NIHRDataInsights/HRCSData huggingface dataset:
Title: Clonal dynamics and self-renewal in normal and transformed intestinal epithelium
Funder: Cancer Research UK

Abstract: The somatic mutations that increase the risk of developing cancer can only become fixed within renewing tissues if they occur in stem cells. Subsequent mutational spread depends on stem cell replacements and expansions the extent of which is largely unknown. This programme aims to build a comprehensive clonal-level view of how neutral and advantaged variants arise, become fixed, spread and impact upon subsequent behaviours that predispose to cancer. At the population level how cells organize and interact to mediate self-renewal and support cancer growth is still not well understood. Previously we discovered that changes in epithelial clone size distributions with time are explained by competition between a small bottleneck population in intestinal crypts to which both stem and committed/lineage-primed progenitors contribute. To understand the role of progenitor plasticity in facilitating the fixation of mutations in homeostasis genetically altered mouse lines and clonal-level lineage tracing will be used to derive a fate map of self-renewal first describing, and subsequently inhibiting, the net contribution of committed or lineage-primed absorptive and secretory progenitors to the stem cell pool. The extent of lateral expansions mediated by altered crypt fission/fusion processes resulting from pro-oncogenic mutations that are implicated in CRC mutations will be determined. The notion that altered clonal behaviours arising within expanded fields of such mutations can confer a novel mutator phenotype based on biased or accelerated stem cell replacements to promote the rapid fixation of secondary mutation will be explored. To determine if field effects and clonal interactions allow tumours to form as a single expansion (or BigBang) event synergistic mouse tumour models dependent on initial epithelial priming of a field of pro-oncogenic mutation (including KrasG12D, Pi3kca, loss of p53, Fbxw7) followed by ENU chemical mutagenesis will be used. A combination of lineage-tracing and next generation sequencing will establish the extent of oligoclonality and identify cooperating events that drive tumour growth with different priming events. Comparable determination of clone dynamics in human colon will establish the extent to which the aged epithelium is a mosaic of juxtaposed and overlapping clones and how such changes in such dynamics associate with cancer risk. New methods for visualizing somatic variants will be developed and applied to patients stratified by genetic or lifestyle factors. Developing strategies to restrict the age-related mutational burden of pro-oncogenic mutation and cancer risk requires the knowledge of the rates of mutation fixation, expansion and interactions that this programme will generate.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Developing drugs for the treatment of Epstein-Barr virus-associated cancers using more widespread targets
Funder: Cancer Research UK

Abstract: Epstein-Barr virus (EBV) causes 200,000 lymphomas and carcinomas world-wide each year. These include Burkitt’s lymphoma (BL), Hodgkin’s lymphoma, diffuse large B cell lymphoma, post-transplant lymphoproliferative disease, nasopharyngeal carcinoma (NPC) and gastric carcinoma. The continued presence of EBV in tumour cells provides an excellent opportunity to develop anti-EBV therapies to specifically target these cancers and leave normal cells unscathed. However, to date no anti-EBV drugs are available and patients are treated with the same toxic and invasive chemotherapy, radiotherapy or surgical regimens as patients with tumours of non-viral origin. This project addresses this unmet need. All EBV-positive tumour cells produce the viral protein EBNA1 as it is required for the survival of the virus genome and the host cell, making it an excellent target for anti-EBV therapeutics. Screening for compounds that block EBNA1 activity performed thus far have used one EBV reference strain. New data shows that variants of EBNA1 distinct from the reference strain are more representative of globally-circulating strains. This project uses EBNA1 from the EBV reference strain and a widespread newly-identified strain in a fragment-based screen to identify hit matter for drug discovery. Our aim is to identify hits that target both strains, or the most widespread strain if not possible. We will then use medicinal chemistry approaches to produce analogues with appropriate ligand-binding and drug-like properties to test in in vitro and cell-based assays for disruption of EBNA1 functions and specific inhibition of EBV-positive tumour cell growth. We aim to identify a lead-like compound for onward studies to help reduce disease burden and provide targeted and kinder alternatives to current therapies.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/14/039: Add-Aspirin SC - Prospective sample collection for translational research within the Add-Aspirin trial
Funder: Cancer Research UK

Abstract: Background: The Add-Aspirin project incorporates four parallel, large phase III, double-blind, placebo-controlled randomised trials assessing the effects of aspirin on disease recurrence and survival after primary therapy in four common non-metastatic solid tumours (breast, colorectal, gastro-oesophageal and prostate cancer) within one overarching protocol. Overall we aim to recruit 11,023 participants in the UK and India. Recent evidence has suggested that aspirin could be an effective agent for the treatment of cancer in a number of tumour types, particularly in the adjuvant setting when the disease burden is low. Given that aspirin is a low cost, generic agent, available in both resource poor and resource rich countries, it has the potential to have a major impact on the global cancer burden. Aims: The aims of the Add-Aspirin sample collection are to provide a resource for future translational research that can: 1. Investigate the mechanisms of action by which aspirin exerts its anti-cancer effects. 2. Identify biomarkers that can select patients who are most likely to benefit from aspirin therapy. 3. Establish biomarkers that can identify patients who are most likely to experience serious toxicity on aspirin. 4. Allow the development of future proposals and collaborations utilising these samples. A unique strength of the proposed sample collection for the Add-Aspirin project is that collecting samples from participants with four different tumour types in a consistent manner will facilitate the study of mechanisms and processes common to the development of a number of tumours, as well as allowing the investigation of tumour site-specific questions. Methods: We propose to collect and store a blood and tumour sample from all participants registered in Add-Aspirin. Samples will be collected at registration, where consent is provided, and sent to the biobank (divided between two sites). A number of future translational projects utilising the collection are planned. Access to the samples (and linked clinical data) will also be available for other research groups, via an application process managed by the Add-Aspirin Translational Subgroup Access Committee. How the results of this research will be used: Establishing biomarkers to identify those that benefit most from aspirin, as well as those who are most likely to experience toxicity, will allow us to optimise the balance of risks and benefits. Furthermore this research aims to establish the mechanisms by which aspirin exerts its anti-cancer effects and so, potentially, provide new targets for cancer therapy.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: High-throughput laser-assisted Rapid Evaporative Ionisation Mass Spectrometry (Laser-REIMS) in the early detection and diagnosis of cervical pre-invasive disease.
Funder: Cancer Research UK

Abstract: Background: Although HPV-based screening offers a 60-70% greater protection against cervical cancer in women over the age of 30 when compared to cytology, it is expected to increase women that will test positive at screening due to low specificity. Reflex cytology that is currently used to select women for colposcopy, has demonstrated only moderate sensitivity and specificity, lacks automation and is prone to human error. Given the high prevalence of passenger HPV infections with no carcinogenic potential and the mediocre performance of most existing triage tests, novel technologies that offer rapid, cost-affordable and simultaneous HPV testing as well as automated triaging of women at high risk of high-grade precancer are highly sought after. Screen-positive women that are referred to colposcopy often require multiple punch biopsies for diagnosis prior to being offered local excision of precancer at a separate visit, as the diagnostic accuracy of colposcopy is poor and operator dependent. Innovative technologies are needed to offer bedside diagnosis at one-stop clinics minimising the risk of non-compliance, repeat visits and over-treatment. Aims: We aim to assess whether an innovative metabolomics-based platform, laser rapid evaporative ionization mass spectrometry (laser-REIMS) can A) replace hrHPV test and reflex cytology with a single, automated test for early detection in cell pellets of exfoliative cells. B) Offer a bedside diagnosis for women referred to colposcopy replacing the need for punch biopsies and permit immediate treatment. Methods: We propose a case-control cross-sectional to assess the diagnostic performance of laser-REIMS study of 380 liquid-based cytology and cervical tissue samples. We will explore whether laser-REIMS can detect: A) the presence high-risk HPV (hrHPV) infection and severity of cytological abnormality in the cell pellet derived from liquid-based cytology (LBC) samples (gold standard HPV test and cytology); B) the presence/grade of precancerous changes in cervical tissue biopsies (gold standard histology). We will calculate diagnostic accuracy parameters that include sensitivity, specificity and the area under the curve (AUC). How the results of this research will be used: Laser-REIMS holds promise as a single automated holistic platform for early detection and diagnostics in cervical disease. This rapid, low-cost, user-independent alternative can lead to improved patient satisfaction, compliance and substantial cost savings. Preliminary data suggests that this technology can detect with high accuracy (90-100%) hrHPV infection, abnormal cytology and cervical disease in tissue biopsies. Follow-on clinical studies will be performed to assess the value of laser-REIMS against current clinical workflows and allow clinical implementation.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Mitochondrial Oncogenetics
Funder: Cancer Research UK

Abstract: Mitochondria are a cellular nexus, performing numerous signalling, biosynthetic and bioenergetic functions. In humans, mitochondria are composed of ~1200 proteins, the vast majority encoded in nuclear DNA, with a minor subset encoded in the spatially and heritably separate mitochondrial DNA (mtDNA). The human mitochondrial genome is a genetically compact, circular, double-stranded DNA molecule of 16.5?kb, typically present at between 100 and 10,000 copies per cell on a cell type-specific basis. Encoded exclusively in mtDNA are subunits of the mitochondrial respiratory chain and ATP synthase, required for functional oxidative phosphorylation, and all RNA components necessary for their translation by mitochondrial ribosomes. Mutations, deletions and rearrangements of mtDNA are a known source of hereditary metabolic disease in humans, causing a broad spectrum of pathology underpinned by mitochondrial dysfunction. Mutations of mtDNA are also found in approximately 60% of all solid tumours, often at levels that would result in profound mitochondrial dysfunction. Mitochondrial dysregulation and dysfunction, particularly a switch from oxidative to glycolytic metabolism, is often observed in cancer. Our research focuses on determining the role of mitochondrial genetics and gene expression in human cancer.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Liquid Biopsies and Cancer Diagnostics
Funder: Cancer Research UK

Abstract: Background Methods for sensitive genomic characterisation of cell-free circulating tumour DNA (ctDNA) have enabled development of molecular diagnostic tools for cancer using plasma samples and other body fluids. So-called “liquid biopsies”, including those we developed, have entered clinical use for molecular stratification of patients to help select targeted therapies. ctDNA has shown promise for other applications such as prognostication and monitoring. One area of great interest is earlier diagnosis of cancer, recent data showing that ctDNA can be detected in nearly half of patients with stage I disease. However, most applications are still in early phases of translation to clinical practice. Aims 1) Develop cutting-edge methods to generate increasing data from non-invasive samples. 2) Identify further clinical unmet needs where cell-free genomic analysis can be informative, and demonstrate feasibility through proof of concept studies. 3) Delineate the potential of ctDNA as a diagnostic tool in early-stage disease, for earlier diagnosis and to detect residual disease after treatment. 4) Follow through discoveries to achieve clinical implementation of ctDNA testing for oncology. 5) Study the composition, biology and physiology of ctDNA and other nucleic acids in body fluids, to help guide their optimal use in cancer diagnostics and research. Methods We will refine an approach we developed using patient-specific sequencing panels, which provide exquisite sensitivity and resolution to study the features of ctDNA fragments. We will enhance technologies we pioneered including targeted and size-selected sequencing. Employing in-depth bioinformatic and machine learning tools to this multi-parametric data, we will learn about cell-free DNA biology and optimise assays. We will use model systems and study alternative sampling and processing methods. Applying these to clinical cohorts carefully curated by ourselves and collaborators, we will continue to develop the utility of ctDNA. In particular, we will leverage sensitive assays to study ctDNA where it is most difficult to detect, in early-stage disease, prior to diagnosis or after treatment, and in cancers with low levels of ctDNA. We will work with partner labs to standardise SOPs, scale and deploy assays for clinical use. How the results of this research will be used Initial ctDNA assays have been approved and are entering clinical use, but there are many opportunities to use information from cell-free DNA to improve cancer care. This research aims to translate the potential into clinical reality, by improving and standardising technologies; identifying and exploring unmet needs; and demonstrating and validating utility through clinical 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: A03 - Glo-BNHL: A Global Study of Novel Agents in Relapsed and Refractory B-NHL
Funder: Cancer Research UK

Abstract: Glo-BNHL is an international collaborative academic-led early phase clinical platform trial developed as a partnership between Innovative Therapies for Children with Cancer (ITCC), European Intergroup for Childhood NHL (EICNHL) and the US Children’s Oncology Group (COG). The trial is designed to efficiently assess the safety and efficacy of multiple prioritised novel agents in paediatric relapsed and refractory B-cell Non-Hodgkin Lymphoma (B-NHL). A direct output from the 2nd ACCELERATE Paediatric Strategy Forum, it is designed to successfully overcome two critical challenges: a paucity of patients and a plethora of potential assets. Despite significant improvements in frontline B-NHL treatment, the outcome for children with relapsed and refractory disease remains poor with long-term survival rates less than 30%. In addition, a ceiling of tolerable frontline therapy has been reached with toxicity now accounting for an equal number of deaths as disease. However, de-escalation trials cannot be prioritised until an effective regimen for those failing current first line therapy is established. Glo-BNHL will efficiently assess multiple novel agents in parallel, enrolling children with relapsed and refractory B-NHL into one of several cohorts, each containing a different novel agent. Potential assets will undergo a robust systematic scientific assessment by the International Trial Steering Committee to prioritise those with maximal potential for benefit. The initially prioritised cohorts include; bi-specific T-cell engager, antibody-drug conjugate and chimeric antigen receptor (CAR) T-cells. The primary objectives are to estimate the efficacy of each novel agent as a single agent or in combination with chemotherapy. Secondary objectives include; confirmation of the recommended phase II dose, assessment of the safety profile in children and young adults and determination of the pharmacokinetics and pharmacodynamics markers for the novel agent. An embedded translational project will improve our understanding of the biology of relapsed disease. The Bayesian design will facilitate efficient go/no-go decisions and assets with limited or no activity will be dropped quickly, facilitating inclusion of assets with greater potential. Those meeting ‘go’ criteria will transition seamlessly into an expansion cohort to deliver confirmatory evidence. The trial will be conducted according to International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and other regulatory standards to enable submission of data to the Regulatory Authorities to support Market Authorisation applications. Glo-BNHL will improve outcomes for future children with relapsed and refractory B-NHL by rapidly evaluating novel agents from multiple industry partners and supporting efficient registration of products shown to prolong survival.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/02/013: High Risk Neuroblastoma Study 1 of SIOP - Europe (Extension)
Funder: Cancer Research UK

Abstract: The aim is to improve the treatment of neuroblastoma.The trial has 3 randomised questions. The first to see if white blood cell growth factor during induction chemotherapy is beneficial. The second looks at 2 types of high dose consolidation treatment. The third at the role of a specific tumour antibody. Last updated 10/08/2006


Research activity codes: 6.1 PHARMACEUTICALS;6.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: In-depth investigation of the role of inflammation and the immune system in renal cancer incidence and survival
Funder: Cancer Research UK

Abstract: Background Incidence of renal cell carcinoma (RCC) is rising globally, especially in the UK. The only established potentially modifiable risk factors for RCC are obesity, smoking, and blood pressure, and sex is a strong risk factor. Little is known regarding biological pathways underpinning these associations. Aims 1) Identify novel circulating inflammation biomarkers of RCC risk and survival through analyses of prospective cohort studies and clinical case-series. 2) Evaluate whether inflammation markers mediate or moderate associations with known RCC risk factors including sex, obesity, tobacco smoking, and blood pressure. 3) Examine the association between inflammation markers and tumour characteristics by conducting molecular pathological and genomic analyses. Methods 1) In a discovery analysis we will measure 92 circulating immune/inflammation proteins using the Olink Immuno-Oncology platform on (i) 550 case-control pairs within the European Prospective Investigation into Cancer and Nutrition cohort to investigate markers of risk, and (ii) 750 RCC cases from the Mutographs study to investigate survival. We will then conduct a replication analysis of these results using a custom panel of biomarkers. We will use the Northern Sweden Health and Disease Study (250 case-control pairs) to replicate associations with RCC risk, and the K2 study (630 cases) to replicate associations with RCC survival. 2) We will identify inflammatory signatures of RCC risk factors including obesity, smoking, blood pressure, and sex, by examining associations of RCC risk factors with individual biomarkers and sets of biomarkers. Discovery and replication analyses will be conducted as in objective 1. We will follow-up sets of markers associated both with risk factors and RCC risk in mediation analyses. 3) Biomarkers identified in objectives 1 and 2 will be investigated for associations with tumour size, stage, and grade, and genomic characteristics (such as abundance of somatic mutations and mutation types) in renal tumour tissue from 750 RCC patients. How the results of this research will be used The evidence on biological mechanisms can inform prevention measures by highlighting the strategies most likely to have an effect on the underlying pathway to disease, and to inform public health messages aimed at reducing the burden of RCC. Newly identified aetiologically relevant biomarkers could be used as intermediate outcomes in intervention trials for weight change, smoking cessation, or blood pressure reduction. Newly identified strong immune and inflammatory biomarkers of RCC could subsequently be evaluated for clinical utility, and rapidly translated into practice for risk prediction, early detection, prognostication, and clinical management.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS