NIHRDataInsights/HRCSData huggingface dataset:
Title: Validation and cellular origins of clonal expression biomarkers in lung cancer
Funder: Cancer Research UK

Abstract: Background: Transcriptomic biomarkers hold the translational potential of capturing features of cancer cell aggressiveness to stratify pre-invasive lesions, allowing early clinical intervention, and the identification of “born to be bad” primary tumours, which are at high-risk of early systemic dissemination. Despite two decades of research, prognostic gene expression signatures have not been translated into clinical practice for lung cancer owing to poor reproducibility in independent patient cohorts or failure to provide information additional to established clinical risk factors. Working in the TRACERx lung study, we have observed that the pervasive intratumour heterogeneity observed in lung cancer confounds molecular biomarkers, as 30-40% of tumours gave a different molecular read-out depending upon where the biopsy needle was placed. To solve this, we derived a subset of genes that were homogenously (“clonally”) expressed within individual tumours to design the Outcome Risk Associated Clonal Lung Expression (ORACLE) signature. This novel biomarker validated in a meta-analysis of more than 900 patients, and associated with survival independent of clinicopathological risk factors in a multivariate analysis. These data indicated that, if further validated, ORACLE could help identify high-risk lung cancer patients missed by current clinical criteria. Aims: 1. Biomarker qualification of a prognostic assay for early-stage lung cancer patients. 2. Determine if clonal transcriptional signals demarcate “born to be bad” lung lesions. 3. Explore the pan-cancer applicability of clonal biomarker design. Methods: Perform transcriptomic profiling on clinical samples from a longitudinal cohort study (TRACERx) and a prospective screening study (ASCENT) towards prospective validation and clinical translation of the ORACLE biomarker. Use transcriptomic profiling to examine clonal expression signatures in pre-invasive (TRACERx) and disseminated (PEACE) lesions in relation to the paired primary tumour (TRACERx), asking whether high-risk clonal expression changes are “hard-wired” prior to tissue invasion, and whether the lethal, disseminating clone detectable in the transcriptome of the primary tumour. Utilise multi-region expression datasets for breast and colorectal cancer to investigate whether ORACLE can be optimised within individual tumour types for risk stratification. How the results of this research will be used: Data from these analyses will prospectively validate ORACLE towards clinical translation as a prognostic biomarker in lung cancer. In addition, our ‘clonal expression biomarker’ framework will be extended to fuel biomarker discovery for early detection of lung tumours at high-risk for early systemic dissemination, and the use of clonal biomarker design as a general strategy across cancer-types.


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: A “top-down” organ-on-chip approach for personalised medicine in ovarian cancer
Funder: Cancer Research UK

Abstract: Background: The tumour microenvironment (TME) determines how patients respond to cancer drugs, but current models do not fully replicate the native TME. In this project, we develop a “top-down” organ-in-chip technology to maintain the viability and function of large tumour explants outside the body for ex vivo screening and analysis. “Top-down” contrasts with 3D culture and organ-on-chip methods that engineer the TME from the “bottom-up” using a limited toolbox of cell types and matrix components that will always struggle to reproduce the full complexity of real TME. The EPS challenge is that large explants die quickly in static culture due to hypoxia and limited nutrient diffusion. Aims: To maintain viability, we place the explant into a microchannel that achieves perfusion and advective nutrient delivery. We aim to demonstrate that perfusion preserves viability and gene expression of the native tumour, such that the drug response measured ex vivo reflects the clinical response in vivo. Methods: We focus on ovarian cancer, a leading cause of cancer related death due to high therapeutic resistance. We first develop the design using the transplantable ID8 mouse model that provides reproducible metastatic tumours with minimal biological variability. We then move to human samples obtained from debulking surgery. Results will used to establish a novel model for ovarian cancer that preserves the native TME for drug testing that is more predictive of the patient response. Our device could be used for personalised medicine by determining which patients are best suited for PARPi therapy. Once established for ovarian cancer, our technology can be adapted to other cancer types where explants can be obtained from surgery or core needle biopsies.


