NIHRDataInsights/HRCSData huggingface dataset:
Title: Chromosome segregation
Funder: The Francis Crick Institute

Abstract: Aneuploidy, i.e. missing or supernumerary chromosomes, is a hallmark of malignant tumour progression. A large number of genes that orchestrate faithful chromosome segregation during mitotic cell divisions are tumour suppressors or turn into potent oncogenes if misregulated. The aim of the Chromosome Segregation Laboratory is to investigate the function of these genes and the cellular mechanisms that safeguard accurate chromosome segregation. In particular, we are investigating the contribution of structural chromosomal proteins to sister chromatid cohesion and chromosome condensation, processes that ensure faithful segregation of centimetre-long chromosomal DNA molecules within micrometre-sized cells. We also investigate how the kinases and phosphatases of the cell division cycle machinery bring about ordered completion of chromosome segregation.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS
Title: Cellular signalling and cytoskeletal function
Funder: The Francis Crick Institute

Abstract: Our research focuses on understanding how signalling networks and the cytoskeleton regulate cytoplasmic transport, cell adhesion and cell migration, which are essential during the development and throughout the lifetime of multi-cellular organisms. To achieve our goals, we use Vaccinia virus as a model system. Intracellular pathogens, such as Vaccinia have co-evolved with their hosts to develop multiple mechanisms to hijack the many cellular processes of their unwilling host to facilitate their entry, replication, survival and cell-to-cell spread. Understanding how pathogens take advantage of their host offers the promise of obtaining fundamental insights into basic cellular processes that are frequently deregulated during pathogenic situations. To this end, we use a combination of quantitative imaging and biochemical approaches to study Vaccinia virus as a model system to interrogate the regulation and function of Src and Rho GTPase signalling, cytoskeletal dynamics, actin and microtubule-based transport as well as cell migration. Outside the context of vaccinia infection, we are investigating the cellular function of Tes, a component of focal adhesions and tumour suppressor that negatively regulates Mena-dependent cell migration. In addition, we also examine how different subunit isoforms impact on the actin nucleating activities and cellular function of Arp2/3 complex family members, as well as, the mechanisms regulating the assembly and function of invadopodia.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: DNA recombination, repair and cancer
Funder: The Francis Crick Institute

Abstract: Mammalian cells possess a large repertoire of DNA repair processes that maintain the integrity of our genetic material. But some individuals carry mutations in genes required for DNA repair, and this often leads to inheritable disease. An important repair process involves recombination, and defects in this process have been linked with cancer predisposition, in particular breast cancers caused by mutation of the BRCA2 gene, acute leukemias associated with Fanconi anemia, and a wide range of cancers found in individuals with the chromosome instability disorder known as Bloom’s Syndrome. The focus of our research is to determine the molecular mechanisms of recombinational repair, and to define why defects in these processes cause cancers. For several years we have been interested in the mechanisms of homologous recombination, how they contribute to the repair of DNA double strand breaks, and how they promote genome stability. Our work led us to show that the specialized chromosome segregation patterns of meiosis and mitosis, which require the coordination of recombination with cell cycle progression, are achieved by regulating the timing of activation of the two crossover-promoting endonucleases.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Oncogenes and tumour metabolism
Funder: The Francis Crick Institute

Abstract: Altered metabolism is one of cancer hallmarks. Metabolic changes are thought to provide tumour cells with a proliferation and survival advantage over healthy cells. However, these alterations can also make tumour cells selectively dependent upon certain nutrients and metabolic pathways, making tumour metabolism an attractive therapeutic target. One of the main challenges in designing efficient and specific anti-cancer therapies is tumour heterogeneity. Multiple factors contribute to metabolic heterogeneity of tumours. Both the genetic lesions and the tissue of origin are known to be critical factors that determine tumour cell metabolism. Each tumour can contain cells carrying different genetic lesions resulting in inter and intra-tumour metabolic heterogeneity. Furthermore, tumour cells interact with other cell types composing a tumour, including blood vessel cells, immune cells and tumour associated fibroblasts. All of these cells influence each others metabolism determining metabolic requirements and vulnerabilities of tumour cells and contributing to the metabolic heterogeneity. Last but not least, metabolism of cells in different tumour regions is influenced by differential supply of oxygen and nutrients throughout a tumour. The relationship between all these factors and their contributions to the metabolic requirements of different tumour types in the context of the whole organism remain largely unknown and are the focus of our research. Using stable isotopes (molecules carrying additional atoms of either carbon, nitrogen or hydrogen) and metabolomics analytical platforms, such as nuclear magnetic resonance, gas chromatography and liquid chromatography mass spectrometry, we are evaluating how metabolism is changed in tumours induced by different genetic lesions in different tissues. To be able to dissect the inter-tumour heterogeneity and metabolic interactions between different cellular components of a tumour we are employing mass spectrometry imaging modalities, MALDI, DESI and SIMS, which is done in collaboration with National Physical Laboratory (Josephine Bunch and Ian Gilmore). Once tumour-specific metabolic pathways identified we use genetic approaches to evaluate their requirement for different aspects of tumorigenesis including initiation, progression and metastasis. We further use stable isotope-based metabolomics approaches in vivo to evaluate the mechanisms underlying metabolic vulnerabilities and flexibilities of tumours induced by different genetic lesions in different tissues. Finally, in collaboration with Carlos Caldas’s group (Cambridge CRUK Institute) and Anna Grabowska’s group (Nottingham University) we evaluate the interaction between genetics, tissues of origin, cellular composition and metabolism in patient derived xenograft models of breast and lung tumours.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Small molecule inhibitors of the anti-apoptotic FLIP-FADD protein-protein interaction for the treatment of non-small cell lung cancer
Funder: Wellcome Trust

Abstract: In most organs and tissues, old cells are constantly dying and being replaced by new cells. This balance is critical for normal organ/tissue function and is maintained by a balance between new cells being created by cell division and old cells dying by a process known as "apoptosis". One of the key characteristics of cancers is that the old cells do not die efficiently by apoptosis and therefore accumulate giving rise to a tumour that ultimately disrupts organ function. This block in apoptosis is also a major problem when it comes to treating cancers as the effectiveness of chemotherapies and radiotherapies usually rely on their ability to activate this type of cell death. Dr Daniel longley's team at Queen's University of Belfast have identified an intra-cellular protein called "FLIP" that plays a critical role in preventing the death of cancer cells treated with chemotherapy and radiotherapy. This protein plays a prominent role in increasing the resistance to therapy in a number of types of cancer, including non-small cell lung cancer, which is a particularly drug-resistant cancer and is the focus of this proposal. The project team plan to generate drugs to block FLIP's function and thereby overcome drug resistance and improve the therapeutic management of patients with this disease.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: IMage-guided Pancreatic Ablation for Cancer Therapy (IMPACT)
Funder: Wellcome Trust

Abstract: Pancreatic cancer is a biologically aggressive cancer, which is resistant to chemotherapy and radiotherapy and has a high rate of recurrence. Surgical resection remains the only treatment with potential for long-term survival and cure. However, many patients have metastatic disease at presentation and a third have locally advanced pancreatic cancer, leaving only 10% - 20% suitable for potentially curative resection. Even after resection, recurrence is common and adjuvant chemotherapy is used but thermal ablation, which is established for palliation of other cancers, is not recommended for unresectable pancreatic cancer because of risk of injury to the pancreatic duct or nearby major blood vessels. This project will develop a patient-specific planning, simulation and intra-operative navigation system for individualised ablation and palliation of inoperable pancreatic cancer. We will investigate a new technique – irreversible electroporation ablation (IRE) – which causes cell death through a different mechanism to thermal ablation that can minimise damage to the pancreatic duct and major blood vessels. We will develop a navigation system so that accurate IRE electrode placement can be carried out percutaneously or under laparoscopic guidance. The potential impact of the project will be to prolong and increase the quality of life for a patient population with limited treatment options.


Research activity codes: 5.4 SURGERY
Health categories: CANCER AND NEOPLASMS
Title: Computer Aided Diagnosis Guided by Hierarchical Granular Computing
Funder: Welsh Government Office for Science

Abstract: The use of computer aided diagnostic systems (CAD), which are computer based tools for the automatic analysis of medical images such as mammograms and prostate MRI, can assist in the early detection and diagnosis of developing cancer, thereby providing better diagnosis opportunities for patients across the world. Typically, the scale of the data reflecting the information content in medical images is rather large, in terms of both quantity and dimensionality. As a result, the inevitable existence of redundant and noisy information will significantly decrease the diagnosis efficiency and accuracy. In such cases, advanced intelligent systems techniques are expected to be helpful, being capable of untangling poor factors inherent in the medical data, information or knowledge. Granular computing (GrC) offers a potential approach for building such advanced systems. In this project, GrC methods will be adopted to help discretise and partition medical image data in order to better capture and describe information entities, at different levels of information granularity. Such information granules are collections of entities that otherwise originate at the numeric grey level, which are arranged together due to their similarity, functional or physical adjacency, and medical indistinguishability or coherency. Through granulation, they can be more efficiently dealt with, in a block by block manner, within a CAD system. As the impact of the noisy data is diluted in such information granules, the quality of the decisions can be significantly enhanced. These strengths of the GrC techniques will aid in extracting the most appropriate information from medical images to develop effective CAD tools.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Polymorphism in the ERAP1 gene and its relevance to the prognosis and treatment of Cervical Cancer
Funder: Wessex Medical Research

Abstract: Natural genetic variation in a gene important for generating immunity to tumours could identify women at high risk of developing aggressive cervical cancer, and point the way to a new cancer therapy.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Role of the tumour microenvironment in cancer cell invasion and therapy failure
Funder: The Francis Crick Institute

Abstract: Our research is focused on understanding cancer invasion and therapy failure. Given the major effect of cancer invasion on mortality and morbidity there should be great benefits to be had if this process could be targeted pharmacologically. Further, acquired resistance to therapy is a huge problem with both cytotoxic and targeted cancer therapies. However, because both cancer invasion and therapy failure happen within the context of an organism, getting mechanistic data about the molecular basis of processes involved, as opposed to simply measuring the end-point of tumour growth/shrinkage, presents a formidable challenge. Our research combines genetic and molecular analysis of cell motility with state-of-the-art imaging technologies - particularly intravital microscopy and novel fluorescence-based probes and reporter genes - to visualise when and where signal pathways are active, and to test the mechanistic predictions of cell biology and tissue culture experiments. The work involves not only analysis of the tumour cells themselves but also their context; in particular, we are interested in the interplay between stromal fibroblasts, the extracellular matrix, and cancer cells. Our work in this area has revealed how cancer-associated fibroblasts promote cancer invasion via remodelling of the extracellular matrix, the presence of pathological heterotypic junctions between carcinoma cells and fibroblasts, and how melanoma-associated fibroblasts are activated by BRAF inhibitors and how this ultimately undermines the efficacy of the therapy. Over the next five years, we will continue to focus on cancer invasion and therapy responses, with an emphasis on integrating information over length scales up to millimetres and longer timescales associated with the development of acquired resistance. Our goal is to understand how the spatial and functional heterogeneity of cells within tumours is determined by the interplay between cell-intrinsic variation, cell-cell communication, and cell-matrix interactions. Crucially, we want to develop sufficient mechanistic understanding to identify new strategies that will re-shape tumours leading to reduced invasiveness and improved therapeutic responses.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Warwick-KU Collaboration on Domain-Invariant Artificial Intelligence for Robust Analysis of Pathology Images
Funder: Medical Research Council

Abstract: 1. Conduct an independent and cross-domain validation of two specific CPath algorithms, mitotic cell detection in breast cancer (BCa) and microsatellite instability or MSI detection in colorectal cancer (CRC), to investigate the effect of domain-shift on CPath algorithms; 2. Develop a framework for domain-invariant tissue representations and test the framework for the two algorithms at both ends; 3. Develop a web interface to collect external BCa and CRC histology images and to construct an enhanced dataset for testing and validation of the algorithms’ robustness; 4. Make the enhanced dataset publicly available for further research and development.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES;6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: CANCER AND NEOPLASMS
Title: Cancer - Using complex state-of-art mouse models of cancer to improve the understanding and treatment of human cancer
Funder: Medical Research Council

Abstract: Of all disease areas, cancer has one of the poorest records for converting preclinical leads into successful new therapies. Despite extensive investment and large consortia that have genomically profiled cancers, there has been a disappointing paucity of new step forwards in cancer treatments. The emergence of deep molecular phenotyping datasets of human cancers has however allowed the recent development of new models of certain cancers that recapitulate the human disease with increasing accuracy in terms of both their genetics and their transcriptional signatures. These few exemplars have highlighted the need for the scientific community to disease-position mouse models of cancer that will allow us to better understand the biology underpinning the major cancer types, generate novel targets and rigorously apply these to a therapeutic pipeline with better prediction to patient response. The Cancer Cluster will address this on a network scale, combining clinical, biological and computational expertise to undertake deep (molecular and spatial) phenotyping and disease-positioning, comparing across species and different cancers. In addition we will harness novel strategies (in harmonization with NMGN expertise) to create sophisticated models allowing for temporal regulation of gene activation; to model new cancer drivers; and target inhibition using protein degradation to more accurately align with future drug discovery efforts. Of key importance to our aims will be engagement with the UK network, achieved through the delivery of an easily accessible repository of fully phenotyped models, and the establishment of clinically relevant preclinical trials platforms based at the Mary Lyon Centre. Our cluster will work closely with academic, clinical and pharmaceutical partners to enable relevant preclinical trials, facilitating translation into new clinical trials throughout the course of this funding cycle.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Discovering inhibitors of gain-of-function Phospholipase C gamma1 for T-cell lymphomas
Funder: Medical Research Council

Abstract: "We propose to generate inhibitors to target gain-of-function PLCgamma1 variants in the context of dysregulated T-cell signalling, for the treatment of T-cell lymphoma. This is a relatively rare cancer, with dismal prognosis for more aggressive forms. A need remains for a selective agent that targets biology specific to these cells. This proposal is based on clinical insight provided by our team. Dr Lucy Cook is not only treating the patients but recently led a consensus for a best practice and has opened clinical trials while Professor Charles Bangham has the long-term involvement in defining the mechanism of leukaemogenesis in T-cell lymphoma (in particular ATL). Notably, the proposal also exploits our expertise in PLCgamma enzymes in physiology and pathology and a focus on structural and mechanistic aspects of their regulation, provided by the Katan team. Based on our recent structural insights (collaboration with AstraZeneca) and further characterization of the variants supporting a distinct conformation of gain-of-function proteins, we are in a leading position to take the proposed approach. This proposal also builds on our current, MRC-funded project (Assessing new therapeutic opportunities linked to TCR signalling in mature T-cell lymphomas with unmet need) led by Professors Katan and Bangham. Dr Richard Angell has participated in generating leads for a number of novel targets at UCL, including two Open Innovation collaborations with AstraZeneca. The team has extensive experience of working effectively with the AstraZeneca team. We propose to carry out a high throughput screen for PLCgamma inhibitors using the AstraZeneca proprietary compound library. Primary assay development has been completed by the Academic Partners (Dr Trevor Askwith, Dr Tom Bunney) and the downstream cascade assays identified. Small-scale reagent generation has also been performed and we are in a position to generate the reagents required for a high throughput screen."


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Senescence: Cellular senescence in cancer and ageing
Funder: Medical Research Council

Abstract: Senescence is a cellular stress response induced by oncogene activation, chronic inflammation, telomere erosion or DNA damage. Senescent cells activate a dynamic transcriptional programme leading to stable cell cycle exit, chromatin reorganization, metabolic reprogramming and the establishment of a senescence-associated secretory programme (SASP). The SASP allows senescent cells to communicate with their surrounding microenvironment and is thought to explain the many effects played by senescence in cancer and age-related pathologies. The goal of my research program is to elucidate the molecular mechanisms that implement and regulate senescence. We intend to exploit this knowledge to devise novel strategies that target senescence in age-related pathologies, especially cancer. To investigate senescence, we combine high-throughput screens and mechanistic analyses in cell culture, with in vivo analyses in mouse models. We then analyse clinical samples to uncover the relevance of our observations for human disease. My research programme has two overarching aims: (1) Uncover novel (epi)genetic mechanisms controlling senescence. We will use functional (CRISPR, RNAi and drug) screens, proteomic and genomics to identify trans factors and cis elements that control senescence and elucidate how they function. (2) Investigate how the SASP mediates the effects of senescence. We will perform screens to discover regulators and functions of different subsets of the SASP (e.g. pro- inflammatory or fibrotic) and use novel mouse models to uncover the roles of the SASP in ageing and disease. Connecting both aims, we will search for vulnerabilities of senescence. By better understanding how senescence is regulated and implemented, we expect that our research will inform therapies that harness senescence in cancer and ageing.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Targeting the complement system to improve radiation response
Funder: Medical Research Council

Abstract: Our lab studies how tumours exploit innate immune pathways to their advantage, using a combination of cancer patient data, in vitro experiments and in vivo models. We are particularly interested in how we can use these mechanistic insights to improve radiotherapy. Our most recent work has focused on the complement system, a central innate immunity pathway which we have found is frequently dysregulated in human cancers with poor prognoses. Importantly, our work suggests that, in response to radiotherapy, cancer cells may be particularly dependent on the functions of dysregulated complement for their survival. Indeed, pharmacological inhibition of certain members of the system can enhance the effects of radiation on the tumour. Intriguingly, our work also indicates that blocking certain members of the complement system can reduce side effects from radiotherapy. We are actively investigating the mechanisms underlying these beneficial effects. The ultimate goal of our research is to identify pharmacological targets that can improve the therapeutic index of radiotherapy and ultimately improve patient’s quality of life.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: CANCER AND NEOPLASMS