NIHRDataInsights/HRCSData huggingface dataset:
Title: Refining the lung cancer mouse model through environmental enrichment
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: The 5-year survival rate of patients with stage IV non-small cell lung cancer is less than 10%(Ettinger et al. 2010). Although lung cancer mouse models have led to ground breaking findings in recent years, current models do not fully recapitulate the immune response and mutation burden observed in human tumors(Dupage et al. 2011; McFadden et al. 2016). Accumulating evidence suggests that housing mice in environmentally enriched environments has a variety of benefits(Pedersen et al. 2016; Song et al. 2017; Rampon et al. 2000; Benaroya-Milshtein et al. 2004; Kovesdi et al. 2011; Bice et al. 2017). In my proposal, I aim to refine the lung cancer mouse model by housing mice in an enriched environment to improve their well-being and assess if enriched housing inhibits tumour growth, increases the cancer immune response, and inhibits cancer associated cachexia. Mice will be habituated to their environments for 5 weeks prior to intravenous injection with a novel immunogenic cell line KPAR1.3 derived from a tumour grown in a Rag-/-;KrasLSL-G12D;P53fl/fl;R26LSL-APOBEC3Bi mouse model of lung cancer. Anxiety will be assessed using an elevated plus maze. Tumour growth will be measured at 3 weeks post-injection by microCT, and at 4 weeks a grip test will be performed to determine cachexia levels. A subset of mice will be treated with checkpoint inhibitors to examine if tumours are more sensitive to immunotherapy in mice housed in enriched environments. Tumours will be analysed by immunohistochemistry and flow cytometry to analyse tumour immune infiltrate. A representative muscle in the mouse will be stained to assess muscle size to assess if cachexia is reduced with environmental enrichment. This refined model system is easy to setup and applicable to many different cancers, so should have a broad impact across the cancer biology field. This model system should also reduce the number of mice required as complex breeding schemes are not necessary.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: CANCER AND NEOPLASMS
Title: Refining in vivo studies of cancer metastasis with next-generation explant-in-chip perfusion models
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: In this project, we develop and validate a novel "explant-in-chip" device to study early stages of metastasis, specifically cancer cell arrest, extravasation, and early colonisation within different secondary tissues of interest. Our prototype device achieves self-sealing around a millimetre-sized explant lodged within a microchannel. Effective sealing is important because it forces flow to pass through, rather than around, the explant, delivering oxygen and nutrients to preserve explant viability over several days. Cancer cells included in the perfusate enter severed microvessels at the explant surface and pass into the microvascular network to mimic the hematogenous route of tumour cell dissemination in vivo. Importantly, the explant captures the native tissue microenvironment, which determines whether cancer cells successfully adhere, extravasate and survive in the secondary tissue. We envisage our technology being used in place of in vivo studies to screen different drugs or drug combinations on the early stages of metastasis. The benefit is that our approach reduces the experimental unit from the individual animal to the individual explant, many of which can isolated from a single mouse and exposed to a wide range of different treatment conditions. This greatly increases our ability to identify the most promising drug treatments for more refined follow-on in vivo studies. Further, because the design is compatible with time-lapse microscopy, it is possible to investigate the spatiotemporal dynamics of cancer cell interactions with the vasculature and initial colonisation, while comparable studies in vivo would require intravital microscopy and implantation of optical windows. By the end of this project, we will have developed and validated a user-friendly device that will provide single cell resolution of the early spatiotemporal events involved in metastatic dissemination, alleviating the need for technologically challenging and invasive procedures in mice.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: CANCER AND NEOPLASMS
Title: New Players in Organ Size Determination and Homeostasis
Funder: Welsh Government Office for Science

Abstract: The mechanisms of cancer and the control of growth are closely linked. The current proposal focuses on the growth control and homeostasis aspects, using multi-faceted methodologies from genetics to genomics and quantitative imaging


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Smallmolecule immune checkpoint inhibitors: an innovative approach to treat cancer.
Funder: Welsh Government Office for Science

Abstract: In order to protect our body, the immune system detects, attacks and kills all the “bad” cells, which are recognised as “foreign”. This activation is regulated by different proteins, called immune-checkpoint activators. To switch-off the immune system function, the activity of immune-checkpoint deactivators is required. During a cancer process the activators switch-on the immune system that attacks and kills the tumour cells, helping in the fight against cancer. Unfortunately, different cancer cells develop the ability to avoid immune system detection by switching-on the deactivators, therefore the immune system activity is blocked, the cancer cells are not killed anymore and continue to grow. Blocking the deactivators function has been demonstrated to prevent cancer cells from escaping immune system, therefore they are killed again by the immune system activity. A new anticancer strategy to kill resistant tumour cells is to use molecules able to block the deactivators function restoring again the anti-tumour activity of the immune system. At the moment, no drugs against immune-checkpoint deactivators are available. In this project, using different computer, chemistry and biology techniques, we aim to find new molecules that can block different immune-checkpoint deactivators (CD200, PD-1, CTLA-4) to be used for the treatment of different cancers.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Targeted Dual-acting Magnetic Nanoparticles for Anticancer Activity
Funder: The Academy of Medical Sciences

Abstract: Magnetic nanoparticles are regarded as being among the most accepted metallic ones that are currently being tested in clinical trials for their potential use in diagnostics by magnetic resonance imaging technique. The proposed research group is regarded as an expert in this field in particular and thus staying there, i will do my best to maximize my benefits. During my visit, i plan to have a full package experience as follows: Culturally, I plan to visit the major monuments in the city like Parliament Square and Big Bin tower and attend cultural events such as plays. Scientifically within the selected research group, the plan of my visit is to spend the first week in getting to know the research group members and start to have hands on the polyol synthesis protocol for the synthesis of ferrite nanoparticles. I plan studying the playing parameters of the reaction such as precursor concentration, surfactant concentration, reaction temperature and reaction time. In the second week, I will start the characterization of the synthesized nanoparticles using new techniques for me such as VSM and conclude a relationship between the synthesis protocols and the obtained results in terms of magnetism effect. In the third week, i plan to start chemical modification of the nanoparticle surface by plasma treatment which is a new technique for me. I plan various reaction setup and will characterize the results using FTIR technique. In the last week, I will set up various reactions for surface conjugation with a model molecule and characterizing the products by UV-Vis technique.At the same time, I plan to be engaged in discussions with scholars working in imaging technique since it is totally new for me and will do my best to witness one of the sessions that they conduct. To promote networking within the group, I plan to deliver a talk at my arrival to explain my experience and allocate potential collaboration plans and just before departure, a reporting talk is planned to highlight the gained knowledge and clearly define the obtained results. I will schedule a special meeting with the group leader and discuss possible funding opportunities and future collaboration plans to start working on proposal draft within my stay. I will do my best to schedule a follow-up meeting in which we discuss the draft since this is more efficient than electronic communication. I plan as well to network with nearby research groups such as attending seminars and scientific talk or discussion panels. This aims to maximize the network and potential collaborators.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Single-cell analysis dissects clonal specific chromatin states relevant to pathology and relapse in AML
Funder: The Academy of Medical Sciences

Abstract: Acute myeloid leukemia (AML) is a rapidly progressing hematopoietic malignancy, characterized by the accumulation of clonal myeloid stem or progenitor cells arrested in their ability to differentiate into mature blood cells. Although most patients initially respond to chemotherapy, ~75% relapse and death within 5 years. The t(8;21)(q22;q22) translocation is one of the most frequent genetic alterations in AML, and is typically present in French-American-British (FAB)-M2 subtype. Despite progresses in the understanding of AML pathophysiology, the molecular pathogenesis and relapse of AML has not yet been completely defined. Here, we use a new single cell profiling technology called mtscATAC-seq, which allows us to define the epigenomic clonal evolution of AML using endogenous mitochondrial DNA variants as well as the cellular output of each clone, in order to identify putative epigenetic mechanisms of AML pathogenesis and relapse at the single-cell resolution. Combining with the bioinformatic analysis, we will define the epigenomic clonal evolution of AML hematopoietic stem and progenitor cells and their progenies in patients with AML.

Lay abstract: Acute myeloid leukemia (AML) is an aggressive blood cancer characterized by an accumulation of immature cells of the myeloid lineage. Although 60%–80% of patients achieve complete remission after standard chemotherapy, more than 50% patients experience relapse. Efforts to link AML relapse to genetically resistant clones have only met with limited success, raising interest in non-genetic drivers of functional heterogeneity. In this project, we aim to dissect the clonal evolution in AML from diagnosis to relapse and further uncover subclone specific chromatin states. We anticipate that a better understanding of chromatin states of malignant cells will improve our understanding of the epigenetic processes that confer clonal advantage in pathogenesis and therapy resistance during relapse. we will be able to clonally trace thousands of cells from AML patients, linking epigenetic variability to subclonal evolution, and infer clonal specific hematopoietic differentiation in t(8;21) AML patients. This will help us to identify the epigenetic mechanisms of t(8;21) AML associated with pathogenesis and progression to relapse.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Defining the genomic landscape of acute myeloid leukaemia in adults using whole genome sequencing
Funder: The Academy of Medical Sciences

Abstract: The identification of driver genes is central to the understanding and treatment of cancer. In acute myeloid leukemia (AML), a number of mutations in driver genes have been described with cytogenetic abnormalities being present in 50% of newly diagnosed cases. The full complement of mutations and other molecular lesions that contribute to the pathogenesis and diversity of AML in adults is not known. The availability of whole genome sequencing (WGS) data through initiatives such as the 100,000 genomes project offers the opportunity to identify different classes of functional mutations for AML and to decipher their biological impact. I shall use complementary bioinformatic and experimental approaches to: (i) Catalogue the mutational landscape of AML by analysis of 100,000 genomes project WGS data and publicly accessible WGS data (The Cancer Genome Atlas (TCGA)) comprising a total of 240 AML whole genomes; (ii) Generate ChIP-seq, ATAC-seq and Micro-C data from representative AML cell lines; (iii) Identify recurrently mutated driver loci (coding, non-coding and copy number) by integrating mutation data with gene expression (TCGA RNA-seq n=50), epigenetic and topographical data; (iv) Characterise mutational signatures to provide insight into disease aetiology; (v) Where available, integrate genetic data with clinical data to inform on diagnostic and prognostic driver mutations. These findings should facilitate discovery of novel therapeutic and agents and improve patient stratification for targeted therapies.

Lay abstract: Cancers are caused by changes in DNA (mutations) that drive tumour growth. Identifying these mutations has produced benefits, such as new targeted treatments. Acute myeloid leukaemia is an aggressive leukaemia (AML) and in adults is associated with a poor 5-year survival (15%). Genetic studies of AML have focused on mutations that cause changes in the proteins that genes encode, without considering the 98% of the cell's DNA that does not directly make proteins. We already know of a few mutations in this "non-coding DNA" that are important for cancer growth, but there has not been a comprehensive analysis. It is now timely to add non-coding mutations to the catalogue of cancer drivers and decipher their functional consequences. I will combine DNA sequencing, other laboratory methods and computer programs to identify new mutations in DNA that are cause AML. This work may lead to new strategies to treat AML.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: MicrosatEllite Womb Surveillance (MEWS) study
Funder: The Academy of Medical Sciences

Abstract: Aim: The overarching aim of this study is to explore the promise of a urine based endometrial cancer detection tool that could be used to provide endometrial surveillance in women with Lynch syndrome (LS). If successful, this would avoid the current need for invasive, repetitive, and costly diagnostic tests and allow women with LS to self-test. Objectives: 1. Establish a MSI testing protocol for urine that is effective in endometrial cancer 2. Define the accuracy of this method 3. Recruit 50 women with MSI endometrial cancer and 30 controls with no cancer but LS and test their urine for MSI. 4. Publish these results in the literate and seek substantive funding to analyse this method in a large LS cohort. Background: Around 1:300 women will have LS, putting them at a significantly increased risk of endometrial cancer. Women with LS are advised to undergo risk reducing surgery however, this is not suitable for those who wish to have children or are too unfit for surgery. Therefore, many women opt for endometrial surveillance which is often performed by repeated endometrial biopsies. These are painful and costly and can miss cancer. It is now known that women with endometrial cancer shed cancerous cells into urine samples. Micro-satellite instability (MSI) is a feature of cancers seen in LS. Therefore it could form the basis of new method of endometrial cancer surveillance in LS. However the protocols and accuracy of such a testing method is yet to be established.

Lay abstract: Around 1:300 people have a condition known as Lynch syndrome (LS); this puts them at an increased risk of womb cancer. Women with LS are offered a hysterectomy around the age of 40, put some will get cancer before this, will not be fit for surgery or will not wish to have a hysterectomy. Therefore, it is important to offer these women an effective method of womb cancer surveillance. Currently this can only be achieved by taking repeated biopsies of the lining of the womb. These are painful and require women to come to a hospital. Many therefore forgo surveillance due to the discomfort and inconvenience. We would like to explore the accuracy of using a test that is based on a urine sample. This could be done by women at home and would be painless. I am passionate about improving the current care of women with LS. I have asked women with LS what they believe is a research priory; consistently they say they would like a better method of womb surveillance. Women with LS find the current methods unacceptable. Research I recently was involved in found that urine samples from women with womb cancer contain cells from the cancer. It is exciting to think that this could be used to provide an acceptable method for women with LS to test for womb cancer. Urine based testing will also save money and free up hospital resources. We will seek to confirm these results in a larger future study.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: All-optical Photoacoustic and Fluorescence Endomicroscopy Probe for Guiding Minimally Invasive Surgery
Funder: The Academy of Medical Sciences

Abstract: Gliomas are the most common type of brain tumour with a grade-dependent prognosis. Glioblastomas (grade 4) have a 5-year survival rate of only 2%. Accurately determining the tumour grade is crucial to optimise patient outcome; however, grading accuracy with stereotactic biopsies is currently limited by inaccurate tumour sampling. In this fellowship, I will develop a novel a fibre-optic high-resolution photoacoustic and fluorescence endoscopy probe that provides 3D functional, molecular and microstructural information from within biopsy needles, to enable targeted biopsies. Objectives: i. Photoacoustic and fluorescence endomicroscopy (PAFEM) probe development. A custom console will be developed for signal acquisition, image reconstruction and real-time display. ii. Phantom imaging. The performance of the developed imaging system will be evaluated and optimised with tissue mimicking phantom. iii. Human tumour tissue imaging. As a first validation step, imaging with the needle probe will be performed in the neurosurgical suite with human brain tissue ex vivo, immediately before it is submitted for histology.

Lay abstract: Gliomas are the most common type of brain tumour. Higher tumour grades are associated with lower chances of survival. For clinicians it is crucial to accurately determine the tumour grade, in order to effectively plan treatments for patients. Currently, tumours are graded and studied using stereotactic biopsies, in which needles are positioned into the brain and small volumes of tissue are removed. The removed tissue samples are then sent to pathology for a rapid examination to obtain a preliminary diagnosis while the patient is still in the theatre. If the samples are extracted from non -tumour tissues, additional biopsies are taken. To accurately determine the tumour grade and to reduce the risks of damaging major blood vessels in the brain and infections during biopsy procedures, it is important to visualise the tumour during the procedure. Currently our visualisation capabilities are insufficient. With this AMS Springboard Award, I will develop a novel miniature optical imaging probe that will be positioned inside biopsy needles to visualise tumours from within the brain. This probe will make use of recent advances in two state-of-the-art optical imaging technique namely photoacoustic imaging and fluorescence imaging. I will lead a research team that will work closely with a leading clinician. I will start with imaging tissue mimicking phantoms and progress to biopsied tissues from patients.

Research activity codes: 5.4 SURGERY
Health categories: CANCER AND NEOPLASMS
Title: AuguR: a scalable open-source interactive cancer analytics web application for routinely collected data
Funder: The Health Foundation

Abstract: Most data collected by hospitals as part of routine care is not utilised for analytics or organisational intelligence. Although hospitals are required to produce datasets that are shared and analysed by organisations such as NHS Digital or National Cancer Registry and Analytics Service, the outputs of these national bodies are not designed to provide detailed information at a local or regional level. Skill shortages, insufficient resources, limited data access and interoperability issues are barriers to embedding data science into clinical care and hospital management. This project aims overcome these by combining routinely collected cancer data with open-source analytics tools in a web application. The app will provide health care professionals and hospital managers with easy to use, interactive analytics for cancer outcomes and waiting time data. Results will be easily exportable to create reports for use in patient records or for managerial oversight. This project will build on an existing prototype app, AuguR, and will be deployed within a secure regional cloud environment, The Yorkshire Data Arc, so that hospital staff across the region can easily analyse their own cancer data. Hospitals can also have automatically generated data analytics reports emailed straight to key decision makers. A clinical user group and managerial user group will ensure that the software meets the needs of end users. The project team aims to showcase how this software could be scaled up to harness the power of cancer data and enable efficiency, generate insight and ultimately improve patient care nationally.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: CANCER AND NEOPLASMS