NIHRDataInsights/HRCSData huggingface dataset:
Title: Prospective collection of acute myeloid leukaemia samples within the NCRI AML trials
Funder: Cancer Research UK

Abstract: There are about 2000 cases of acute myeloid leukaemia (AML) in adults aged over 60 years and about 700 cases of AML aged 18-60 years each year in Great Britain alone. Although treatment has improved over time, cure and survival of patients remain unsatisfactory. Reasons include the often poor tolerability of current therapy and the development of resistance, allowing the leukaemia to return. A growing amount of information about the genetic changes in AML cells has revealed substantial differences between patients. To improve and eventually personalise treatment, and to predict what will work best for each patient, we will have to increase our understanding of the biology of AML, identify who will respond well to a certain treatment and who needs an early change of treatment. We will need to develop effective treatments for patients in whom the leukaemia has returned. Increasingly sophisticated technologies now enable research on leukaemia samples from patients with well-characterized subtypes of AML that will improve knowledge about the efficacy and safety of new treatment. The UK NCRI AML trials are the worldwide largest Cooperative Group trials for patients with acute myeloid leukaemia (AML) and are recognized internationally as playing a pivotal role in developing state of the art treatment for patients with AML. As part of these UK AML trials, blood and bone marrow samples from patients with AML are collected for the following purpose: a) To establish the precise diagnosis and determine the genetic characteristics of the AML based on known information b) To measure the level of disease during therapy to determine the quality of response to treatment (minimal residual disease) and to potentially change treatment as a result c) To store leukaemia samples for future research to increase our knowledge of AML so that we can develop more precise, effective and better tolerated treatments. This is facilitated by a prospective sample collection that is specifically associated with the UK NCRI AML trials, and has been ongoing for many years. Patients who enter the trials are informed about this sample collection and have to provide informed written consent for their leukaemia samples to be banked. The current proposal and application for funding is intended to ensure that this prospective sample collection can continue in the future, in order to continue the highly successful research that has been conducted in the past, for the benefit of the patients by improving treatment.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/13/026 CompARE Collect: Prospective biological sample collection from patients with intermediate and high-risk oropharyngeal cancer recruited to CompARE randomised controlled trial
Funder: Cancer Research UK

Abstract: Background The incidence of oropharyngeal cancer (OPC) is increasing dramatically, due largely to Human Papillomavirus (HPV) infection. The incidence has doubled between 1996-2006, then doubled again between 2006-2010 in the UK. Studies have demonstrated significantly different outcomes for OPC, depending on 2 prognostic variables; HPV and smoking status. These prognostic classifiers divide patients into low (HPV+ve/non-smoker), intermediate (HPV-ve/non-smoker and HPV+ve/smoker), and high (HPV-ve/smoker) risk groups. Treatment de-escalation for low-risk disease is currently under investigation by our group (De-ESCALaTE trial), aiming to reduce treatment toxicity while maintaining survival. For patients with intermediate or high-risk disease, survival outcomes remain poor. Our CRUK funded CompARE trial is investigating the effectiveness of treatment intensification in these higher-risk patients. Utilising a multi-arm, multi-stage design, different strategies of treatment escalation over standard chemoradiotherapy are being studied, including dose-escalated IMRT, surgery and immunotherapy. Aims CompARE collect aims to collect high quality tissue, blood and oral rinse samples from patients recruited to the CompARE trial, for use in future translational research. Methods Using standardised protocols, formalin fixed tissue blocks (diagnostic, resection and neck dissection specimens), oral rinse and 40ml blood samples will be collected at pre-treatment, 3 and 12 months post-treatment. Samples will be taken if evidence of disease progression or recurrence. The CompARE trial will recruit 680 patients, generating 2244 blood samples, 2244 oral rinse samples and 1784 tissue blocks. Samples will be managed through a dedicated state-of-the-art tissue banking facility (The Human Biomaterials Resource Centre) at the University of Birmingham. REC and MHRA approval for trial and tissue collection is already secured. 9 centres in the UK are currently open and recruiting, 22 are in set-up, and 38 patients have been recruited. Tissue collection has already been piloted in 30 patients. How the results of this research will be used. The bio-banking of high quality tissue, saliva and blood samples from patients with intermediate and high-risk oropharyngeal cancer will provide an invaluable future resource. Together with those from low-risk patients from De-ESCALaTE collect and Pathos-T, it will create a unique and complete set of bio-banked OPC samples. Examples of how these samples may be used include: 1. Developing and validating biomarker classifiers for better treatment selection and patient stratification using genomic, methylation and immune markers. 2. Developing and validating markers of early recurrence including circulating DNA, and circulating tumour cells.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: Cell Signalling Group
Funder: Cancer Research UK

Abstract: Neoplasia is driven by deregulated intracellular signalling resulting from mutation, altered expression or hyperactivation of critical signalling molecules. Cumulative findings from human tumour specimens and cancer cell lines, and from mouse tumour models implicate Rac and its upstream activators, the guanine nucleotide exchange factors (GEFs), in the formation and dissemination of a range of cancers. Moreover, pharmacologically inhibiting Rac-GEF/Rac interactions strongly suggest that targeting Rac signalling could provide an effective treatment against several malignancies. However, owing to multiple physiological roles of Rac and moreover Rac functions that potentially antagonize tumour dissemination, sustained suppression of Rac signalling may prove detrimental. The Cell Signalling group at Cancer Research UK Manchester Institute aims to unravel Rac-dependent effects that promote tumour growth and malignant progression from those that antagonize malignant progression or that are essential for normal physiology, as well as identifying tumour types where the net effect of inhibition is beneficial. These are pivotal challenges facing the field. Central to our approach is our previous demonstration that total ablation of the gene encoding the Rac GEF Tiam1 in mouse, while not affecting viability, resulted in a dramatic reduction in skin and intestinal tumour formation. However, it was also apparent that Tiam1-Rac signalling antagonises malignant progression, as the few remaining tumours were, as a proportion, more invasive. Focusing on Tiam1 thus allows us to both uncover Rac-dependent effects promoting tumour growth but also to address the antagonistic role of Rac signalling in tumour dissemination. Previous work addressed the contrasting roles of Rac signalling in malignant progression by investigating post-translational modifications of Tiam1 and Rac in cells stimulated to migrate and invade. In addition, we’ve addressed the hypothesis that GEFs determine selectivity in biological output downstream of Rac revealing distinct sets of Rac effectors dependent on the upstream GEF. Moreover, we’ve investigated the contribution of Rac signalling to tumour growth by demonstrating a role in regulating apicobasal polarity, in cooperating with Ras for melanoma formation, and in controlling centrosome separation. Over the next 5 years, our research will continue to examine Tiam1-Rac but also Tiam2-Rac signalling dependent mechanisms modulating tumour growth and malignant progression, and will rigorously evaluate the potential therapeutic value of antagonising Tiam homologue-Rac signalling for lung cancer and lymphoma, diseases where significant strength has been built in basic, translational and clinical research within the Manchester Cancer Research Centre.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: A01: Rare germline genetic variation in the coding and non-coding genome and susceptibility to ovarian cancer
Funder: Cancer Research UK

Abstract: Background Less than half of the inherited component of susceptibility to epithelial ovarian cancer is explained by the known rare, uncommon and common risk alleles. The advent of large scale sequencing together with chip genotyping it is now feasible to move much closer to complete characterisations of inherited susceptibility to epithelial ovarian cancer. Aims The purpose of this project is to utilise publicly-available exome and genome sequencing data from UK Biobank and the 100,000 Genomes Project together with chip genotyping data from the Ovarian Cancer Association Consortium to identify novel uncommon and rare germline genetic variants in the coding and non-coding genome that are associated with risk of epithelial ovarian cancer. Methods We will utilise exome sequence data generated on OCAC cases and controls sequenced on the same platform. We will combine these data with data available from 100,000 Genomes Project, UK Biobank and other sources. Variant calling will be carried out using our standard pipeline. The principal strategy will be to test for association for categories of variants likely to be similar by simple burden testing using logistic regression. The primary analysis will be for variants predicted to result in protein truncation (frameshift indels, splice site and nonsense variants). We will also evaluate association for rare missense variants. We will utilise whole genome sequencing data data available from 100,000 Genomes Project and UK Biobank to analyse non-coding variation that cannot be assayed through chip genotyping arrays. This includes structural variation and rare single nucleotide variants. It is not possible to evaluate rare, non-coding variation on a variant-by-variant basis. We will carry out variant calling on the available whole genome data and apply burden association testing within functional elements thought to be important in ovarian cancer (such as specific transcription factor binding sites) to identify those potentially associated with risk. Clinical translation Clinical testing for high- and moderate-penetrance ovarian cancer susceptibility genes using gene panels is well-established. Follow-up, large-scale case-control sequencing will be required to confirm novel susceptibility alleles identified by this project and to obtain robust penetrance estimates prior to clinical translation (funding for this not requested).


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Virus-Based Immunotherapies for the Benefit of Patients in Yorkshire and Beyond. (Yorkshire Cancer Research University Academic Fellowship – part of “Capacity Building tomorrow’s leaders in cancer research to improve outcomes for cancer patients in Yorkshire.)
Funder: Yorkshire Cancer Research

Abstract: My research aims to develop treatments to stimulate the body’s own immune system to attack cancers. Much progress has recently been made using ‘checkpoint inhibitors’, drugs that stimulate cells in the body’s immune system to attack cancers. However, only a minority of patients benefit from these drugs. One of the projects that I am undertaking is to improve the likelihood of benefit from checkpoint inhibitors, by first treating patients using live viruses. This strategy has the potential to broaden the benefit of checkpoint inhibitors from a minority of patients to the majority, across different types of cancer. I am working to develop these virus-checkpoint inhibitor combinations for the benefit of patients with liver cancer, aggressive brain tumours and other cancers. In another project, I am developing treatments for cancers of the liver by targeting the viruses that first caused the cancer. The focus of my work is in testing these treatments in patients, within carefully designed clinical trials. The results generated from these clinical trials, help to continue the learning process, bringing the possibility of routinely using these treatments in the clinic a step closer.

Lay abstract: My research aims to develop treatments to stimulate the body’s own immune system to attack cancers. Much progress has recently been made using ‘checkpoint inhibitors’, drugs that stimulate cells in the body’s immune system to attack cancers. However, only a minority of patients benefit from these drugs. One of the projects that I am undertaking is to improve the likelihood of benefit from checkpoint inhibitors, by first treating patients using live viruses. This strategy has the potential to broaden the benefit of checkpoint inhibitors from a minority of patients to the majority, across different types of cancer. I am working to develop these virus-checkpoint inhibitor combinations for the benefit of patients with liver cancer, aggressive brain tumours and other cancers. In another project, I am developing treatments for cancers of the liver by targeting the viruses that first caused the cancer. The focus of my work is in testing these treatments in patients, within carefully designed clinical trials. The results generated from these clinical trials, help to continue the learning process, bringing the possibility of routinely using these treatments in the clinic a step closer.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/16/029 Intergroup Study (EORTC-1420-HNCG-ROG) Phase III study assessing the “best of” radiotherapy compared to the “best of” surgery (trans-oral surgery (TOS)) in patients with T1-T2, N0 oropharyngeal carcinoma.
Funder: Cancer Research UK

Abstract: Background: The incidence of Oropharyngeal Squamous Cell Carcinoma (OPSCC) has increased significantly over the last 10-20 years in developed countries, including the UK. A proportion are caused by Human Papillomavirus (HPV) infection whilst the remainder are usually associated with exposure to tobacco. Early stage OPSCC can be effectively managed by either surgery or radiotherapy, with an average 5-year survival rate of over 80%. Reducing long-term toxicities of treatment, particularly swallowing dysfunction, is an important goal in patients who are likely to be cured of their disease. Aims: Transoral surgery, a minimally invasive form of surgery, and Intensity Modulated Radiotherapy (IMRT), a highly targeted form of radiotherapy, are both currently regarded as standards of care for the management of early stage OPSCC. Both are associated with comparable, high tumour control rates but result in different acute and late side-effect profiles. The EORTC-1420-HNCG-ROG (“Best-Of”) study is a randomised phase III study which will compare the “best-of” transoral surgery and the “best-of” IMRT, for the treatment of patients with T1-T2N0 OPSCC. The main aim of the study is to determine which treatment modality results in the best long-term swallowing outcomes for patients. Methods: Eligible patients will be randomised 1 to 1 to receive either IMRT (Arm 1) or Transoral surgery (Arm 2). In the IMRT arm, a total dose of 66Gy (T1 tumours) or 70Gy (T2 tumours) will be delivered to the tumour in 2Gy/fractions over 6 weeks, with 54.25Gy-56Gy being delivered to the elective nodal areas. Trans-oral surgery can be by either Transoral Laser Microsurgery (TLM) or Transoral Robotic Surgery (TORS), together with a neck dissection. The primary endpoint is swallowing function, measured using the MD Anderson Dysphagia Inventory (MDADI) within 12 months following treatment. A total sample size of 160 patients (80 in each arm) is required to detect a difference of 8 points in the MDADI score, which is considered the minimal clinically important difference for the trial. In order to account for a 5% early drop-out rate and missing values for MDADI score, the total sample size will be 170 patients. Patients will be recruited from across Europe, with 40 being recruited within the UK. Secondary endpoints include loco-regional control and survival and a panel of swallowing assessments. Impact: The "Best-Of" study has the potential to change clinical practice internationally and will provide an evidence-base on which to recommend a future standard of care for early stage OPSCC.


Research activity codes: 6.4 SURGERY;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Accelerating our ability to understand and target complexity and heterogeneity in cancer through automated imaging of 3D cancer models including patient derived organoids - Studentship
Funder: Cancer Research UK

Abstract: Drug resistance is a major challenge for cancer therapy, arising from heterogeneous cellular behaviours within tumours, where initially identical clonal cells can mutate and adapt to diverse microenvironments. This complexity is rarely addressed in standard assays that typically measure the average response of cell populations in highly artificial contexts and fail to account for outlier cells that may drive drug resistance. There is increasing interest in more complex 3D tissue models, such as patient-derived organoids (PDO) that better recapitulate the complexity of the in vivo context compared to conventional high throughput assays of homogenous 2D cell cultures. However, increasing the physiological complexity of cancer models makes them harder to image – limiting opportunities for high throughput (phenotypic) screening. We aim to explore the trade-off between complexity of 3D cancer models and power of assays (in terms of single cell resolution and throughput) by developing modular open source automated instrumentation optimised for 3D imaging of complex cell cultures with a range of optical properties. We will also explore cell culture and sample preparation (e.g. labelling, mounting, clearing) techniques to enable researchers to optimise 3D assays to address their specific cancer biology questions. The proposed automated 3D imaging instrumentation aims to provide quantitative single cell-resolved readouts of drug-target engagement and responses in fixed and live cell cancer models. It will extend the commercial state-of-the-art with modules for faster 3D imaging, e.g. of cell morphology, dynamics and migration in multiwell plate arrays, alongside the ability to tune performance between speed and imaging depth for larger and/or more scattering samples. We will develop open source instrumentation and software for 3D image acquisition and analysis and will develop and validate robust and reproducible protocols and SOPs for culturing and assaying PDO. Following instrument development at Imperial and the Crick, we will utilise and validate the Accelerator capabilities with Edinburgh, the ICR and the IRB Barcelona through exemplar cancer biology assays, e.g. determining which cells within a heterogeneous cancer population are effectively killed by chemotherapy and which of the persisting cells are responsible for disease recurrence. We will also explore the role of the tumour microenvironment for quiescent resistant tumour cell sub-populations. To better understand side-effects of chemotherapy, we will assay the effects of chemotherapy on normal tissue. A PhD cohort trained in these technologies will help introduce them to the cancer biology and drug discovery communities.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);5.1 PHARMACEUTICALS;5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: CANCER AND NEOPLASMS
Title: Improving Cancer Prognosis Through Circadian Time-Telling
Funder: Cancer Research UK

Abstract: Recent studies have established that the circadian clock influences onset, progression and therapeutic outcomes in a number of diseases including heart disease and cancer. There were previously, however, no practical tools to monitor the functional state of the circadian clock and its downstream targets in humans. Substantial preliminary evidence suggests that our recently constructed algorithm TimeTeller can measure the functionality of the clock and that this measurement is a potentially new prognostic and predictive breast cancer biomarker. The aim of this grant is to extend TimeTeller so that it can be used with multiple expression technologies, notably RNA-seq, to facilitate the study of the data contained in large cancer databases. This will allow validation of the approach and facilitate the detailed study of the link between clock-controlled processes in the cell and breast cancer.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Microfluidic Platforms to Investigate the Genesis and Transport Capabilities of Vessels during Vasculogenic Mimicry in Small Cell Lung Cancer
Funder: Cancer Research UK

Abstract: Background: Vasculogenic mimicry (VM) is the ability of tumour cells to generate vessels independently of angiogenesis. VM is hypothesized to be an adaptive strategy enabling solid tumours to bypass nutrient/oxygen limitations. However, because of a lack of physiologically-relevant model systems, the factors involved in the genesis of VM vessels and their ability to transport fluid/nutrients is poorly understood. Aims: The goal of this project is to develop next generation microfluidic platforms to advance our understanding of the factors that influence VM genesis and the capability of VM vessels to transport fluid, nutrients and cells in small cell lung cancer (SCLC). Methods: We will first develop a microfluidic platform that recapitulates the unique microenvironmental conditions required for the formation of both VM and angiogenic vessels. We will then use this platform to study how factors such as oxygen tension, matrix stiffness and cellular composition interact to promote or inhibit VM genesis. Finally, we will use high molecular weight dyes to explore VM vessel permeability, the ability of VM vessels to transport fluid & tumour cells, and how standard therapies for SCLC influence VM-competent tumour cells. How the results of this research will be used: The VM microfluidic devices developed here will be broadly disseminate to the research community for exploring the many other cancer types where VM supports aggressive behaviour. A better understanding of key microenvironmental factors that influence VM genesis and how VM vessels affect drug distribution, tumour responses and transit via the circulation will reveal opportunities for VM targeted therapeutic strategies. Finally, understanding the role that VM plays in cancer cell dissemination will also enable the development of tailored therapeutics that operate within the metastatic niche.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: CANCER AND NEOPLASMS