NIHRDataInsights/HRCSData huggingface dataset:
Title: Quiescence and the origins of plasma cell neoplasia
Funder: Cancer Research UK

Abstract: Background: Myeloma is a cancer of plasma cells (PCs), which provide the source of secreted antibody in the immune system. Myeloma generally follows a relapsing incurable course with around 4500 cases/year in the UK and 50% 5-year survival. Symptomatic disease is preceded by an indolent phase, monoclonal gammopathy of undetermined significance (MGUS). In myeloma and MGUS disease progression is difficult to predict and in early disease balancing treatment benefit and risk is problematic. Thus, we are currently unable to exploit our capacity for early diagnosis to impact on outcome. A fundamental lack of understanding of early disease mechanisms plays a significant part in this problem. A central paradox in myeloma is that the putative cell of origin, the bone marrow PC, is considered to have irreversibly exited cell cycle. However, myeloma is preceded by progressive expansion of a neoplastic clone. To explain this paradox, we proposed and are testing the hypothesis that normal long-lived PCs, while quiescent retain capacity for self-renewal divisions, and that changes in quiescence threshold underpin evolution in neoplastic precursors. We have data to support the labile quiescence model, and now aim to further explore the relationship between normal and neoplastic PCs. Aims: We aim to address: 1) how PC/niche interactions deliver mitogenic signals that drive cell cycle re-entry; 2) how myeloma-associated oncogenic events impact on human PC biology; 3) whether modular patterns of gene expression identify key features of PC biology that allow enhanced prediction of early disease course. Methods: We will use advanced models of human PC differentiation to dissect signal transduction and gene regulatory responses related to cell cycle re-entry. We will extend these to single cells using expression and functional assays, and microfluidics to establish lab-on-chip models of normal and neoplastic PCs. In parallel we have developed a highly efficient bioinformatic platform for gene expression data, Parsimonious Gene Correlation Network Analysis (PGCNA). This allows us to exploit extensive available resources and link our models to clinical data. In collaboration with our unique regional resource the Haematological Malignancy Research Network, we aim to use this approach to establish new prognostic and predictive tools in PC neoplasms in a UK population setting. How the results of this research will be used: The results will be used to understand early disease biology in PC neoplasia focusing on niche responses. Using PGCNA we will drive clinical application and define exploitable characteristics for patient benefit.


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: An international prospective umbrella trial for children with atypical teratoid/rhabdoid tumours (ATRT) including A randomized phase III study evaluating the non-inferiority of three courses of high-dose chemotherapy (HDCT) compared to focal radiotherapy as consolidation therapy
Funder: Cancer Research UK

Abstract: Background Atypical Teratoid Rhabdoid Tumour (ATRT) is rare, but still the most common malignant CNS tumour of infancy. The prognosis has been historically very poor, although overall survival rates (OS) of 40% has been reported by several groups using multi-agent chemotherapy and radiation therapy. The tumour typically affects very young children, for whom the use of radiation leads to severe neuro-cognitive impairment, and in infants, this is generally regarded as not an ethical approach. Use of high dose (HD) chemotherapy has been used in some centres, and anecdotal reports have suggested that this may be an acceptable alternative, but no comparative study has been performed. Aims The aims of this trial are to evaluate progression-free survival rates (PFS), OS, neuro-cognitive, and Quality of Life (QoL) outcomes at 2 and 5 years, and to document response to induction therapy and the incidence and severity of adverse events in each arm. Additional aims are to establish a structured approach to ATRT management and to enhance the active research community in this field. Specific sub-studies are included within the trial including further evaluation of possible sub-types of ATRT, tumour heterogeneity, germ-line mutations and development of xenograft models. Methods This international study has three arms: Arm A is a randomised non-inferiority study of radiation and conventional chemotherapy vs HD therapy in children with ATRT aged 12 to 36 months (m). A total of 82 patients will be recruited into each arm over a period of 5 years. Arm B is a non-randomised study in infants aged <​12m, or young children under 36m for whom radiation therapy is deemed inappropriate. These patients are allocated HD chemotherapy. An estimated 101 patients will be allocated to this group. Arm C is a non-randomised study in children aged >36m. These children will be allocated conventional chemotherapy with radiotherapy. An estimated 64 patients will be allocated to this group. Tools developed by the SIOPEurope QoL group allows for evaluation in very young children. How the results of this research will be used Results of this research will provide clear evidence of the relative roles of radiation and HD therapy in this tumour, and have direct clinical consequences for many patients. It will lead to improved outcomes through consistent treatment plans, better understanding of ATRT, and development of improved prognostic factors and a coordinated network of researchers across Europe.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Time-resolved single cell mapping of breast cancer premalignancy
Funder: Cancer Research UK

Abstract: Breast cancer affects one in eight women and remains the number one cause of cancer related death. Despite significant advances in therapies and survival outcomes, the statistics point towards a need for developing better methods for the early detection of breast cancer. At present, women diagnosed with breast cancer at stage one have a 90% chance of surviving ten years or longer, compared to only 20% when diagnosed at stage four (CRUK). In this study we will use sophisticated mouse models to build a detailed map of how the cells in the breast change before cancer is detectable. We will then use this map to find key markers that can act as early warning signs that breast cancer development is imminent. We will then test these markers on human breast tissue and blood samples to ensure they are suitable before embarking on larger human studies.


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: CRUK/14/045 P3BEP Trial Phase 3 Accelerated BEP Trial: A randomised phase 3 trial of accelerated versus standard BEP chemotherapy for patients with intermediate and poor-risk metastatic germ cell tumours
Funder: Cancer Research UK

Abstract: Background: Current first-line chemotherapy for intermediate- and poor-risk metastatic germ cell tumours (GCTs) is inadequate. Previous strategies to improve outcomes have included use of alternative or additional chemotherapy agents and high dose chemotherapy with stem cell support. None of these strategies improved cure rates, and all were more additionally toxic. New strategies are needed for patients with intermediate- and poor-risk disease. Accelerating standard chemotherapy regimes by cycling drugs more rapidly has increased cure rates in several other cancers. Previous studies have shown that accelerating BEP in advanced GCTs is safe and feasible. Aims: To determine if accelerated BEP (Bleomycin, Etoposide, cisPlatin) is superior to standard BEP as first-line chemotherapy for intermediate and poor-risk metastatic GCTs. Primary endpoints To compare the two treatment arms with respect to: 1) Progression-free survival (disease progression or death) Secondary endpoints To compare the two treatment arms with respect to: 2) Response following treatment completion (protocol-specific response criteria) 3) Adverse events 4) Health-related quality of life 5) Treatment preference 6) Delivered dose-intensity of chemotherapy (Relative to standard BEP) 7) Overall survival (death from any cause) Methods: Open-label, randomised, stratified 2-arm International multicentre phase 3 clinical trial undertaken in two stages. Participants will be male, aged 16 to 45 years with intermediate or poor-risk metastatic GCTs. Patients will be randomised in a 1:1 ratio to receive 4 cycles of either accelerated BEP or standard BEP. The only difference between accelerated BEP and standard BEP is that cisplatin & etoposide are cycled 2-weekly rather than 3-weekly. Stage I of the study will recruit 150 participants (75 per arm) which will provide 80% power at the 5% level of significance to detect an improvement in the favourable response rate from 59% with standard BEP to 80% with accelerated BEP. If results from Stage I are sufficiently promising, Stage II of the study will recruit an additional 350 participants for a total sample size of 500 participants (250 per arm). The UK will contribute 50 patients to Stage I and 125 patients to Stage II. How the results of this research will be used: Direct outcomes of the completed trial will be- 1. To determine whether accelerated BEP is superior to standard BEP, improving cure rates with little or no increase in cost 2. To potentially establish a new standard of care for advanced intermediate and poor prognosis germ cell tumours


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: TEP-eDx: Validating the use of Tumour Educated Platelets for early cancer diagnosis
Funder: Cancer Research UK

Abstract: Earlier detection greatly improves outcomes for patients with cancer, and studying the gene changes in cancer cells greatly helps in identifying risks and 'tailoring' treatment. There is currently significant interest in ‘liquid biopsy’ approaches that are geared towards enabling cancer detection via blood sampling rather than tissue biopsy. However, as current approaches are generally technically challenging and of poor sensitivity, novel approaches that would improve detection would be highly beneficial. Platelets are highly abundant blood cells that take up proteins and molecules that they encounter while circulating in our blood. Sampling platelets from a simple blood test may thereby provide a 'window' to detect and study proteins released by cancer cells. In this proposal, we aim to validate “tumour educated” platelets (TEPs) as an enticing platform for early cancer diagnosis. This will be achieved via three experimental objectives: (1) determining if enriching for DNA fragments associated with platelets may be more sensitive than current ‘liquid biopsy’ techniques for cancer detection; and if there are specific fragmentation and epigenetic ‘signatures’ identifiable in patients with cancers; (2) determining the role and consequence of tumour cell-derived extracellular vesicles in transferring tumour cell protein biomarkers to platelets; (3) identifying if biomechanical properties are present that are unique to platelets exposed to tumour cells. Our overarching goal is to validate and develop TEPs as a new platform for non-invasive cancer diagnosis and molecular profiling that may be applicable to a range of different types of cancers. This project will cement new collaborations formed between clinicians, scientists and physicists to undertake highly innovative experiments. This project will leverage significant combined expertise and maximising utilization of key resource facilities at each host institute. This includes expertise in platelet biology/cancer genomics and clinical expertise (Psaila, Oxford), computational biology and novel analytical pipelines (Thongjuea, Oxford), extracellular vesicles and cancer cell biology (Gregory, Edinburgh), advanced imaging (Meissner, Swansea) and instrumentation development (Gersen, Bristol), with additional collaborators at each institute, thereby delivering significantly more impact than would be possible from a single institution project. This proposal is the natural extension of a CRUK Innovation Award (2019), closely aligns with the key focus areas of the CRUK Early Detection Programme and has a clear line of sight to clinical translation.


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: CanTest- Cancer diagnostic testing in primary care: a paradigm shift for cancer diagnosis
Funder: Cancer Research UK

Abstract: Background Health funders worldwide increasingly view primary care as the preferred setting for the majority of health care. The Independent Cancer Taskforce reflects this in calling for increased diagnostic capacity for GPs. To date, efforts in the UK and elsewhere to increase diagnostic capacity for cancer have been predicated on a secondary care-centred model, with consequential risks of longer access times, higher costs and greater risks of error and delay. Aims The CanTest Collaborative aims to transform the primary care physician (PCP) office to a hub of diagnostic excellence. The objectives are to: • Increase capacity and sustainability of clinical cancer detection research in the UK and internationally; • Establish an International School for Cancer Detection Research in Primary Care; • Identify existing and emerging tests, and alternative international models of care delivery related to diagnostic evaluation for cancer, and assess their potential for UK use; • Evaluate the availability, acceptability (to patients and PCPs), accuracy, and cost-effectiveness of cancer tests when used in primary care. This includes optimising the use of existing tests, of tests currently used solely in secondary care, and of as yet unused tests. • Quantify any possible harms arising from increased testing for cancer in primary care, and create strategies to balance harms and benefits. Methods Our project has two key interrelated strategies. Firstly, by increasing the capacity and sustainability of clinical cancer detection research in the UK and internationally we will drive a paradigm shift in the identification and evaluation of alternative or novel approaches to cancer detection in the context of the work system, informed by the Institute of Medicine’s model of the diagnostic process. This strategy will be enabled and sustained by our International School for Cancer Detection Research in Primary Care. Secondly, CanTest researchers will be engaged in workstreams to evaluate specific tests for cancer detection, gain international perspectives of test provision and usage, and undertake assessment of patient-centredness and safety for use in primary care, to develop strategies to balance harms and benefits to patients, healthcare providers and healthcare systems. We will prioritise ‘difficult-to-diagnose’ cancers, which are also associated with poorer survival outcomes, and assess both existing and novel technologies. How the results will be used CanTest will establish new and ongoing collaborations to increase research capacity in the field, ensure long-term sustainability of the paradigm shift, and influence policy and practice to improve cancer diagnosis and patient outcomes.


Research activity codes: 4.4 POPULATION SCREENING
Health categories: CANCER AND NEOPLASMS
Title: Maps of Malignancy: Epidemiologists and Cancer in Sub-Saharan Africa
Funder: Wellcome Trust

Abstract: Epidemiological efforts to map cancer in sub-Saharan Africa have a long history, playing an important role in how the disease has been imagined in the region. In the late colonial and early postcolonial period, British and French doctors produced small-scale epidemiological maps to advance understandings of cancer aetiology and improve treatment strategies at home. More recently, global surveillance initiatives seeking to rationalise health policy and planning in Africa have generated political atlases of the continent with national cancer burdens. This project carries out an archival and ethnographic study of these epidemiological efforts to chart malignancy in sub-Saharan Africa over the past 70 years. It takes these cartographies of diseases as its object of study, examining their scientific, political and material conditions of possibility and analysing their influence on cancer imaginaries and healthcare policies in Africa. In doing so, the project aims to draw attention to the crucial role that epidemiological maps have played in the postcolonial history of biomedicine in Africa, while developing an innovative approach to epidemiological surveillance that highlights its socio-technical infrastructure and performative power. At the same time, the project also purports to move Africa out of the margins of the global history of cancer.

Lay abstract: Epidemiological maps of disease have multiplied and become critical to contemporary global health policy and planning in recent decades. Given the ubiquity and importance of these maps, it is critical that we have a good understanding of their histories, the way they are made and the power they have on understandings of disease and healthcare agendas. In this project, I aim to shed light on some of these issues by carrying out a historical and anthropological research of the efforts of epidemiologists to survey and map cancer in Sub-Saharan Africa over the last 70 years. Specifically, I hope the project will give us a better understanding of the political and scientific reasons for mapping cancer in Africa, of the forms of expertise and labour that are necessary to make these cancer maps and of how these maps influence (or not) health policy and planning in Africa.

Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: CANCER AND NEOPLASMS
Title: DIAGNOSING BLADDER CANCER – EVALUATING THE ROLE OF A URINARY BIOMARKER TEST IN THE RECONFIGURATION OF HAEMATURIA CLINIC INVESTIGATIONS (‘BC-Recon’)
Funder: Cancer Research UK

Abstract: BACKGROUND Bladder cancer (BC) is the seventh most common cancer in Western society. Haematuria is the presenting symptom for >90% of newly-diagnosed BC cases (and an indicator of upper tract urothelial cancer (UTUC) and kidney cancer (KC)). However, only 10-12% of patients investigated for haematuria in the UK will be diagnosed with urinary tract cancer: BC (8.0-10.3%), UTUC (0.3-0.7%), KC (1.0-1.5%), and prostate cancer (0.3%). Haematuria investigations comprise imaging, urine cytology, and flexible cystoscopy. Flexible cystoscopy is invasive, costly, morbid, operator-dependent, and fallible (with estimated sensitivity of ≤85% and specificity ≤87%). Since >80% of haematuria patients have no abnormalities upon investigation, accurate urinary biomarkers could triage patients for flexible cystoscopy in order to reduce patient burden, reduce waiting times, increase healthcare capacity, and reduce healthcare costs, permitting urine test-negative patients to avoid flexible cystoscopy following imaging and urine cytology. Such reconfiguration is now feasible with a sensitive and specific DNA-based BC diagnostic urine test that we have developed with CRUK funding (now commercialised as the “Inform-Bladder” test (IB)). AIMS We hypothesise that the IB diagnostic urine test for bladder cancer (BC) could reduce (by >45%) the number of patients requiring flexible cystoscopy for the investigation of haematuria METHODS We will instigate a nested case-control study with 336 BC cases and 400 randomly-selected controls from a cohort of 3200 participants recruited over 3-years from 6 partner NHS institutions. We will identify the proportion of BCs detected by flexible cystoscopy in whom IB-testing is negative. For sensitivity, a sample size of 336 BCs will result in 80% power for assumed sensitivity of 87%. To confirm 91% specificity, 400 controls will be IB-tested for a 95%CI width of 6%. If IB sensitivity/specificity are 87%/91%, cancer prevalence among IB test-negative individuals would be sufficient to avoid cystoscopy; half of missed cancers would be detected by imaging and urine cytology. Thus, one could reduce the need of cystoscopy by >45%, whilst achieving a sensitivity to detect BC of c.95%. HOW THE RESULTS OF THIS RESEARCH WILL BE USED Through IB testing, we could potentially reduce UK haematuria clinic flexible cystoscopy episodes by 30,000-60,00 annually (reducing healthcare costs and increasing clinical capacity), and considerably reduce the burden of such investigations (contributing to increased health-seeking behaviour in symptomatic patients). If correct, these data would lead to definitive randomised studies accompanied by health-economic and implementation analyses, potentially resulting in national/international guideline adoption.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Birmingham United Molecular Pathology Technology Hub: SMP2 - Costed Extension
Funder: Cancer Research UK

Abstract: The laboratory will deliver targeted NGS analysis using a Nextera gene panel on FFPE lung biopsy samples. The panel of 20+ genes will detect SNVs, gene amplifications and translocations. Results will be reported back to a network of UK Clinical Hubs by xml messaging. Patients recruited through CR-UK SMP2 will be stratified through molecular profiling for recruitment into the national Matrix lung cancer trial.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: CANCER AND NEOPLASMS