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: CANCER AND NEOPLASMS
Title: RNA and Translational Control in Cancer
Funder: Cancer Research UK

Abstract: The dysregulation of protein synthesis in the tumour clone and the supporting stroma is essential for the delivery of oncogenic gene programmes that allow the establishment of both the intracellular and extracellular environments. This is driven by two fundamental post-transcriptional processes. First, hyperactivation of the eIF4F translation initiation complex results in the specific upregulation of oncogenic mRNAs. Secondly, a fundamental shift within tRNA pools promotes oncogenic gene expression programmes by altering the protein synthesis landscape. Recent data from our group and others show that these two processes are coordinated by a number of distinct regulatory RNA-binding complexes and suggest that there is cross-talk between these key steps of the translation process. Our current hypothesis is that these complexes control and connect all post-transcriptional stages of the mRNA lifecycle, from selection, through decoding, to turnover. The balance of expressed tRNA and codon usage of oncogenic mRNAs that are sensed by these complexes represent a targetable axis of the malignant phenotype, which could be explored therapeutically if mechanistic understanding was available. The research in our laboratory focuses on understanding how RNA-binding protein complexes, tRNA abundance and codon optimality dictate oncogenic protein production in a coordinated manner. We employ biochemical, biophysical and computational methods to address these questions. We are interested in how the changing tumour environment results in the redeployment of mRNA-binding complexes that control the balance between upregulation of protein translation and mRNA turnover and translational silencing. These mechanistic insights drive our endeavours in designing assays and drug discovery pipelines to target the heart of tumour cell biology.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Improving patient outcomes in oesophageal adenocarcinoma using cancer evolutionary trajectories
Funder: Cancer Research UK

Abstract: Normal healthy cells in our bodies regularly divide to form 2 daughter cells, each of which carries the DNA from the parent cell. During this process, errors occur during the creation of DNA, leading to mutations. Most mutations are harmless, but some may cause cells to become cancerous. By detecting mutations in apparently healthy oesophagus tissue we aim to identify people that are likely to develop oesophageal cancer. When we compare cancers occurring in different people, we can group them according to the types of mutations that have occurred, and by the order in which mutations have occurred. In prostate cancer we have classified cancers into groups that we call ‘evolutionary subtypes’ or just ‘evotypes’. In this project we will combine data generated in previous research projects with new DNA sequencing data from normal tissue from patients with cancer, and use novel analysis techniques to identify evotypes of oesophageal cancer. Previous work suggests that different evotypes may be more or less aggressive. By identifying at an early stage patients that are likely to develop an aggressive cancer, we will help doctors to tailor treatment appropriately for these tumours, moving one step further towards personalised medicine.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: From primary diagnosis to relapse or cure; a comprehensive sample collection from patients with stage II melanoma
Funder: Cancer Research UK

Abstract: Background Most patients with stage IIB/C melanoma have low relapse risk after surgery but a minority develop metastatic disease. A biomarker is urgently required that enables accurate prediction of that minority who progress to stage IV disease and may benefit from early therapy. We demonstrated that circulating tumour DNA (ctDNA) detects early relapse when there is no radiological evidence of disease (by CT scan) and are currently running the CRUK-funded DETECTION trial to test whether early treatment of disease relapse based on detectable ctDNA with immunotherapy improves survival. Aims This sample collection will enable 1. Improved identification of patients at risk of relapse with additional liquid biomarkers measured at baseline and longitudinally. 2. Identification of biomarkers for early prediction of systemic immune responses when patients with micro-metastatic disease are treated with immune checkpoint inhibitors (IO), compared to clinical/radiological relapse. 3. Patients to be spared potential toxicity and NHS costs reduced by early identification of those who are refractory to IO and need alternative treatment approaches. Methods DETECTION is a Phase III, multicentre trial of early vs. standard treatment of melanoma relapse based on ctDNA detection in patients with stage IIB/C melanoma (n=1050). In addition to the funded blood sampling for BRAF/NRAS/TERT promoter ddPCR ctDNA analysis within the trial to direct treatment, baseline and longitudinal blood samples will be analysed for ctDNA methylation and for circulating tumour cells (CTCs). Assay sensitivity and specificity will be compared to the current ddPCR assay to better identify patients at high risk of relapse. Blood for biomarker discovery will be sampled at baseline and on day 1 of the first 3 treatment cycles (6 weeks of treatment) in patients with detectable ctDNA or who relapse and are then treated with IO. Peripheral blood mononucleated cells will be immune-phenotyped, T cell receptors sequenced and cytokines assessed. Algorithms based on candidate biomarker data will be used to develop predictive scores that identify early, those relapsing patients who will progress on IO. How the results of this research will be used We will a) evaluate whether liquid biopsies based on assays including ctDNA methylation and/or CTCs are superior to the current ddPCR ctDNA mutation detection approach for early identification of melanoma relapse; b) develop biomarkers that identify patients with high risk of progression on immunotherapy. These data will support future trial designs examining early treatment switching to improve patient outcomes.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: A complete cartography of cancer through multiscale molecular imaging
Funder: Cancer Research UK

Abstract: Research Abstract Background: As our knowledge of systems biology rapidly increases, there is a growing imbalance between identifying key functional nodes and the ever increasing information we are generating. We learn more and more about alterations in gene expression patterns and genetic mutations driving alterations in protein function. In contrast to the recent advancements in functional genomics, the actual molecular mechanics is poorly understood. Building an understanding of the inter- and intra- heterogeneity of tumours and their evolution over time and in response to therapy requires greater insight into the underlying biology, using in vivo and in vitro models. Aims: By pursuing a multiscale (organ to sub cellular) and multi-omics approach with a range of mass spectrometry imaging (MSI) techniques (MALDI, DESI, SIMS, ICP MS and REIMS), we aim to deepen our understanding of the interplay of genes, proteins, metabolites and the role of the immune system in cancer development and growth. Methods: We will establish a multimodal imaging pipeline which gives a comprehensive, spatially resolved picture on the metabolism of solid tumours from subcellular to anatomical levels using in-vivo, ex-vivo and in-vitro analyses. We will analyse a selection of highly heterogeneous GEMMs before exploring the heterogeneity of histological segments in healthy and cancerous tissues of 3 epithelial cancers (breast, colorectal, pancreatic). We will image the metabolic effects of a range of therapeutic interventions. How our results will be used: These experiments will provide new information about the broader metabolic wiring and allow us to better determine the plasticity of the tumour metabolism pre-clinically. Importantly our strategy will allow us to spatially link this to an underlying genotype. We will elucidate specific metabolite profiles determined by individual stromal cell lineages and the metabolic relationship between tumour cells and the microenvironment. We will uncover site specific metabolic profiles and compare the differences in tumours in primary and secondary sites (delivering a 4D solution; tracking a cancer through time). We will innovate methods for the non-invasive/minimally invasive detection of tumour phenotypic segments by MRS and include real-time intraoperative detection of tumour phenotypic segments using REIMS/iKnife technology. During our project we will release a scalable database for complex multi-modality datasets and metadata, and a web visualisation tool providing a Google Earth view of a tumour. Throughout the project we will undertake the metrology studies required to deliver reliable, repeatable and translatable methodologies to the wider community.


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: Molecular risk stratification in patients with T1 colorectal cancer
Funder: Cancer Research UK

Abstract: Background: Molecular interrogation has improved our biological understanding of colorectal cancer (CRC), although it is yet to significantly contribute to standard patient care, particularly in early stage disease. The CRC landscape has changed in recent years, due to the implementation of the bowel cancer screening (BCS) programme, which detects asymptomatic cancers earlier; prior to BCS, stage I accounted for approximately 9% of CRC, but within the screening programme 42-48% of CRCs are diagnosed at stage I. Within these early BCS-detected cancers there are “born-to-be-bad” lesions; tumours with highly aggressive phenotypic and adaptive traits, which would otherwise be diagnosed as metastatic disease, but due to BCS are being detected earlier. Non-aggressive lesions can be managed with local excision, however, current standard of care histological assessment is unable to reliably differentiate between aggressive and non-aggressive early lesion; information that is essential in tailoring appropriate clinical management decisions. This is particularly relevant in rectal cancer, where the choice of radical resection over local excision is associated with significant mortality (up to 6.5%) and morbidity (30–68%), including sepsis, permanent/temporary stoma and diminishing quality of life. BCS provides an opportunity to both learn about aggressive CRC biology, and critically, to generate biomarkers of risk to aid clinical decision making. Aims: This proposal aims to develop and independently validate a stratifier, based on risk-of-relapse in early-invasive CRC, through comprehensive molecular and histological profiling of a novel T1 cohort. In doing so, we will generate the World’s largest molecularly characterised T1 cohort (n=550+), enabling further biological discovery and improved biological understanding of early-stage CRC. This stratifier will ultimately be used to inform the clinical management of CRC disease at the earliest stage. Methods: • Collection and molecular/pathological profiling of T1 CRC with mature clinical data, using discovery and validation cohorts. • Translation bioinformatics analyses and histological assessment to comprehensively characterise biological signalling associated with early-dissemination. • Generation and validation of a robust panel of molecular and/or histological markers applicable to formalin-fixed diagnostic or archival tissue, which discriminates between T1 lesions based on risk-of-relapse. Uses: In order to find any effective treatment you have to first understand the biology underpinning disease. Given paucity of focussed molecular studies of T1 CRC, there remains a lack of understanding of specific factors underpinning prognosis at this early stage. Therefore, a molecular biomarker to discriminate T1 lesions based on risk would significantly influence clinical intervention and address an area of clinical need.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Developing Early Intervention Strategies for High-Risk Clonal Hematopoiesis
Funder: Cancer Research UK

Abstract: The myeloid malignancies are a group of related blood cancers, including acute myeloid leukaemia, myeloproliferative neoplasms and myelodysplastic syndromes. Together, they affect 8-10 per 100,000 individuals per year and remain lethal to the majority, due to a lack of effective treatments. In the last few years, we discovered that these cancers arise from the shared pre-cancerous phenomenon of clonal haematopoiesis (CH). CH develops due to DNA mutations in blood-making cells that make them grow more than normal cells to establish a “clone”. CH becomes increasingly common with advancing age affecting more than 25% of people aged 60 years or older. Thankfully, most remain asymptomatic and have no clinical problems. However, in approximately 1-2% of cases CH develops into a myeloid malignancy. Recently, we reported that individuals that develop these cancers can be identified years in advance by the type of DNA mutations in their blood. This raised the possibility that we can identify and treat at-risk individuals in time to prevent the development of myeloid malignancies. Here, we propose to use stateof-the-art genetic and compound screens to find the vulnerabilities of high-risk CH and develop treatments.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Development of a cheap sensitive blood test for early detection of new and proven biomarkers of glioblastoma using fluorescent carbon dots and nanophotonics
Funder: Cancer Research UK

Abstract: Background Around 60,000 patients in the UK are living with a brain tumour. Overall only 20% of brain tumour patients are alive 5 years after diagnosis, in part because they present late with large inoperable tumours. In the UK in 2013: 38 % of brain tumour patients visited their GP 5 times or more before referral to secondary care for diagnosis by imaging MRI/CT scan and neurosurgical biopsy, because the symptoms such as headache are non-specific. There is an urgent need to develop new sensitive tests of brain tumours to help GPs in primary care. The most common malignant primary brain tumour called glioblastoma is characterised by abnormal blood vessels resulting in a leaky Blood Brain Barrier BBB. Glial Fibrillary Acid Protein (GFAP) is unique to the brain not present in normal peripheral blood. Antibodies to GFAP are used to diagnose gliomas in tissue samples. There is evidence that GFAP crosses the leaky BBB and is an early non-specific peripheral blood biomarker which predates the clinical diagnosis of glioblastoma. However GFAP levels are too low for routine detection by routine protein detection tests such as ELISA. We have already identified other novel potential protein biomarkers of brain tumours using an epidemiological approach called Mendelian Randomisation (MR) which may be present in low levels in the blood. Nanoparticles have shown promise in early detection of cancer by fluorescent labelling of very low levels of biomarkers in blood samples and other fluids. Fluorescent Carbon Dots (FCDs), nanoparticles designed by Prof. Galan (Co-I), are cheap and easy to create using a three-minute synthesis. FCDs can be readily attached to ligands such as antibodies targeting specific protein markers. FCDs labelling biomarkers can then be detected using nanophotonic technology developed by Fluoretiq (Co-I) for rapid, sensitive, and low-cost diagnosis. Computational modelling is used to predict tumour size given biomarker availability in blood, and determine the theoretical limits of the detection. Aim Development of a highly-sensitive cheap blood test to aid early diagnosis of brain tumours using Fluorescent Carbon Dots attached to antibodies to known and novel protein biomarkers. Methods 1) Identification of novel glioma biomakers using on Gliogene Consortium and GICC datasets 2) Patient sample collection and neuropathological analysis 3) Antibody based functionalisation of FCDs to target blood-based proteins 4) High-sensitivity detection using FluoretiQ device 5) Computational modelling of biomarker levels in blood samples given tumour size This will inform a cohort study.


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: The TRACC Programme: to Train and Retain Academic Cancer Clinicians
Funder: Cancer Research UK

Abstract: We aim to build a cadre of cancer-orientated clinician scientists, trained for clinical and research excellence and leadership through a fully integrated clinical academic training programme. These clinician scientists will interface with the wider cancer clinical community, making critical contributions to CRUK’s mission to improve 10-year survival rates to 3 out of 4 cancer patients by 2034. Our vision combines the excellent scientific and clinical research strengths and complementarity across the CRUK Beatson Institute and CRUK Glasgow and Edinburgh Centres, together with existing expertise in both cities in developing clinical academic training, to create a person-centred and flexible clinical academic training programme that will attract the best undergraduate and postgraduate medical trainees and enable them to contribute to world-leading basic, translational and clinical research. We will provide mentorship and practical support to sustain them post-PhD to completion of their clinical and research training and a long-term clinical academic career. We thereby aim to nurture and retain the next generation of leading clinical academics in cancer for Scotland and beyond.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS