NIHRDataInsights/HRCSData huggingface dataset:
Title: CRUK/17/011 FaR-RMS: A multiarm-multistage study for children and adults with localised and metastatic Frontline and Relapsed RhabdoMyoSarcoma
Funder: Cancer Research UK

Abstract: BACKGROUND: Rhabdomyosarcoma (RMS) is the commonest malignant soft tissue sarcoma in children. Outcomes in high risk (HR) RMS have improved but 25% of children with HR localized RMS still die of disease and in metastatic or relapsed RMS outcomes remain extremely poor with only 25% and 17% long term survival. Trials incorporating improvement of local disease control (radiotherapy) and new systemic therapies, including targeted agents are needed. Adults with localised RMS have a reported 5 year survival of only 47%. AIMS: This proposed study is the next European international study for both children and adults which aims to improve outcomes in (A) newly diagnosed and (B) relapsed RMS. METHODS: The proposed study has 3 components: 1) Radiotherapy (RT): Localised disease: i) Randomised study investigating RT dose escalations for patients with tumours with higher local failure risk (HLFR). ii) standard and high risk tumours deemed resectable will be randomised to pre- versus (standard) post-operative RT (feasibility study) and iii) Metastatic disease: patients with more than 3 distant metastases will be randomised to receive loco-regional RT versus RT to all metastatic sites. 2) Chemotherapy: (A) Newly diagnosed patients will be stratified into Very High Risk (VHR), High Risk (HR) and Standard Risk (SR) groups and investigated as follows: i) Single arm phase Ib (dose finding) for new treatment combinations and ii) Randomised phase II/III MAMS component, comparing the established chemotherapy for VHR and HR respectively to new treatment combinations. iii) A randomised phase III study to investigate duration of maintenance chemotherapy. (B) Relapsed patients: i) Single arm phase Ib (dose finding) study for new addition of chemotherapy or targeted agent to standard backbone chemotherapy (ii) Randomised phase II/III MAMS design, comparing new combinations from the phase Ib study with standard chemotherapy. 3) Biology: i) Study entry will expect assessment of PAX-FOXO 1 fusion gene status; this will be used in place of conventional histopathology in risk stratification and impact on patient outcomes will be assessed prospectively. ii) Tumour samples at diagnosis and relapse and sequential on-treatment serum samples will be collected for separately funded biological studies to facilitate identification of therapeutic strategies, relevant biomarkers for disease monitoring and to improve molecular risk stratification. A virtual bio-bank will be established. HOW THE RESULTS OF THIS RESEARCH WILL BE USED: To provide evidence base for future care of patients with RMS.


Research activity codes: 6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Reinterpreting the ‘field of injury’ through understanding cellular level damage and dynamics and consequences for the Prediction, Prevention and Early Detection of lung cancer: ELIMINATE
Funder: Cancer Research UK

Abstract: The global problem of lung cancer (2,000,000 cases/year) is unabated and likely to escalate given tobacco smoking trends in the Far East, India and Africa. While smoking rates are decreasing in the UK, lung cancer remains the biggest cancer killer of men and women (34,000 deaths/year from 44,000 new cases). We remain convinced that to improve lung cancer survival we must detect lung cancer early or intervene to prevent its formation. While CT screening programmes have demonstrable success in reducing death rates, they are difficult to fund and implement. The US programme only screens ~4% of those eligible. Furthermore, the perfectly run screening programme will only detect 20% of lung cancers as the majority occur in individuals outside the highest ‘at-risk’ population qualifying for CT screening. A successful biomarker-driven early detection programme needs to detect tumour cells or their fragments in body fluids, or to define the molecular footprint of a ‘field of injury’ that better predicts those at risk of future cancer, allowing more intensive surveillance. These strategies are currently too inefficient for mainstream use. A better biological understanding of the individual cell and clonal architecture in normal airways could enable new avenues for early detection and potentially effective therapeutic interception strategies. Cancers are thought to develop from an area of epithelium where individual cells have been equally exposed to toxins producing a ‘field of injury’. Within this an individual cell may eventually form a dominant clone and with the correct evolutionary sequence of events (including genetic, epigenetic, transcriptional and microenvironment cues) proceed to cancerous transformation and invasion. We have data demonstrating that the traditional understanding of a ‘field of injury’ is flawed. We have demonstrated the airway as a whole can reverse genetic damage through clonal expansion of less mutated cells or deletion of more mutated cells, thereby protecting individuals from cancer despite a heavy previous ‘dose’ of smoking carcinogens. We believe this a seminal discovery. First, our current understanding of ‘field of injury’ is too simplistic; we need cellular level understanding to predict an individual’s risk of future cancer. Second, if we can understand the cellular mechanisms driving the loss of highly mutated cells over low-mutant cells in those quitting smoking, we will not only be able to potentially titre cancer risk but also open a new field of medical science manipulating this process, thereby intercepting cancer prior to even pre-cancerous lesion development.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Earlier Diagnosis in women at high risk of breast and ovarian cancer
Funder: Cancer Research UK

Abstract: Background. Earlier diagnosis of cancer may reduce mortality and morbidity. Recent technological advances allow tiny amounts of tumour DNA to be detected in blood or other tissues. The purpose of this project is to study cohorts of women at high genetic risk of breast or ovarian cancer to investigate the potential to use DNA in blood or cervical samples for early detection of breast and/or ovarian cancer, using state-of-the-art methodology. Aims 1. Establish a new cohort of women at high risk of breast and ovarian cancer (EDBOC) through the regional clinical genetics service and the breast screening programme. 2. Establish a resource of blood and cervical fluid/cytology samples, from a national study of BRCA1/2 carriers (EMBRACE) and EDBOC, suitable for genomic analysis. 3. Evaluate the sensitivity of early detection of breast or ovarian cancer using state-of-the-art next-generation sequencing approaches and serial blood samples from at-risk women. 4. Establish the sensitivity of early detection of ovarian cancer using cervical sampling. Methods We will build on the national cohort of BRCA1/2 carriers (EMBRACE), which will be extended to include carriers of mutations in other breast/ovarian cancer susceptibility genes. Carriers will be asked to provide annual blood and cervical smear samples. In addition, we will recruit a new cohort (EDBOC) of women undergoing annual mammographic screening. We will develop risk scores based on genotype, mammographic density and lifestyle risk factors. We will apply two methods for tumour detection in both the blood and cervical samples: Tagged Amplicon Sequencing (TAm-Seq) and size-selected shallow whole genome sequencing (sWGS). We will also develop patient-specific assays using Tailored Panel Sequencing (TAPAS) based on the spectrum of mutations identified in a subset of incident primary tumours. This panel will be sequenced in all serial samples from these patients. These highly sensitive patient-specific assays should enable tumour DNA to be detected down to parts per million. The research will establish: (a) whether current methods of ctDNA analysis, using either in blood or cervical samples, are sufficiently sensitive to have utility in early detection. (b) the time course of ctDNA levels in the years preceding diagnosis and, hence, the earliest point at which tumours might be detectable. (c) the relative sensitivity/positive predictive value in different risk groups. (d) protocols for cervical sampling that can be implemented in larger trials. These results will inform the design of future trials to establish the utility of such methods in clinical practice.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.4 POPULATION SCREENING;4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: Cancer Research UK Birmingham Centre
Funder: Cancer Research UK

Abstract: The CRUK Birmingham Centre aims to increase understanding of oncogenesis mechanisms, tumour immunobiology, and tumour heterogeneity, providing the scientific basis for novel rational targeted therapies and immunotherapies, and for their integration into stratified treatment pathways. Building on strengths in stratified medicine and immuno-oncology, and leveraging our closely linked Experimental Cancer Medicine Centre, integrated biomedical campus and large population, our aim is to drive major improvements in patient outcomes. Discovery science is focussed on three interlinking research themes, each represented by a UoB research centre (the Cancer Immunology and Immunotherapy Centre, the Birmingham Centre for Genome Biology, and the Centre for Human Virology): • Immunology (Leads Willcox/Middleton) explores how anti-tumour immunity is regulated, including the immunobiology of the tumour microenvironment, and how factors such as tumour genetics, oncogenic signalling and microbiota combine to influence it. Linking with these studies, we are characterising novel axes of cancer immunosuppression, new molecular targets, and immunotherapeutic strategies, to develop new immunotherapeutic strategies. • Genomics (Leads Taylor/Beggs) is defining how DNA damage and repair defects influence cancer predisposition, how epigenetic reprogramming drives tumourigenesis, and, aligning with clinical trials on epigenetic modifiers, highlights new therapeutic opportunities. Linking with our clinical infrastructure genomics studies can identify how mutational profiles/epigenetic signatures influence patient outcomes/treatment response, providing novel stratification approaches. • Virology (Leads Murray/Steven) featuring substantial workstreams on all major human oncogenic viruses, is investigating how such viruses influence tissue microenvironments to promote tumourigenesis. Importantly, we will exploit novel viral oncogenesis models to define fundamental pathways of dysregulation, and identify favoured routes for therapeutic intervention and exploitation.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: ACRCelerate: Colorectal Cancer Stratified Medicine Network
Funder: Cancer Research UK

Abstract: Colorectal cancer (CRC) remains the second most common cause of cancer death, and patients with stage 3/4 cancers at diagnosis only have a 10% survival rate at 5 years. Chemotherapy relies on the use of combination cytotoxics against the proliferating tumour epithelium, with novel targeted therapies having disappointing trial results to date. CRC presents an opportunity for precision medicine as it is common, has known and established driver molecular pathways and pre-treatment molecular stratification is achievable. Recent advances in sequencing technology and biological models have resulted in paradigm shifts in our understanding of CRC biology, but have failed to significantly impact upon patient care. Indeed, stratified medicine clinical trials such as FOCUS4 have been hampered by the lack of robust preclinical prediction, which have left many therapeutic arms of the trial unfilled. This Accelerator application brings together a European-wide consortium at the forefront of CRC research to align and interrogate a suite of state-of-the art preclinical models (GEMMs, organoids and PDXs). Our platform will accelerate therapeutic target identification and preclinical validation of new and repurposed drugs, to accomplish rapid clinical translation. Our focus will be to generate and share models of CRC that correlate with human CRC molecular subtypes, to enhance testing of CRC therapeutics in functionally relevant microenvironments. By placing molecular phenotyping and stratification at the heart of this programme we will target biologically plausible pathways known to be dysregulated in CRC, and design molecularly stratified clinical trials to test them, to ensure that no therapeutic opportunities are overlooked. The overarching aim of this proposal is to generate robust and reproducible preclinical data to de-risk future clinical trials based on patient stratification. We will employ and develop preclinical models that recapitulate the molecular subtypes of CRC, characterise their signalling pathways, use DNA and RNA sequencing to subtype the models, identify and test new therapeutics and integrate the data in a bioinformatic analysis pipeline. The data will be shared amongst the consortium for cross-validation, reducing the number of mice used in cancer research and to inform future stratified clinical trials for CRC.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Benefits and Risks of Cancer Treatments
Funder: Cancer Research UK

Abstract: Benefits and Risks of Cancer Treatments Background: Individual treatment decisions can only be made on an informed basis if patients and clinicians have information on the absolute magnitudes of both the likely benefits and the risks of all available management options. These can then be compared and the option with the best chance of a favourable outcome identified. Aims: Our overall research aim is to provide reliable information to do this. Our specific objectives arise from clinical problems facing clinicians around the world on a daily basis in early invasive breast cancer, in-situ breast cancer, lymphoma and advanced cancers. Many treatment options are often available, and selecting the best one is often difficult. Methods: During the past five years, our team has worked with Public Health England to produce high quality population-based datasets describing patterns of mortality and morbidity following a diagnosis of cancer. We have developed innovative radiation dosimetry and statistical methods. We plan to build on this foundation as follows: 1. Individual patient data meta-analyses: For some breast cancer treatment options, reliable estimates of the benefits and risks are unavailable. To fill the gaps we will conduct individual patient data meta-analyses of randomised trials. 2. Doses and dose-response relationships: The benefits and the risks of most radiotherapy and chemotherapy treatment options vary according to dose. But doses in clinical practice today sometimes differ from those in the trials. Therefore dose needs to be considered when using past trials to predict the effects of today’s treatments. Our innovative studies will combine dosimetry with epidemiological data to characterise benefits and life-threatening risks of today’s radiotherapy and chemotherapy. 3. Absolute effects: We will provide absolute rates of recurrence, second primary cancer, life-threatening side effects and cause-specific mortality for patients with early invasive breast cancer, in-situ breast cancer and lymphoma. These will be combined with the benefits and the risks to provide estimates of the net absolute effects of treatments as they are used in the clinic today. We will also use these data to support clinical trials and practice. How the results will be used: Clinicians will be able to use our studies to assess the benefits and risks of cancer treatments for individuals, and groups of patients. Existing cancer treatments will be used to optimal effect so that more patients are cured of their cancer, and fewer survivors develop side effects.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: CANCER AND NEOPLASMS
Title: Multimodality Early Detection of Head and Neck Cancer Recurrence
Funder: Cancer Research UK

Abstract: The optimal frequency of post-treatment imaging surveillance for head and neck cancer patients who are at risk of recurrence is not well-defined and non-imaging biomarkers for recurrence (required for a risk-stratified imaging surveillance strategy) are lacking particularly in the HPV-negative cohort of patients. Our goal is to derive an integrated set of imaging-multianalyte based technologies that link studies of tumour cell molecular and immune microenvironment mechanisms to establishing a robust risk model for predicting cancer recurrence. A new prospective clinical study will be conducted and will expand on the exosomal microRNA and immunological parameter model that we have built within a recent Phase 2 clinical/translational head and neck cancer study, and can delineate a high risk patient subgroup who has significantly lower recurrence free survival compared to that classified as low risk. We will address the potential clinical utility of peripheral blood sampling of the exosome/immunome, in combination with individual patients’ genome (CtDNA) as a longitudinal surveillance tool to achieve risk-stratified imaging surveillance. Our multidisciplinary experts will combine our tools/expertise to work on pre-defined biological hypotheses to provide the scientific rationale for an integrated non-invasive diagnostic. As an example hypothesis, MR elastography which can detect at an early stage, intra-lymphatic invasive form of cancers; will be combined with peripheral blood sampling of specific immune cells which may facilitate cancer metastasis through lymphovascular remodelling or lymphovascular invasion by tumour cells. We will examine changes in intratumoural and circulating immune cells using mass cytometry (cytometry by time of flight (CyTOF)) and conventional cytometry methods. We postulate that a combination of deep immunophenotyping by multiplexed imaging of tissues (at baseline), coupled to blood monitoring during treatment when biopsy material may not be obtainable; would be a better way to assess the risk of early recurrence than either modality alone. For genomics, we will utilise a sequencing approach that incorporates a combination of error-suppression and signal enrichment techniques for sensitive detection of cfDNA. Where detected, we will correlate the mean variant allele frequency of e.g. p53 mutations in cfDNA and the corresponding exosomal p53 mutant protein level, with the quantification of tissue- and circulating immune cells. The multivariate model for early cancer recurrence risk detection will be used to risk-stratify patients prior to, or shortly after primary radical treatment. The potential benefit is for patients at high-risk of recurrence to receive treatment intensification, such as the addition of immunotherapy to chemoradiation.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Risk Adaptive Breast Screening - a tailored imaging approach
Funder: Cancer Research UK

Abstract: In the UK women 50-70 years are invited for 3 yearly mammography as early detection has been shown to be cost effective in prevention of breast cancer deaths. The only risk adaption is for women who are BRCA1/2 gene carriers stratified at 30% lifetime risk who are offered annual MRI and Mammography. Current research suggests that using questionnaires, breast density and SNPs it is possible to stratify the population into the lowest 20% risk who will develop less than 4% of the cancers and the top 10% who will develop 18% of the cancers. Mammography is a good screening test but has low sensitivity of 60% in the 9% of women with the highest category of breast density (BIRADS D). These women have a 2.5-4 fold risk of breast cancer from their breast density. There is some evidence that adding Ultrasound to the screening mammogram can increase the cancer detection rate and reduce advanced stage interval cancers. Similarly alternative tests such as contrast enhanced mammography or Abbreviated MRI may in fact be more cost effective in the high risk group with dense breasts. We wish to undertake a programme of work to develop the feasibility of a risk adaptive approach and assess these various imaging tests in a screening setting to establish feasibility before conducting large scale Randomised Control Trial. The applicants will identify a prospective cohort of women at increased risk due to dense breasts to assess and test the feasibility of different imaging techniques in addition to standard mammography in a screening setting. The tests are Abbreviated Magnetic Resonance Imaging, Contrast Enhanced Spectral Mammography and Whole Breast Ultrasound. We wish to test a range of automated breast density assessment tools which are needed to robustly and reproducibly contribute to a risk prediction score to determine which one is the most appropriate for a UK cohort of women. We wish to establish which density score would serve as a cut off in which it would be appropriate and effective to offer additional supplemental imaging tests. At recruitment we will collect personal information as well as collecting genetic material to analyse in the future in order to validate the BOADICEA model in a normal risk UK population with dense breasts. This is an integrated approach in order to produce evidence for the NHS Breast Screening programme to risk stratify the population and identify which women would benefit from additional imaging.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.4 POPULATION SCREENING
Health categories: CANCER AND NEOPLASMS