NIHRDataInsights/HRCSData huggingface dataset:
Title: “Using the force”: An investigation into the perception of stiffness in CTLs and its importance in activation and killing in cancer.
Funder: Wellcome Trust

Abstract: Cytotoxic T lymphocytes (CTLs) are important agents of immunity responsible for clearance of infected or malignant cells. The understanding of their activation is incomplete. Recent advances have unveiled their ability to sense the stiffness of the opposing surface, with stiffer surfaces resulting in larger forces being transmitted to the CTL, promoting activation, leading to CTL-mediated killing of the target cell. Furthermore, decreased stiffness of malignant cells has been observed and posited as an avenue for their evasion of the immune system. I will create cell lines in which intracellular stresses can be visualized with state-of-the-art microscopy via force probes. I will activate CTLs to varying degrees and measure the effect on the force probes. I will knock out cytoskeleton-associated genes in order to screen for genes that are involved in CTL force perception. Interactions between T cells and target cells of manipulated stiffness will also be investigated as a means of understanding the role of target cell stiffness in malignant immune evasion. A final screen will be performed to identify gene mutations associated with this immune evasion in target cells. This work will broaden our understanding of T cell function and provide us with useful avenues for cancer immunotherapy.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS
Title: A novel anti-tumour tri-specific engager to promote T cell and NK cell activation within the tumour microenvironment
Funder: Wellcome Trust

Abstract: Antibodies are proteins, naturally produced by the immune system, that bind other molecules. This interaction can block the function of the bound molecule and is exploited in anti-tumour treatments. For instance, antibodies can block immune inhibitory receptors. These receptors are responsible for stopping the immune system from killing infected cells and cancer cells. For various reasons, some cancer patients do not respond to treatments with antibodies. Some can be attributed to the relatively large size of antibodies and the presence of immune inhibitory molecules within the tumour.The aim of our project is to develop a new anti-tumour treatment to unleash the capacity of the immune system to attack and kill cancer cells. Our goal is to use genetic engineering to design small antibody proteins that can bind more than one distinct immune inhibitory receptor simultaneously. By doing this, we aim to restore the natural ability of the patient to recognise and eliminate tumour cells.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: “Investigating regulatory landscapes in oesophageal adenocarcinoma”
Funder: Wellcome Trust

Abstract: Oesophageal cancer is the 14th most prevalent cancer and the 7th most common cause of cancer death in the UK. Oesophageal Adenocarcinoma (OAC) is the most common subtype within Western populations. A poor understanding of the disease drives poor patient outcomes.The disease is thought to arise from a pre-cancerous state known as Barrett’s Oesophagus (BO). Changes in the regulation of transcription and chromatin environment have been identified in the transition from regular oesophageal tissue to BO to OAC. This includes evidence of reversion to an embryonic developmental cell state. Additionally, Little is known about the changes in gene regulatory networks and chromatin environment which initiates and maintains metastatic cancer state. I will use functional genomics approaches to identify elements which play a role in transcriptional regulation such as enhancers, super-enhancers and silencers. This will include developing bioinformatics methods to scale up existing unsupervised clustering methods and experimentally validating bioinformatics results e.g. endogenous reporter assays for enhancers. I will compare the regulatory landscape in regular and metastatic OAC, and embryonic tissue from the oesophagus, stomach and duodenum. This will help elucidate the origins of OAC and molecular drivers of OAC metastasis and provide bioinformatics tools potentially applicable to other diseases.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS
Title: Modelling the impact of increased extracellular matrix stiffness on mammary epithelial cells
Funder: Wellcome Trust

Abstract: Mammographic density (MD) refers to the proportion of the breast occupied by radiographically dense tissue, as assessed by mammography. It has been shown that women with significantly higher MD are four times more likely to develop breast cancer than those with predominantly radio-lucent tissue. High MD is associated with increased stiffness of the stromal extracellular matrix (ECM) surrounding the breast epithelial ducts. Despite a clear mechanistic link between ECM stiffness and breast cancer risk, little is known about how mammary epithelial cells (MECs) sense and respond to the altered mechanical properties of the surrounding microenvironment.We want to understand how MECs within the duct mechanically sense altered stiffness of their surrounding ECM by using 3D culture models combined with mathematical modelling. We will utilise 3D traction force microscopy (TFM) to measure the forces on MECs within a 3D ECM model of tuneable mechanical stiffness. We will use these observations, alongside other biological readouts, to parameterise an individual-cell based mathematical model of a 3D acinar structure. We will develop this model to provide quantitative predictions enabling mechanistic insight into the behaviour of MECs and the link between high mammographic density and increased breast cancer risk.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Understanding how BCL3 promotes homologous recombination in colorectal cancer cells
Funder: Wellcome Trust

Abstract: Background: Colorectal cancer (CRC) patients often present at clinic with advanced disease (where the tumour has spread) making it more difficult to treat. Rectal cancer patients are treated with chemotherapy and radiotherapy (CRT) prior to surgery, although response is variable and patients who do not respond have a worse prognosis. The aim of this work is to improve the response of CRC patients to therapy. Previous work from our laboratory suggests tumours with high levels of the BCL-3 protein are less responsive to CRT because BCL-3 promotes DNA damage repair, allowing the cancer cells to become resistant to DNA damaging therapy.Approach: I aim to investigate how targeting BCL-3 levels inhibits DNA repair, leading to sensitization of cancer cells to therapy. We will study the effect of BCL-3 on the density of DNA (which can modify repair processes), and identify which proteins interact with BCL-3 when DNA is damaged to understand the mechanism. We will test the suitability of BCL-3 as a therapeutic target, using a small molecule BCL-3 inhibitor to treat colorectal cancer models.Impact: This work will help us understand the link between BCL-3 and therapeutic resistance, and the validity of BCL-3 as a therapeutic target for CRC.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Utilization of limited resources to improve equity in breast cancer outcomes in the South African public health sector.
Funder: Wellcome Trust

Abstract: South Africa, like most developing countries, has a burden of breast cancer characterised by late presentation and high mortality rates. It has the highest level of wealth inequality in the world, which is accompanied by inequalities in health, including cancer inequalities. These inequalities need to be addressed to achieve the goal of reducing within country health inequalities associated with the Sustainable Development Goal 10 (SDG 10) for which South Africa is a signatory. We will construct a mathematical model which illustrates the impact of various interventions that can be implemented in improving breast cancer outcomes. The proposed interventions will only utilize available resources in the country. We will use information obtained from the literature, a local dataset and informal stakeholder consultation to inform and populate the model. We expect to produce a model that can be used in decision making to predict the impact of interventions in reducing breast cancer inequalities in South Africa and possibly in sub-Saharan Africa. The research will contribute to the body of knowledge on the modelling of breast cancer inequalities in a resource constrained setting.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: CANCER AND NEOPLASMS
Title: CRUK/17/015 CEDAR: Chemoradiation with Enadenotucirev as a radiosensitiser in locally advanced colorectal cancer
Funder: Cancer Research UK

Abstract: Background Between 2010-12 11,567 people in the UK were diagnosed with rectal cancer. The use of radiotherapy, especially in combination with chemotherapy (CRT) and/or surgery is standard of care in locally advanced rectal cancer (LARC). Efforts to intensify local treatments to achieve better response have failed, due to increased toxicity. Additional chemotherapeutics, such as oxaliplatin or irinotecan have not meaningfully improved outcomes, whilst concurrent biologic therapies have shown, in part, promising results at the expense of increased toxicity. One explanation is that radiosensitisation remained unchanged. Oncolytic viruses are novel anticancer agents that target, selectively replicate in and kill cancer cells, spreading through the tumour microenvironment, generating local and systemic immune response both to themselves as well as dying tumour. Enadenotucirev (EnAd) is a tumour tropic type Ad11pAd3 chimeric adenovirus. The low level pre-existing immunity enables this agent, uniquely, to be given intravenously in order to target both primary and metastatic legions and is currently undergoing Phase I/II trials in a range of epithelial tumours. Intracellular replication of an adenovirus suppresses DNA repair pathways used by cancer cells to repair radiation induced damage. There are 5 pre-clinical publications exploring the utility of adenovirus combined with radiotherapy. All show significant synergy with between a 5 to 10-fold increase in response. The published, combination, clinical trial data across a range of solid organ malignancies demonstrates consistent findings improved response rates and the absence of toxicity. All the constructs were limited to intratumoral injection, however. This obstacle is overcome by EnAdenotucirev. Aims The primary outcome is to determine the safety, toxicity profile and MTD (or phase II dose if MTD not reached) of Enadenotucirev, administered concomitantly with neoadjuvant CRT for locally advanced rectal cancer. Secondary outcomes are the response rate of Enadenotucirev in combination with standard CRT on imaging by MRI tumour regression grade and on surgical specimen. Translational work will seek to confirm proof of concept through gene expression profiling of tumour immune infiltrates and DNA damage genes, of on treatment biopsies and post treatment resection specimens. Methods This is phase I study. Statistical design is a Bayesian continuous reassessment method (CRM) for adaption to observed toxicity, with efficacy modelling built in. Target recruitment is 30 patients. How results of research will be used The results of the trial will inform a dose schedule for dose expansion/Phase II trial to determine the efficacy and response.


