelial stem cell culture system to elucidate the mechanisms by which vitamin D modulates abnormal, age-related DNA methylation and determine the consequences these changes have for gene expression, signalling pathways and ultimately the cell.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: CANCER AND NEOPLASMS