NIHRDataInsights/HRCSData huggingface dataset:
Title: Endothelial scavenger receptors shape the immune microenvironment in hepatocellular carcinoma
Funder: Cancer Research UK

Abstract: Hepatocellular cancer (HCC) is a major cause of cancer related deaths worldwide and the number of cases in the UK is rising dramatically. Licensed medical therapy for this cancer only extends median survival by a few months. 90% of patients with HCC have an underlying chronic liver disease and therefore inflammation and fibrosis that accompany liver disease are crucial factors in the development of HCC. For HCC to develop and grow in this microenvironment it needs to evade the immune system, yet the underlying mechanisms are poorly understood. The endothelium is the gatekeeper to immune cell trafficking and my pilot work on the scavenger receptors stabilin-1 and mannose receptor (MR) demonstrates that they are highly expressed on the endothelium of HCC. I have previously shown that stabilin-1 regulates the immune microenvironment by recruiting immunosuppressive regulatory T cells (Tregs) across liver endothelium and pilot data now demonstrates that stabilin-1 expression correlates with high Treg accumulation in HCC. I hypothesise that stabilin-1 and MR provide a link between the endothelium and an immunosuppressive niche for HCC to develop and grow in chronic liver disease. Aims 1) To understand how stabilin-1 and MR directly promote immunosuppressive lymphocyte recruitment across tumour endothelium in HCC. 2) To define the role of scavenger receptor mediated endothelial pathways in the recruitment of immunosuppressive lymphocyte subsets in HCC. 3) To assess if blocking scavenger receptors as well as directly targeting their downstream endothelial pathways in models of HCC inhibit tumour growth. Methods I will use primary HCC endothelium in flow based adhesion assays which allow me to study the recruitment of T cell subsets under physiological conditions of shear stress. Stabilin-1 and MR function will be elucidated by using blocking antibodies, siRNA and competition assays with other scavenger receptor ligands. Preclinical models of HCC in the setting of stabilin-1 and MR knockout/inhibition will be used to understand the impact of these scavenger receptors on liver tumour development. I will also use models where relevant endothelial pathways are directly inhibited to explore the underlying mechanisms of lymphocyte recruitment to the tumour microenvironment. These experiments aim to identify stabilin-1 and MR as molecules which drive the resistant tumour microenvironment seen in HCC. This fellowship will determine the mechanisms by which these scavenger receptors regulate HCC growth and the best therapeutic approach to using scavenger receptor directed therapies in solid organ tumours.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Dissecting glioblastoma invasion: from mutation-driven mechanisms to glioma stem-like cell biology
Funder: Cancer Research UK

Abstract: Background Glioblastoma (GBM) are deadly brain tumours, for which there is no adequate treatment. A leading cause of therapeutic resistance is the diffuse invasion of the tumour cells into the surrounding brain parenchyma, predominantly along blood vessels, which limits efficacy of surgery and radiotherapy. Emerging evidence suggests that invasion might be driven by glioma stem-like cells (GSC), the chemoresistant tumour propagating GBM compartment, which is thought to underlie tumour regeneration following treatment. An additional obstacle to therapy, is the molecular heterogeneity of GBM, which comprise three main molecular subtypes, associated with distinct mutations and signalling alterations, highlighting the need to tailor treatment to underlying genetics. Therefore, understanding the mechanisms of perivascular invasion, how they are driven by subtype-specific genetic alterations and the contribution of GSC to this process is crucial for the development of more effective therapies for this devastating disease. We developed robust mechanistic assays to study perivascular invasion in vitro and in vivo and identified Eph/ephrin signalling as a key mediator of GSC perivascular invasion and ephrin-B2, specifically, as a potential anti-invasion target in the mesenchymal GBM subtype. Aims Building upon these findings, the aims of this proposal are to: 1) systematically assess the role of ephrin-B2- and other Eph/ephrin-dependent mechanisms of perivascular invasion across GBM subtypes; 2) identify additional mediators of GSC/vascular interactions and link them to underlying mutations; 3) characterise the cell biology of GSC within the invading tumour front during progression and recurrence. Methods We will generate genetically-defined GSC and de novo tumours that model all three main human GBM subtypes by viral delivery of subtype-specific mutations in murine neural stem cells in vitro or into the lateral ventricles in vivo, respectively. In vitro engineered GSC will be used to dissect Eph/ephrin-dependent mechanisms in our established assays, which combine co-culture systems with intravital imaging of GSC/vascular interactions in syngeneic mice. Identified mechanisms will be validated in intracranial xenografts of well-characterised primary human GBM-derived GSC lines. Novel mediators will be identified by gene expression profiling of invading tumour cells acutely FACS-sorted from the de novo tumours. The cell biology of the invasive front will be studied by coupling analysis of human samples and de novo mouse tumours with intravital imaging of the invading tumour front. The results of this research will be used to identify, mechanistically assess and validate novel anti-invasion targets with a view to devise molecularly-targeted strategies to overcome therapeutic resistance in GBM.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/15/008:Myeloma XII-A phase III study to determine the role of ixazomib as an augmented conditioning therapy in salvage autologous stem cell transplant (ASCT) and as a post-ASCT consolidation and maintenance strategy in patients with relapsed multiple myeloma (supported by Stand up to Cancer)
Funder: Cancer Research UK

Abstract: BACKGROUND: The NCRI Myeloma X trial defined a new standard of care for patients with myeloma at first relapse. The use of a salvage high dose chemotherapy/autologous stem cell transplant (ASCT) demonstrated a clear advantage in terms of durability of response. However, though the depth of response to a salvage ASCT was similar to first-line ASCT, the durability was less. Therefore, there is a need to build upon the results of Myeloma X by examining the impact of augmenting the conditioning regimen of the salvage ASCT, and determining whether the use of post-ASCT consolidation and maintenance can improve the durability of a salvage ASCT. AIMS: The study aims to re-induce relapsing disease following a prior ASCT with a novel oral proteasome inhibitor combination, before determining the impact of augmenting high dose melphalan on depth of response through a first randomization. The impact of a consolidation/maintenance strategy on the durability of response (TTP) will be examined through a second randomization. Exploratory end-points will complete this composite phase III clinical intervention study. METHODS:This phase III study has 2 randomization steps. The first will compare a standard high dose melphalan ASCT with a high dose melphalan augmented by a proteasome inhibitor, the primary end point wil be improvement in depth of response (VGPR). The second randomization will examine the impact of a consolidation and maintenance schedule compared to no consolidation/maintenance schedule on the durability of response, as determined by TTP. The trial will stratify patients on key parameters at each randomization and incorporating both molecualr risk stratification (FISH) and MRD assessment (by flow cytometery)in the delineation of progress through the clinical interventions. IMPACT: The influence of the outcome from this study on international clinical practice is significant. There is the potential to not only determine the impact of a novel oral re-induction regimen, but to define what is the best way to conditioning a salvage ASCT, whilst defining the role, if any, that post ASCT therapy may have on the durability of such responses. This defined therapeutic intervention has the potential to significant affect overall survival in selected patients with first relapsed disease.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: The heme oxygenase-1 expressing perivascular macrophage subset as a non-redundant facilitator of cancer progression
Funder: Cancer Research UK

Abstract: Background: Tumour associated macrophages (TAMs) are a heterogeneous collection of cell phenotypes, with specialised effector functions that are dictated by the microenvironment in which they reside. The prevalence of TAMs is a poor prognostic factor in a variety of cancers, but the key functional TAM phenotypes which contribute to cancer progression are still being resolved. There is growing evidence that macrophages which reside in close proximity to blood vessels, termed perivascular macrophages, play a fundamental role in vasculature function. We hypothesise that a specialised subset of perivascular TAMs represents a non-redundant facilitator of cancer progression. Aims: We will investigate this subset of perivascular TAMs, their biology, development and cellular interactions to elucidate their role in cancer progression. We will compare and contrast these cells to those in healthy tissues and cutaneous wound healing, an inflammatory site which shares a stromal reaction similar to cancer, to further our understanding of the role of these cells and establish how to most effectively modulate the population therapeutically. The relevance of these observations will be studied in human cancer. Methods: We will utilise the spontaneous MMTV-PyMT murine model of breast cancer for this study. We will use RNA sequencing, flow cytometry and imaging mass cytometry to investigate the subset of perivascular TAMs. Using in vivo models alongside an in vitro endothelial monolayer trans-well assay we will investigate the mechanism of action of these cells. We will use a reporter mouse that we have generated to permit the ex vivo isolation of the perivascular TAM subset for transcriptomic analyses and in vivo study of the development, dynamics and functions of this population in the perivascular space. How the results of this research will be used: We will use these data to propel our knowledge of the basic biology of this perivascular TAM subset, their mechanistic role in tumour progression and establish these cells as a therapeutic target in cancer.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Defining the contribution of 53BP1 to tumour suppression and oncogenesis
Funder: Cancer Research UK

Abstract: Background: Although inactivated by mutation in many cancers, p53’s tumour suppressor role can also be abrogated by the amplification and overexpression of its inhibitor MDM2. For this reason, p53-reactivation in tumours of wild-type p53 status through MDM2-inhibition is an attractive therapeutic strategy, which led to the development of MDM2-targeting compounds. One such compound is Nutlin-3, a small-molecule that binds MDM2, causing p53 stabilization and activation. Nutlin-3 exerts potent anti-proliferative properties in cancer cells with wild-type p53 status, and confers strong antitumour effects in xenograph models. Recently, 53BP1 was identified in a loss-of-function genetic screen designed to reveal components of the p53 network that cause Nutlin-3 cytotoxicity in human tumour cells. This suggests that 53BP1 could contribute to p53’s tumour suppression activity. In preliminary work, I have now confirmed an important yet uncharacterised role for 53BP1 in mediating p53 signalling. The unique reagents I have generated provide new avenues through which the mechanisms underlying this important yet neglected function for 53BP1 can now be dissected. Aims: I have proposed a comprehensive programme of experiments that will enable me to define the mechanism by which 53BP1 regulates p53-dependent anti-tumourigenic signalling events. In this work I will: 1. Define the mechanism and function of p53-53BP1 interactions in mediating p53-dependent signalling in response to pharmacological MDM2 inhibition and DNA damage treatments. 2. Reveal the mechanism of 53BP1’s contribution to the specificity and strength of p53-dependent transactivation events. 3. Define the addition components that contribute to 53BP1-p53 interplay. 4. Define the contribution of 53BP1 to p53-dependent tumour suppression. Methods: • Biochemical, genetic and structure-led determination of 53BP1-p53 interactions and their contribution to the p53 signalling. • Genomics and transcriptomics to define 53BP1’s influence on p53 transcription factor activity. • Transgenics to generate a DNA repair proficient, yet p53-regulation deficient 53BP1 mutant knockin mouse for in vivo determination of this function. • Murine tumour model to define 53BP1’s contribution to the tumour suppression in mammals. How will this research be used? This work will provide crucial insights into a pathway whose misregulation contributes to around half of all human malignancy. It will also reveal if 53BP1-deficiency or mutation can contribute to tumourigenesis. This work will provide insight into the cellular responses to MDM2-inhibition, and reveal pathways whose mutation could confer drug resistance. These advances may lead to the development of biomarkers, to enable better stratification of patients for personalised medicine.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Sheffield ECMC
Funder: Cancer Research UK

Abstract: Sheffield has a strong commitment to increasing patient access to early phase clinical trials and ECMC support has been vital in the development and expansion of this service. The next quinquennium will see further development of current internal and external collaborations, with the opening of new trials leading to an increase in the number of patients recruited into early phase clinical trials. Both the University of Sheffield (UoS) and Sheffield Teaching Hospitals NHS Foundation Trust (STH) are strongly committed to cancer research as a major priority area. There has been a concentration of resources in areas of strength including ‘Bone Oncology and the Tumour Microenvironment’ and ‘Nucleic Acid and Genome Biology’, both key components of the Sheffield ECMC. In addition, STH has prioritised specialised cancer services and is investing in ‘Research and Precision Oncology’, supporting new clinical appointments and development of the clinical academic workforce. These strategically- focused significant investments will ensure critical mass of researchers and infrastructure, to position Sheffield ECMC at the forefront of translational research and early phase clinical trials in oncology. Our aims for the next quinquennium are to: - Focus on our areas of strength, including bone oncology, genomic medicine, thoracic malignancies, innovative radiotherapy techniques and rare cancers - Maximise the yield from each trial by developing novel biomarkers, and increasing mutation analysis of tumours for access to basket trials - Strengthen our activities across the ECMC Network This strategy will facilitate the translation of preclinical findings into the clinical arena and ensure all patients can benefit from our high quality research.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: CANCER AND NEOPLASMS
Title: Southampton ECMC
Funder: Cancer Research UK

Abstract: The Southampton ECMC will focus its translational research activity within the following 4 core areas (CA1-4) over the next 5 years. 1. Antibody Therapeutics - Targeting and Immunomodulation for Efficacy and Safety 2. Translational Immunotherapy – Novel Therapeutics and Complex Immunomonitoring 3. Tumour Microenvironment – Understanding Immune Evasion and its Therapeutic Targeting 4. Improving Therapy for B Cell Malignancies – Signalling and Stratification. Within CA1 we will build on our mechanistic insights into the effector responses that antibody therapies deliver and their adaptation from pre- clinical model to phase I trials. Within CA 2 we will extend our evaluation of combination immunotherapy through our programme of work with immune modulating antibodies, RNA vaccines, protein vaccines, DNA vaccines, cellular therapies and targeted small molecules. This will facilitate our delivery of next generation immunometric readouts and clinical trial endpoints from systemic and tissue based approaches. These approaches will be directly aligned to the aims of our CRUK Network Accelerator immunotherapy consortium award. In CA3 will address our multidisciplinary approach to the improved understanding of the role of tumour stroma in pathogenesis, tumour mediated immune evasion and the molecular pathways that may be targeted for future novel therapeutic interventions. For CA4, we will deliver improved predictive and personalised medicine through improved understanding of B cell biology and therapeutics, utilizing integrated omic technologies that will contribute to patient responsive Phase I studies, using combinatorial treatment programmes. Our contribution to the expanded Paeadiatric ECMC network will include clinical engagement for trial delivery and expertise in Immunomonitroing for novel cancer immunotherapy protocols in children. The Southampton ECMC will also continue to play an active leadership and membership role to all National ECMC groups including Junior Investigator Network Group (JING), Quality Assurance and Translational Science (QATS) Group, Research Nurses Group, Cellular Molecular Pathology (CM-Path) Network Group and UK Therapeutic Cancer Prevention (UKTCPN) Network Group. Over the next 5 years the Southampton ECMC will continue to work closely with the Southampton CRUK Centre, Clinical Trials Unit and new Centre for Cancer immunology to deliver an integrated ‘discovery to trial’ pipeline that will accelerate the delivery of the cancer treatments of tomorrow.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES;6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: CRUK/16/017 PETReA: Phase 3 evaluation of PET-guided, Response-Adapted therapy in patients with previously untreated, high tumour burden follicular lymphoma (PETReA)
Funder: Cancer Research UK

Abstract: Background: Follicular lymphoma (FL) is the most common type of indolent non-Hodgkin's lymphoma. Frontline treatment for patients with high tumour burden consists of rituximab (R) combined with chemotherapy (R+chemo). Most patients achieve tumour regression but disease recurrence and re-treatment is inevitable. R maintenance after frontline R+chemo delays early progression in about 1 in every 5 patients treated and time to next chemotherapy in about 1 in every 10 patients treated. However, the routine use of R maintenance in this setting is controversial as it does not prolong survival and is associated with significant toxicity. Post-induction FDG-PET provides powerful prognostic information in FL. About 80% of patients achieve a complete metabolic response (CMR) following R+chemo and have an excellent prognosis irrespective of whether R maintenance is given (~95% survival at 6 years). In contrast, the ~20% of patients who fail to achieve a CMR have a significantly worse outcome. Aims: We propose to use post-induction FDG-PET to stratify patients into two groups as a basis for asking the following research questions: 1. Can R maintenance be omitted in patients who achieve a CMR (PET -ve) following frontline R+chemo without compromising outcome in a meaningful way? If so, such patients could avoid an unnecessary treatment that produces significant toxicity and costs the NHS £50M per annum. 2. Can outcome be improved in patients who fail to achieve a CMR (PET +ve) following frontline R+chemo by adding the immunomodulatory drug lenalidomide to R maintenance? Methods: All patients will initially receive R+chemo induction (R-CVP, R-CHOP or BR). Anatomical responders who achieve a CMR will be randomised (1:1) to receive R maintenance vs no further treatment, whereas those who fail to achieve a CMR will be randomised (1:1) to receive R maintenance vs R plus lenalidomide. The PET -ve study has been designed to detect a difference in 3-year PFS of 8% (80% vs 72%) with 85% power and a one-sided alpha of 0.05, whereas the PET +ve study has been designed to detect a difference in 3-year PFS of 20% (40% vs 60%) with 83% power and a two-sided alpha of 0.05. To generate the required number of events, the study will recruit 840 patients over 53 months with a 36-month post-randomisation follow-up period. How the results will be used: If the stratified approach being tested by PETReA is shown to be beneficial, it is likely to change the treatment paradigm for FL.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: p53 and tumour suppression
Funder: Cancer Research UK

Abstract: Perturbations in the p53 pathway play an important role in development and progression of most human cancers. Our goal is to increase our understanding of p53 function to allow the development of improved cancer therapy. Our research programme explores the functions of both wild type and mutant p53. Over the past years we have learnt that under different conditions, p53 can function to either eliminate or protect cells. The survival functions of p53 are manifest in response to metabolic stress and are closely linked to the ability to limit oxidative stress, which is mediated by several p53-inducible proteins, including TIGAR. We are investigating how p53 and TIGAR function during cancer development, exploring both the establishment of early premalignant lesions and progression to metastasis. We are also analysing the functions of mutant p53 proteins that are frequently expressed in cancers. Our work has shown that these p53 mutants show a number of functions that can contribute to tumour development. Some retain wild type survival activities of p53 while losing cell elimination functions, while others acquire activities that promote invasive behaviour in cancer cells. We are examining how expression of mutant p53 provides cancer cells with advantages and whether the expression of mutant p53 can promote vulnerabilities that might be used for new therapeutic approaches. Overall, our work constitutes a contribution to the global research effort to understand and exploit this important tumour suppressor for cancer patient benefit.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS