NIHRDataInsights/HRCSData huggingface dataset:
Title: Novel optimization framework for real-time automated radiation therapy
Funder: Science and Technology Facilities Council

Abstract: The World Health Organization estimates that over 8 million people die of cancer every year, around 70% of them in low and middle income countries. Radiation therapy (RT), a process whereby x-ray or particle beams are used to kill specific cells in cancer patients, is one of the most commonly used and cost effective ways to help treat cancer patients. It is estimated that over 50% of all cancer patients may benefit from receiving RT during the course of their treatment, either on its own or in combination with surgery, chemotherapy, hormonal therapy, or immunotherapy. However, the delivery of radiation therapy treatment plans is time consuming, involves cumbersome treatment planning systems (TPS), is expensive both in terms of personnel and infrastructure, and can be hampered by inaccurate computational models. This makes the delivery of high-quality and affordable treatment a challenging task globally, but also one which disproportionally affects low and middle income countries. Further, while the availability of RT centres in North America, Europe, Japan and Australia is generally adequate to cover current needs, similar coverage remains poor in Africa (34% of estimated need covered) and in the wider Asia-Pacific region (61%). As a consequence, the majority of the global population does not have sufficient access to appropriate cancer treatment. Unless addressed, this situation is expected to worsen further given that cancer incidence rates are projected to grow significantly in low and middle income countries over the next decade. As such, increasing the availability of high-quality cancer treatment, and of RT in particular, is recognized as a key global and societal challenge. Within this context, making RT more widely available, increasingly accurate, faster, and more cost effective, will play an important part in addressing this challenge. The delivery of high-quality radiation therapy relies on accurate treatment planning systems to create appropriate radiation treatment plans (TP) across a spectrum of different cancer types. Optimizing these TP can require considerable computational resources and is often personnel-intensive. In this project we will develop a fully-automated treatment planning system prototype based on advanced optimization techniques and remote supercomputing, thus addressing an important difficulty in deploying RT systems in challenging and remote environments. The system will make use of a range of cutting-edge computational and machine learning techniques to optimize the efficiency and robustness of treatment planning systems, with the view to reduce infrastructure and personnel costs in radiation therapy centres, and to provide more flexibility for use where expertise and large-scale computational resources may not be readily available.


Research activity codes: 5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Interleukin­6 as a therapeutic target in ovarian clear cell carcinoma
Funder: Target Ovarian Cancer

Abstract: Ovarian clear cell carcinoma (OCCC) responds very poorly to conventional chemotherapy and has significantly worse outcomes than high grade serous cancer (HGSC) in advanced and recurrent disease. The past four years have seen a significant improvement in the understanding of OCCC biology – in particular, the importance of ARID1A and PIK3CA mutations as potential drivers, and a key role for interleukin-­6 (IL-­6) signalling. Moreover, these abnormalities are also evident in endometrial clear cell carcinoma (ECCC), as well as renal clear cell tumours, suggesting a common pathogenesis. We have previously shown that inhibition of IL-­6 is safe in patients with ovarian cancer, and may have some therapeutic potential. However, our previous study focussed on patients with HGSC. In light of recent data, this project will focus purely on OCCC, using well-­characterised cell lines, xenografts and primary patient material from clinical trials to address three questions: 1. Does inhibition of IL-­6 have therapeutic potential in OCCC? 2. Is therapeutic efficacy improved by combining IL-­6 inhibitors and anti-­angiogenesis agents? 3. Why is IL-­6 elevated in OCCC and what is the link between IL-­6 signalling and ARID1A and PIK3CA mutations? The UK’s first OCCC-­specific trial (NiCCC) opened in August 2015, and associated translational sample collection is already funded. The project proposed here will allow usto address key biological questions, as well as providing an excellent adjunct to the NiCCC trial. The immediate goal is to generate sufficient data to support a phase II trial of IL-­6 inhibition in women with relapsed OCCC.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Translating our knowledge of the DNA damage response into clinical benefits for patients with ovarian cancer
Funder: Target Ovarian Cancer

Abstract: Treatment for advanced ovarian cancer is rarely curative; three quarters of patients with advanced disease relapse and ultimately die with resistant disease. Improving patient outcomes will require the introduction of new treatments and better patient selection. However, while many of the tests and treatments needed to achieve this goal are now available, they have yet to be fully integrated. This proposal sets out our plan to achieve this. A defective DNA-damage response (DDR) is a defining hallmark of high grade serous ovarian cancer (HGSOC). Indeed, current evidence indicates that all HGSOCs harbour a defect in a major DDR pathway. However, defective DDR is not mediated through a single mechanism but rather results from a variety of (epi)genetic lesions. Importantly, we have shown that ovarian cancer cells often have defects in more than one pathway. Moreover, our pilot data show that this results in differential sensitivity to both conventional chemotherapies and novel agents. Thus, if we are to apply a truly personalized approach towards treating GSOC, defining the DDR landscape in any given HGSOC will be necessary in order to facilitate appropriate selection of both existing and novel agents. To define the DDR landscape in individual HGSOCs, we have established a pipeline of ex vivo cell cultures and a panel of DDR assays. We now plan to apply this approach to analyse a large cohort of patients whilst also refining the methodology to develop clinically robust assays. Together, this will provide both the knowledge base and tool kit required to improve patient outcomes.


Research activity codes: 6.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: EDMONd – A feasibility study of Elemental Diet as an alternative to parenteral nutrition for ovarian cancer patients with inoperable Malignant bowel Obstruction
Funder: Target Ovarian Cancer

Abstract: Malignant bowel obstruction is common in patients with ovarian cancer and often inoperable. Nutritional support for patients with inoperable bowel obstruction (IBO) is challenging. Parenteral feeding (PN) is the recommended route however it is not widely available. Elemental diet (ED) provides nutrition in the form of amino acids and easily digestible nutrients that are almost totally absorbed in the upper small intestine. It could provide an alternative to PN. Aims The aim of the proposed research is to determine whether ED is an acceptable form of nutrition in patients with IBO. The study will assess whether ED: 1. Is tolerated – with regards to the taste, prevalence of nausea, episodes of abdominal pain and worsening of symptoms of obstruction 2. Has a positive impact on quality of life 3. Can meet some of the patients’ nutritional requirements Plan of investigation It is a mixed-method single arm feasibility study of 25 patients. Patients will be provided with ED-Elemental 028 Extra Liquid and followed-up for 2 weeks. Data on symptom experience, quality of life and nutritional intake will be collected from patients and carers. This research will provide evidence that will help to define the optimal management of patients with IBO."


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: CANCER AND NEOPLASMS
Title: Adult stem cell function in disease
Funder: The Francis Crick Institute

Abstract: Every organ harbours adult stem cells which have the potential for long-term replication, together with the capacities of self-renewal and differentiation. These stem cells function in tissue homeostasis and contribute to regeneration in response to injury. In addition, transforming mutations occurring in tissue-specific progenitor cells commonly cause cancers. Moreover, tumours are also organised in a cellular hierarchy, with the so-called cancer stem cells (CSCs) being at the apex. Our major focus is to elucidate the molecular mechanisms governing stem cell function during homeostasis and cancer. A typical example of our recent work is the characterisation of an adult mammary gland progenitor population. The mammary gland is composed of a complex cellular hierarchy with unusual postnatal plasticity. The identities of stem and progenitor cell populations, as well as tumour-initiating cells that give rise to breast cancer, are poorly understood We identified rare progenitor cell population in the adult murine mammary gland marked by the surface protein Lgr6. Lineage tracing analysis showed that Lgr6-positive cells are unipotent progenitors, which expand clonally during puberty but diminish in adulthood. Oncogenic mutations in Lgr6-positive cells resulted in luminal mammary gland tumours. Conversely, depletion of Lgr6-positive cells in the MMTV-PyMT model of mammary tumourigenesis dramatically impaired tumour growth. Thus, our recent work demonstrates that Lgr6 marks adult mammary gland progenitor cells that can initiate tumours, and that Lgr6 identifies CSC of breast tumours required for efficient tumour maintenance. The characterisation of the molecular differences between cancer stem cells and non-stem cells, may help identifying novel therapeutic strategies to eliminate breast cancer stem cells.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: The DNA damage response
Funder: The Francis Crick Institute

Abstract: DNA is a highly reactive molecule that is susceptible to damage. Fortunately, cells have evolved specialized repair processes that are remarkably efficient in correcting specific types of DNA damage. Failure to correctly repair DNA damage can drive mutagenic change, which can contribute to ageing and cancer. Indeed, defects in genes that repair DNA damage are the underlying cause of a number of hereditary ageing/cancer predisposition syndromes such as Fanconi anemia and Blooms. Arguably the most toxic DNA lesion in cells occurs when both strands of the DNA duplex is severed to produce a DNA double strand break (DSBs). These lesions can arise as a result of exogenous insults (such as exposure to ionizing radiation) but also occur endogenously from the collapse of replication forks. Moreover, programmed DSB are essential for generating the immune system during V(D)J and CSR recombination and for producing viable gametes for sexual reproduction during meiosis. Aberrant repair of mitotic DSBs is believed to be the major source of translocations and other complex structural variations in cancer whereas defects in meiotic DSB repair are a source of infertility in humans. My lab exploits a range of complementary experimental approaches to identify new DSB repair genes, define how they work in cells and the whole organism and operate at a molecular level. This includes genetic and phenotypic studies in C. elegans, mouse and human cells, proteomic approaches, biochemistry, single molecule biophysics and structural studies. We are particularly interested in the regulation and execution of DSB repair during DNA replication, meiosis and at telomeres and have established cutting-edge proteomic methods to identify novel factors that respond to and deal with stalled/reversed replication forks and dysfunctional telomeres. New factors that we have identified are often mutated in human diseases. We hope that our work will provide an improved understanding of how DNA repair works and how, when DNA repair is compromised, it contributes to cancer/ageing and or infertility disorders in humans.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Architecture and dynamics of macromolecular machines
Funder: The Francis Crick Institute

Abstract: A hallmark of cancer cells is genomic instability, arising from errors in the mechanisms that maintain gene copy number and chromosome ploidy. Our research aims to understand how macromolecular machines involved in DNA replication function to preserve chromosome integrity. To address these issues, we employ a combination of single-particle cryo-electron microscopy and biochemistry, to generate mechanistic models that explain the basis of key nucleic acid transactions. For example, we are interested in understanding how replicative helicases collaborate with the polymerases to couple DNA unwinding with DNA synthesis. By describing the architecture and dynamics of the DNA replication/recombination machinery, we seek to establish a molecular framework that explains how higher eukaryotes respond to DNA damage and how cell proliferation is regulated to avoid tumorigenesis.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS
Title: Wnt signalling pathway, intestinal stem cells and cancer
Funder: The Francis Crick Institute

Abstract: Wnt signalling is a highly conserved pathway that plays principle roles in stem cell biology and in cancer. For both, the intestine has emerged as a prime experimental model. In adult intestine, it is well established that Wnt signalling plays complementary roles in physiology and pathology: it maintains crypt stem cell compartments and when activated by mutation, it is the cause of colon cancer. We study how Wnt pathway is regulated in intestinal stem cell and cancer development. Our goal is to translate the basic stem cell research to the clinic to aid cancer treatment and regenerative medicine. To achieve this, we study the Wnt pathway regulation along two complementary aims: 1 How is the Wnt signal gradient regulated during intestinal stem cell homeostasis? We aim to identify the Wnt repressive mechanism in the normal intestinal crypt by expression profile analysis of the intestinal stem cells. We will screen for genes that will potentially inhibit Wnt signalling and/or stem cell gene expression; 2 What is the Wnt activating mechanism in colorectal cancer (CRC)? We aim to identify the Wnt activating mechanism in APC-mutated and non-APC mutated CRCs. Following my recent findings on physiological Wnt pathway activation, we will further study how APC mutation inhibits β‐catenin ubiquitination. For non-APC mutated CRC, we hypothesized that deregulation of Wnt pathway inhibitors is the Wnt activating mechanism. We aim to identify novel Wnt inhibitors from expression analysis of CRC cohort and study their functions both in vitro and in vivo; For the pursuit of these aims, our experimental strategy will lean heavily on the generation of conditional knock‐in/knockout mice, bioinformatics, lenti‐virus infection‐coupled 'minigut' cultures, live‐imaging, proteomics and high-throughput sequencing (RNA-seq and ChIP‐seq). Together, we aim to generate a more complete picture of Wnt pathway, as it controls the biology of intestinal stem cells and CRC. The data generated by aim 2 will potentially provide novel insights for therapeutic development. In the lab, we culture intestinal organoids (also named as ‘mini-gut’ culture) that are essentially stem cell culture. They grow 3-dimensionally in Matrigel to form intestinal crypt-villus budding structures with full self-renewal and differentiative potential. The indefinite and fast growing properties of the organoids provide the ideal cell source for regenerative medicine. In an independent collaborative project, we received the H2020 consortium funding to work on the intestinal tissue engineering project to treat irreversible intestinal failure patients. Our goal is to engineer functional intestinal constructs using our intestinal organoids for regenerative medicine such as orthotopic transplantation and drug testing.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Tumour-stroma interactions in cancer development
Funder: The Francis Crick Institute

Abstract: Aim and importance of the research The Tumour Host Interaction laboratory studies solid tumours (mainly breast, but also skin and lung cancer) in animal models focusing on the comprehensive analysis of cell–cell interactions within the entire tumour heterogeneity. The lab focuses on the surrounding normal tissue cells that associate and functionally become part of the tumour mass. The host build the tumour microenvironment or niche which represents the cellular environment of cancer cells. The tumour niche contains a plethora of cell types that act in concert to support the tumour structure. My lab studies the changes that cancer imposes on host tissue cells locally as well as the systemic changes that via the inflammatory cells extend to distant tissue. We study how those new environments support tumour growth and progression. Our aim is to identify and target these key tumour-host interactions to enhance anti-cancer therapies. We investigate these questions using a combination of mouse genetic model and ex vivo co-culture systems. Translational activities My laboratory has identified a novel activity of systemically mobilized mature neutrophils within the pre-metastatic niche. We found that via the release of leukotrienes, pre-metastatic neutrophils selectively support the more metastatic subset of cancer cells infiltrating the distant tissue. Indeed, an inhibitor of leukotriene production reduces metastasis in vivo providing a strategy to block niche signal to reduce metastatic spreading (Wculek & Malanchi Nature 1–21 (2015)). The translational team of The Crick Institute in collaboration with prof Charles Coombes (Imperial College) is helping me to test a leukotrienes inhibitor drug on a sub-set of breast cancer patients at high risk for secondary relapses.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Structural biology of growth factor signalling and cell polarity
Funder: The Francis Crick Institute

Abstract: Our overall research aim is to understand the structural biology underlying the assembly and activation of growth factor signalling complexes. Growth factor pathway deregulation is a hallmark of cancer and is frequently associated with altered catalytic functions of pathway components. To tackle these large and challenging membrane-associated assemblies, we use multiple structural methods (crystallography, EM and SAXS), biophysical methods (calorimetry and fluorescence polarisation), enzymatic and cell-based assays. We also collaborate with cell biologists and medicinal chemists both within and outside of the LRI. Our current and future research activities are directed at understanding structural aspects of three signalling areas; 1. Cell surface receptor activation and oncogenic deregulation 2. Polarity signalling assemblies at the plasma membrane 3. Rho-actin signalling from the plasma membrane into the nucleus


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Cell biology of the tumour microenvironment
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.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Cancer evolution and genome instability
Funder: The Francis Crick Institute

Abstract: TRACERx is a prospective observational cohort study in primary NSCLC. 842 patients with stage I-IIIA NSCLC will be recruited and followed up for 5 years. TRACERx will allow the investigation of the NSCLC genomic landscape between primary and metastatic sites and the evolutionary dynamics of intratumour heterogeneity over time combined with detailed clinical, histopathological and cancer phenotypic annotation for each patient, in order to significantly improve the outcomes of NSCLC patients (e.g. reduce their chance of recurrence and improve survival). The primary objectives are to define the relationship between intratumour heterogeneity and clinical outcome (disease-free survival and overall survival) following surgery and adjuvant therapy (including relationships between intratumour heterogeneity and clinical disease stage and histological subtypes of NSCLC). In addition, we aim to establish the impact of adjuvant platinum-containing regimens upon intratumour heterogeneity in relapsed disease compared to primary resected tumour. Secondary endpoints include: • Development and validation of an intratumour heterogeneity ratio index ITB as a prognostic or predictive biomarker in relation to its association with DFS and OS • Infer a complete picture of NSCLC evolutionary dynamics: Define drivers of genomic instability, metastatic progression and drug resistance by identifying and tracking the dynamics of somatic mutational heterogeneity, and chromosomal structural and numerical instability present in the primary tumour and at metastatic sites. Individual tumour phylogenetic tree analysis will: a) Establish the order of somatic events in relation to genomic instability onset and metastatic progression b) Decipher genetic “bottlenecking” events following metastasis and drug therapy c) Establish dynamics of tumour evolution during the disease course from early to late stage NSCLC. • Initiate a longitudinal minimally-invasive circulating tumour cells (CTC) and cfDNA biobank to develop analytical methods for the early detection and monitoring of tumour evolution over time. • Develop a longitudinal tissue resource to serve as a platform to assess the relationship between genetic intratumour heterogeneity and the host immune response.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS