NIHRDataInsights/HRCSData huggingface dataset:
Title: Determining the role of Myc in tumour progression and tumour regression
Funder: Cancer Research UK

Abstract: Our work addresses two unanswered and largely overlooked questions in cancer biology. 1. Are cancers irreducibly complex and diverse or does their diversity arise from a small number of shared, mission-critical oncogenic processes upon which diverse cancers absolutely depend? 2. Why do targeted therapies work? Unlike conventional chemotherapies, most target mitogenic signals are not inherently toxic. Nonetheless, they can trigger rapid regression of both tumours and their attendant stroma – at least until their efficacy is circumvented by adaptation or evolution. The answers to these two key questions appear mechanistically entwined. Our past work revealed that Myc, a central transcriptional coordinator of somatic cell proliferation, is essential for the development and maintenance of many, perhaps most, cancers – even when it is not itself a mutated “driver” of the disease. Myc cannot yet be targeted pharmacologically but we showed that genetic inhibition of endogenous Myc triggers immediate regression - of both tumours and stroma - in diverse mouse cancer models. We developed mouse models that allow for rapid and reversible in vivo activation of Myc, allowing us to observe the immediate cause-and-effect process by which Myc activation drives adenocarcinomas, and Myc de-activation triggers their regression. When activated in the epithelial compartment of KRasG12D-driven adenomas, Myc triggers immediate and synchronous progression to adenocarcinomas whose diverse phenotypes differ from tissue to tissue yet all the signature characteristics of spontaneous adenocarcinomas from each tissue. Hence, the basic tumour/stromal phenotypes of adenocarcinomas are properties of their tissue of origin rather than the oncogenes driving them. Subsequent de-activation of Myc, in the epithelial tumour compartment, immediately triggers wholesale and immediate regression of both tumour and attendant stroma. In this proposal, we test two hypotheses. 1. That oncogenic Myc “hacks” into the innate injury repair response of tissues, giving cancers their signature tissue-specific phenotypes. 2. That Myc de-activation also acts as a switch – one that hacks into the physiological resolution programme of tissue normalization that terminates the physiological injury response. Each hack is instructed by discrete, tissue-specific sets of instructive signals that are released from the epithelial compartment and specified by the generic Myc switch in a tissue-specific way. We seek to understand these instructive signals and identify obligate downstream Myc effectors – those that drive the transition to adenocarcinoma when Myc is switched on, and those that reverse that transition and trigger regression when Myc is switched off.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: The Cancer Research UK Newcastle Drug Discovery Unit (2021-2025)
Funder: Cancer Research UK

Abstract: Background: The CRUK Newcastle Drug Discovery Unit (DDU) is an integrated, interdisciplinary team of cancer biologists, pharmacologists, structural biologists and medicinal chemists developing novel cancer treatments. Anticancer drug design is well established in Newcastle, the DDU has played a pivotal role in the discovery and development of two medicines licensed in the previous quinquennium. The same period has seen two further compounds originating from Newcastle programmes entering clinical trials, including the first compound to emerge from the Unit’s productive portfolio alliance with Astex Pharmaceuticals. The current leadership and research team assembles experience from industry and academia to conduct internationally competitive drug discovery. Aims: We aim to identify novel, differentiated small molecule drugs that address unmet clinical needs, using cutting edge technological approaches. Our ambition for this quinquennium is to deliver at least one additional candidate medicine and experimentally evaluate 10 new target hypotheses. Methods: We develop and apply technologies to address challenging cancer targets. We work with clinical colleagues and fundamental bioscientists from Newcastle and the wider cancer community to identify targets and apply comprehensive bioinformatic tools to assess their relevance to a significant patient population. We repeat and extend published target validation results using diverse genetic manipulations and pharmacological tools, exploiting access to clinical samples where this helps to model disease and healthy tissue behaviour. We conduct hit-finding screens either in house or collaboratively with partners, with a focus on structural and biophysical fragment-based approaches that use our strengths in synthetic chemistry and structural biology to develop and apply novel methodologies. Structure-based screening and molecular design are at the heart of our approach to iterative medicinal chemistry to develop hits into drugs. As hits are elaborated, they are assessed in biochemical and biophysical assays, and progressed to sophisticated disease models to verify their mechanism of action and demonstrate the anticipated anti-cancer activity. How the results of this research will be used: The key outputs of this research will be candidate drugs for the treatment of patients with advanced cancers. We will continue to develop technology to enhance the productivity of drug design: the protocols and reagents we develop constitute further results that will be used by the wider drug discovery community. Our programs will also result in probe molecules that will be used to dissect the roles of specific targets in normal and diseased tissue.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: UK Children's and Young People's Cancer Biobank
Funder: Cancer Research UK

Abstract: Background The Children’s Cancer & Leukaemia Group (CCLG) Tissue Bank is combining with the childhood leukaemia bank (CellBank) to form the UK Children’s & Young People’s (CYP) Cancer Biobank to allow streamlining of sample banking, pooling of expertise for sample handling and to enable pan-cancer applications to be handled from a single access point. Aims a) To merge the childhood leukaemia CellBank with the CCLG Tissue Bank to form the CYP Cancer Biobank and promote awareness and visibility of the new Bank. b) To provide a comprehensive, national resource of genetically and clinically well-annotated samples to promote world-class collaborative research into CYP with cancer. c) To consolidate the UKCYP Cancer Biobank as the leading repository for clinical trial-associated collections for solid tumours and leukaemia. d) To increase sample quality and increase numbers of samples, particularly “liquid biopsies”. e) To provide a national repository as a stimulus to increase tissue banking within the teenage and young adult (TYA) community. f) To strengthen Patient & Public Involvement (PPI) links Methods Newcastle University will continue to host tissue from solid tumours and UK Biocentre in Milton Keynes will store liquid samples including blood and bone marrow. The CYP Cancer biobank will be managed by teams predominantly at Newcastle University, but also the University of York, and will be overseen by a Biobank Steering Committee involving multiple stakeholders with strong PPI involvement. A Sample Access Committee will give access to tumours for researchers. The York leukaemia CellBank database will be expanded to store the CCLG tissue database and linked with NHS England whole genome sequencing and Public Health England databases. Links with clinical trial units will be further strengthened. Pathways to increase banking rates for solid tumours and quality of leukaemia samples have been initiated, and will be further developed with a particular focus on improving TYA banking. How the results of the research will be used The CYP Cancer biobank will provide a vital genetically and clinically annotated resource for researchers in the UK and worldwide to advance our knowledge into the causes, diagnosis and treatment of childhood cancer and leukaemia. Through high quality storage of clinical trial associated collections, trial-associated costs can be reduced and material released for approved research in a timely way. By strengthening PPI links, we can optimise the numbers of families offered and participating in tissue banking.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: CANCER AND NEOPLASMS
Title: International clinical research programme to improve outcomes in newly diagnosed Ewing Sarcoma – Trial 1 (INTER-EWING-1)
Funder: Cancer Research UK

Abstract: BACKGROUND: Ewing sarcoma (ES) is a sarcoma of the bone and soft tissue, 80 % occurring in adolescents and young adults, with a peak incidence in the second decade of life. Metastatic ES is a major challenge, with 55% survival in lung/pleura metastatic disease only, and 30% with metastases to other sites. Once relapse has occurred survival is very poor 20 % and 10 % in localised and metastatic relapse. Any improvements in outcomes will need trials incorporating improvements in local control (radiotherapy) and new systemic therapies, including targeted agents driven by biological knowledge. AIMS: INTER-EWING-1 is a comprehensive clinical research programme to improve outcomes in al newly diagnosed ES. METHODS: The INTER-EWING-1 trial includes multiple randomised questions at multiple stages in the treatment pathway in a phase III study with four principal aims. These are to evaluate; 1. The introduction of regorafenib into current standard regimens in metastatic ES (A) 2. Dose escalation of definitive radical radiotherapy as local therapy to the primary tumour site to improve Event Free Survival (EFS) and Overall Survival (OS) by reducing both local and metastatic events (B1) 3. The optimal dose of post-operative radiotherapy following surgical resection of the primary tumour site in achieving optimal local tumour control, EFS and OS (B2) 4. The addition of maintenance treatment after the end of consolidation therapy to reduce events and improve OS (C) In addition, ancillary studies will ; • Validate tumour biomarkers as predictors of drug resistance in all ES, and for patients with localised disease prediction of those at high risk of relapse • Evaluate the predictive and prognostic value of circulating nucleic acids, including circulating miRNAs, mRNAs and DNA. • Investigate the application of circulating nucleic acids, including miRNAs, mRNAs and DNA to monitor patients during consolidation and maintenance treatment. • Evaluate Diffusion Weighted- MRI (DW-MRI) and 18F-fluoro-2-deoxy-glucose ([18F]FDG) positron emission tomography (PET)/computed tomography (CT) (FDG PET- CT) response assessment during induction chemotherapy is a prognostic biomarker for local failure and/ or survival • Evaluate the accuracy of Whole-Body MRI (WB-MRI) in the staging of ES patients • Evaluate whether FDG PET-CT at diagnosis can replace bone marrow aspirations • Evaluate the pharmacokinetics of regorafenib in combination regimens • Evaluate he impact of these new interventions on quality of life (QoL) HOW THE RESULTS OF THIS RESEARCH WILL BE USED: To provide evidence base for future care of patients with ES.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: CRUKD/17/016 TASTER: Defining leukaemic cell clonal architecture to inform and monitor drug responses in the TASTER CML Phase II Clinical Trial
Funder: Cancer Research UK

Abstract: Background:Management of CML requires life-long, expensive tyrosine-kinase inhibitors TKI)that can cause significant side effects. While TKI induce remission they are rarely curative due to persistence of TKI-resistant leukaemic stem cells(LSC) that evolve to drive TKI-resistance and disease progression. Recently our aim has been to identify survival factors that can be exploited therapeutically to eradicate TKI resistant LSC and manage unmet clinical need in CML. We've pioneered a systems biology programme and delivered three evidence-led drug targets,p53,c-Myc and EZH2, which show clear therapeutic windows between CML and normal stem cells. Aims: We hypothesise TKI-resistant LSC will show variability within and between patients and reflect inherent or acquired/evolving molecular differences that can be identified in the laboratory and translated into clinic. We'll evaluate the efficacy of HDM2i,EZH2i or BETi in combination with TKI, integrating the TASTER clinical trial into a scientific work programme. Overall we want to understand how LSC clonal architecture changes during drug treatment and whether these changes can be computationally modelled to predict drug response. Methods: DNA-bar-coding, single-cell genomic,transcriptomic sequencing and SWATH MS proteomics will be used to monitor leukaemic cell clonal architecture in response to TKI and HDM2i,EZH2i and BETi,in CML patient-derived xenografts(PDX). The resultant transcriptomes will be clustered and cross referenced to the barcodes, the proteomics data and the cell surface markers to assemble multi-dimensional molecular signatures of LSC clonal architecture which will be used to train in silico models of drug response. TASTER will be conducted in TKI-non-responder patients to determine whether HDM2i,EZH2i or BETi can be safely combined with TKI to improve treatment response. We will derive LSC molecular signatures directly from patients enrolled in TASTER,and further train our in silico models with the aim of predicting outcomes to these novel agents and as a rationale for switching agents for patients that fail to achieve the primary efficacy endpoint with first agent they receive. We'll determine whether TKI-resistant LSC clones exist at low levels in CML drug-naïve diagnostic samples and use our in silico models as predictors, at point of diagnosis, of the efficacy of standard-of-care or our novel therapies. How the results of this research will be used. We anticipate our experimental programme will yield valuable insights into LSC clonal evolution and predictive molecular signatures across the entire clinical timeline of CML from diagnosis, through TKI therapy and TKI-resistance, and potential for sustained therapy free remission through introduction of novel therapies in TASTER trial.


Research activity codes: 5.1 PHARMACEUTICALS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Defining risk in smouldering myeloma (SMM) for early detection of multiple myeloma (MM)
Funder: Cancer Research UK

Abstract: Background. Multiple Myeloma(MM), a fatal plasma cell cancer, is preceded by a precursor condition, smouldering myeloma (SMM), which carries a 50% risk of progression to MM in the first 5 years. Current clinical practice is to observe patients with SMM, only initiating therapy when signs of organ damage develop. Progression to MM is accompanied by bone pain, fractures, renal failure, and cure is rare. Improved understanding of the molecular basis of tumour evolution will improve detection of MM in SMM patients, leading to earlier intervention and improved outcomes. Aims. 1. Define the genomic characteristics of clonal evolution in bone marrow tumour cells 2. Determine clonal heterogeneity and biomarkers of progression in liquid biopsies 3. Define immunosuppressive mechanisms in the tumour micro-environment that accompany progression from SMM to MM 4. Investigate the effect of RANK-L antibody in high risk SMM patients Methods. We will use an established SMM cohort with biobanked material, and prospectively collected samples (PROMISE study(US), DEFENSE study(UK) and local UCL SMM clinic). Whole genome and exome sequencing of bone marrow(BM) tumour cells for genomic aberrations (mutations, structural variants) associated with early progression, and targeted deep sequencing to identify small sub-clones will delineate clonal architecture and the genomic landscape associated with clonal evolution. Similar methods will be applied to cell free DNA (cfDNA) and circulating tumour cells (CTC) from blood samples. Testing of serial blood samples will determine the feasibility of using such liquid biopsies for disease monitoring. The BM immune environment will be interrogated using high dimensional flow cytometry, computational spatial analysis of BM biopsies, single cell sequencing, and an RNA-based TCR-sequencing platform for diversity and depth of T cell receptor(TCR) repertoire. The DEFENSE study is a randomized trial of the anti-RANK-ligand antibody, Denosumab, in high risk SMM patients. We will track changes in tumour and environment with treatment and disease evolution. Integrated biostatistics and bioinformatics will be coordinated from the Broad Institute, to build a multi-parameter model for biomarkers of progression. How the results of this research will be used. Our model will inform a risk stratified approach to identify SMM patients with early MM/high risk of progression, to receive MM-directed therapy(earlier detection), preventing end organ damage, and improving clinical outcomes. Those at low risk of progression will be managed in primary care, reducing healthcare resource use and improving wellbeing. Mechanistic insights will lead to new therapies that will make MM a preventable or possibly curable disease.


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: Cancer Research UK Radiation Research Centre of Excellence at The Institute of Cancer Research and The Royal Marsden Hospital
Funder: Cancer Research UK

Abstract: Background: For decades, radiotherapy (RT) has been viewed from an entirely tumour cell-autonomous perspective in which successful therapy results from inflicting breaks in nuclear DNA above an unspecified threshold beyond the cell’s capacity for repair. Increased understanding of the importance of non-tumour cell-autonomous, immunological aspects of RT-induced cell death in the context of the tumour micro-environment has altered this perception. Clinical responses to RT are inextricably linked to the immune system. The intrinsic biology of tumours, their associated microenvironments, and the physical characteristics of the delivered radiation, all influence the immunogenicity of RT. We posit that by understanding and modulating cross-talk between molecular responses to RT-induced DNA damage, associated mechanisms of cell death and subsequent innate and adaptive immune responses we will improve clinical outcomes of RT. We hypothesise that these benefits will be amplified by new radiation delivery platforms that allow us to challenge dogma relating to physical concepts of RT delivery, particularly relating to spatial, dose-rate and dose-fractionation aspects of therapy. Aims: The central goal of our RRU will be to link discovery, translational and clinical research with direct line of sight to patient benefit. Our RRU will be based on 5 interlinked research themes. Methods: In Theme 1, we will study molecular responses to radiation-induced DNA damage (MRDD) with particular reference to cancer-specific vulnerabilities that, with or without additional combination therapies, render them susceptible to RT-induced cell death. Theme 2 will focus on harnessing cell death mechanisms to modulate RT-induced immune responses. We will channel irradiated tumour cells towards mechanisms of death that are most likely to activate anti-tumour immunity. In Theme 3, we will evaluate radiation-induced innate and adaptive immune responses, especially with additional therapeutic agents (oncolytic viruses, innate immune agonists, cell cycle-targeted radiosensitisers). Theme 4 will assess novel temporo-spatial dose-modulations and altered fractionation regimens as ways of improving therapeutic outcomes from RT. This research will be based around physical and biological characterisation of microbeam, ultra-high dose-rate and partial tumour intensity-modulated RT. In Theme 5, we will conduct translational and clinical research based on discoveries and insights from Themes 1-4. This work will involve forward and reverse translation with a strong emphasis on clinical samples from biological endpoint studies. How the results will be used: Through a better understanding of molecular responses to RT-induced DNA damage and mechanisms of cell death, we will enhance the therapeutic efficacy of standard and novel forms of RT delivery.


Research activity codes: 5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: CanRisk: Personalising cancer risk prediction for prevention and early detection
Funder: Cancer Research UK

Abstract: Background: Much more reliable and powerful risk prediction for breast, ovarian and prostate cancer can be achieved by combining data on all genetic, lifestyle and hormonal risk factors for the diseases. We have recently enabled multifactorial cancer risk-assessment through the CanRisk tool (www.canrisk.org) which allows healthcare professionals to obtain personalised cancer risks easily. Aims: The objective of this programme is to enable cancer risk prediction within front-line healthcare, to facilitate the identification and management of at-risk individuals and to promote cancer prevention and early-detection. The proposal will address the following specific research questions: 1. What improvement can be achieved in personalised cancer risk prediction that takes advantage of recent discoveries in cancer genomics and epidemiology and that is clinically valid across populations? 2. How can we optimise user-friendly tools to facilitate the use of multifactorial cancer risk prediction in routine clinical practice? 3. How can we operationalise multifactorial cancer risk assessment in primary care and in clinical genetics? Methods: The goals will be achieved through the development of novel cancer risk modelling methods and their application to data from large epidemiological studies to address key challenges in breast, ovarian and prostate cancer risk prediction. These include risk-prediction of cancer subtypes, prediction in individuals of non-European ancestry, prediction of contralateral breast cancer risks and modelling uncertainty in personalised cancer risks. We will incorporate the findings into the CanRisk tool for use by healthcare professionals and develop a new tool for use by patients, enabling them to enter their clinical information into CanRisk prior to their healthcare consultation. We will assess the feasibility, acceptability, the psychological and economic impact of providing multifactorial cancer risk assessment using CanRisk, including polygenic risk scores, in primary care and clinical genetics. We will also use CanRisk to design a new multifactorial cancer risk assessment pathway in clinical genetics. How the results will be used: The proposal will take cancer risk stratification to a new, highly personalised level which will allow prevention or screening approaches to be targeted to those most likely to benefit. It will facilitate informed decisions on the timing and type of cancer risk management maximising benefits and minimising harms. Results will be used to design future trials on risk-stratified cancer prevention and early detection approaches, resulting in state-of-the-art models of service delivery for risk-based approaches in routine clinical care.


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