Research activity codes: 6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/14/035 T-SCALOP2: Prospective sample collection in the SCALOP2 trial
Funder: Cancer Research UK

Abstract: Background: Locally advanced non-metastatic pancreatic cancer (LAPC) has poor prognosis with a median survival of approximately 10 -12 months. The CRUK funded SCALOP2 will randomise patients to induction chemotherapy consisting of combination of Gemcitabine and nab-Paclitaxel followed by randomisation to 1) continuation of the same regimen 2) conventional chemoradiation (CRT) (capecitabine +50.4Gy/28 fractions) 3) conventional CRT + nelfinavir 4) high dose CRT (capecitabine +60Gy/30f) and 5) high dose CRT + nelfinavir. A total of 262 patients will be entered into the study from upto 40 centres within the UK allowing 170 patients to be randomised to the 5 arms following initial chemotherapy (35% unlikely to be eligible for CRT due to toxicity/disease progression). Because of its location and relationship to critical structures, it is often difficult to acquire large biopsies, and the diagnosis is often made on cytological or radiological grounds. T-SCALOP and T-SCALOP2 studies are therefore focussing on developing blood-borne biomarkers for tumour detection and response prediction. Aims: To develop and validate novel tumour markers to allow early detection of cancer and for monitoring response to treatment. Correlation of circulating tumour DNA with contemporaneous tumour material To identify circulating markers which will allow us to predict which patients are likely to respond to nelfinavir and other anti-hypoxia therapy Methods: In addition to residual tumour tissue from diagnostic biopsy, research blood will be collected from patients at trial entry, start of CRT, 4-6 weeks after CRT and at progression. A sub-study in selected centres will also collect additional tumour material at progression. We will: (1)Compare tumour DNA (from EUS biopsy) with circulating cell-free plasma DNA (cpDNA) to determine whether blood borne biomarkers can be used as surrogate for primary tumour. (2)Determine whether alteration in the levels of specific somatic events such as mutations in KRAS and p53 or methylation of RASSF1A correlate with benefit of a given intervention. (3)Evaluate plasma biomarkers related to hypoxia before and during nelfinavir treatment and correlate with clinical outcome. The preparatory work testing the feasibility of the methods outlined above is already underway using the samples from the SCALOP trial. Application of this research: T-SCALOP and T-SCALOP2 aims to develop and validate blood borne markers for early detection of pancreatic cancer and predictive biomarkers for response to a specific type of therapy.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS;4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: Applying human genetics to interrogate the role of the human gut microbiome in cancer aetiology
Funder: Cancer Research UK

Abstract: Background Evidence from humans and model organisms supports relationships between the gut microbiome – a complex system of microorganisms aiding digestion, providing protection against pathogens and creating essential metabolites – and cancer aetiology. However, human studies in this context have been largely observational and suffer confounding, biases and reverse causation, limiting their ability to offer convincing causal evidence. The integration of human genetics within population health sciences has proved successful in facilitating improved causal inference (e.g., Mendelian randomization [MR]) and characterising inherited susceptibility for outcome risk assessment. The former exploits properties of human genetic variation that approximate those of “instruments” to estimate the causal effect of a trait on health outcomes (i.e., the gut microbiome on cancer) and the latter uses aggregate genomic information to assess differential risk for lifecourse health outcomes. Initial genome-wide association study (GWAS) results have enabled the application of MR to assess the impact of the microbiome on various outcomes; however, there is an unmet requirement for careful examination and interpretation of derived causal estimates and host (i.e., human) genetic effects. Aims With the Cancer Research UK Population Research Postdoctoral Fellowship, I will interrogate the causal role of the human gut microbiome in cancer aetiology and the value added in this context by human genetics. I will gather and appraise host microbiome-related genetic variation and apply contemporary causal inference methodologies to challenge the role of the gut microbiome in cancer aetiology (OB1), examine the likely effects of reverse causality in these relationships (OB2) and assess the association between genome-wide predictors of the gut microbiome and cancer risk outside causal framework analyses (OB3). Methods Analyses will be performed using available GWAS summary-level data and individual-level data from cohort studies (the Flemish Gut Flora Project, Avon Longitudinal Study of Parents and Children, and UK Biobank). Triangulating with evidence from epidemiological and basic sciences, I will use established and novel techniques to assess the validity of integrating human genetics in microbiome research, interrogating their appropriate implementation for appraising causality in cancer aetiology. How the results will be used I will position the field by providing clarity on the role of the gut microbiome on cancers implicated in the literature but with little causal assessment. This will have implications for the evaluation and design of targeted strategies for cancer prevention. Findings will provide an evaluation of the utility of human genetics with microbiome data, refining current applications in cancer research.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: CANCER AND NEOPLASMS
Title: Harnessing adenovirus vector induced memory inflation for cancer-antigen specific immunotherapy in vivo
Funder: Cancer Research UK

Abstract: Background Treatments to expand or activate anti-cancer cytotoxic T cells, key players in tumour control, have improved clinical outcome, but are only partially effective and may be used in only a subset of tumours. Simple, targeted and broadly applicable methods to generate a functional anti-tumour CD8 T cell response would have a huge impact. We have developed a platform based on a disabled virus that allows us to generate large populations of a given tumour antigen-specific CD8 T cell that are long-lived, functional, and home to tumours, making them very suitable to combat cancers. Studies in 3 different pre-clinical tumour models demonstrate that immunization with these constructs induced large populations of cancer-specific cells which are long-lived, high magnitude and importantly, control tumours in prophylactic and therapeutic challenge settings. Crucially, immunization synergized with checkpoint immunotherapy to improved tumour control. Aims To have clinical utility, this strategy will need to be translated into a viral vector with low seropositivity in the general population. The study will explore whether this may be translated into a related but rare serotype replication-deficient viral vector. We will test if immunization with a panel of these vectors, encoding discrete anti-tumour T cells antigens will provide an effective broad and targeted T cells response which could combat a range of tumour types reliably with maximal impact. Importantly, we will also collaborate with a new Oxford-based biotech, Ervaxx, and use these findings to help in the vector design of a small subset of novel human antigens destined for human clinical trials in order to establish optimal immunogenicity. Methods A syngeneic tumour model will be used to translate the approach into a clinically useful vector. Flow cytometry, including tetramer/pentamer staining, surface and intracellular cytokine staining and ELISPOTs will track and phenotype the vaccine-raised T cells. In vivo challenge by subcutaneous implantation of tumour cells will assess the efficacy of immunization. For the novel human antigens, the antigen-specific T cell response will be characterized using methods described above – furthermore, mass spectroscopy experiments will be conducted after immunization of a panel of antigens to determine the levels of targeted antigens which are actually presented by MHC Class 1 on the cell surface. How the results of this research will be used The human antigens identified are destined for human clinical trials - the outcome of this research will provide a translational pathway for further development in the context of cancer therapy.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: RNAi, cancer, non-coding RNAs
Funder: Cancer Research UK

Abstract: Our attention has historically been focused on four major areas. First, we have worked for the past 15 years on understanding the biological functions of non-coding RNAs and the mechanisms by which these RNAs act. Most recently, we have worked extensively on a small RNA based innate immune system, the piRNA pathway, and its role in protecting germline integrity in animals. Secondly, we attempt to tackle critical problems in cancer biology, with a major focus on breast and pancreatic cancer. We use mouse models, human tissues, and innovative approaches to understand aspects of disease ranging from the genetics of early, non-invasive cancers to critical pathways driving metastasis. We also work to understand the roles of long non-coding RNAs in normal development and how their functions might be disrupted in cancer. Building from our observations that small RNAs direct DNA methylation during germ cell development in animals, we have developed a broader interest in epigenetic regulation, both in normal cell and in cancer. Finally, have a long history of technological innovation, having developed approaches such as short hairpin RNAs (shRNA) and exome capture. Current technology development is occurring in several areas including mining information inherent in tumor heterogeneity, optimization of crispr-based strategies, and building general platforms for control of biological processes by light.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS