NIHRDataInsights/HRCSData huggingface dataset:
Title: Targeting dysregulated translational control in the tumour environment
Funder: Cancer Research UK

Abstract: Background Oncogenes are exquisitely dependent upon the eIF4F complex for their translation, which unwinds mRNA structure and facilitates ribosome recruitment. It acts as a signalling hub positioned at the end of several mitogenic pathways, and its upregulation is a common feature of malignancy and leads to drug resistance. The effector component of the eIF4F complex is the mRNA helicase eIF4A, and inhibition of this protein shows dramatic well-tolerated anticancer effects in animal models. eIF4A possesses two paralogues: the widely studied eIF4A1, and the highly similar eIF4A2, which are often assumed to be functionally redundant. However, our recent data show divergent functions and expression patterns of these two proteins. eIF4A1 is required for translation initiation and cellular proliferation; its expression defines proliferative regions within tissues and tumours, and predicts poor outcome in many cancers. eIF4A2 is expressed in mature differentiated and secretory cells and tumour stroma, induces growth arrest, and predicts good outcome. eIF4F activity is critical for driving malignant gene expression programs in tumours, and any attempt to target eIF4F therapeutically will require in-depth mechanistic understanding of this process. Aims/Methods This project utilises multiple approaches to mechanistically dissect and evaluate therapeutic targeting of eIF4F, particularly the helicase activities of eIF4A paralogues, in lung, colon and pancreatic cancers. 1. How does eIF4F direct the expression of oncogenes and tumour suppressors in tumour and stromal compartments? Using several approaches, including ribosomal profiling and RNA structure analysis, we will determine how eIF4F drives the translation of mRNAs encoding specific cancer-related proteins, thereby determining its influence over proteomes from both tumour and stromal cells. 2. How does eIF4A function in normal mammalian development, homeostasis, and carcinogenesis? Tissue-specific mouse genetic knockouts that ablate eIF4A1/eIF4A2 will allow us to determine their roles in normal tissues. They will be crossed into established cancer models to test their effects on tumour development. 3. What are the clinical and biological ramifications of eIF4F dysregulation in human tumours? Using quantitative multiplex in situ histological methods we will determine how these proteins and the translational landscapes that they command relate to patient survival, cellular/microenvironmental tumour phenotypes, and tumour genotypes. Outcomes We will characterise the molecular roles of eIF4F/eIF4A in cancer and determine how they control intracellular and extracellular proteomes in both neoplastic cells and stroma. These studies will identify targetable vulnerabilities at the mechanistic heart of the cancer phenotype, and identify molecular targets and patient groups for clinical application.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Stromal rigidity as a driver of pancreatic adenocarcinoma progression
Funder: Cancer Research UK

Abstract: BACKGROUND In pancreatic ductal adenocarcinoma (PDA), an extensive stromal reaction drives tumour progression and contributes to disease lethality. Defining the causes of the desmoplasia, and the consequent effects of elevated extracellular matrix rigidity on tumour cell growth, invasion and resistance, would be pivotal steps in the quest to improve patient outcomes. The development of new strategies to normalise cellular responses to desmoplasia is needed, which requires a deeper biological and mechanistic understanding of the effects of rigidity on cells. In the current quinquennium, our principal discoveries have strengthened support for a functional connection between rigidity sensing and cell cycle control, but have also challenged some current paradigms. AIMS Cancer evolution, including genome instability, and PDA are major strategic priorities for CRUK. In the next quinquennium, we will contribute to the research effort in both areas by defining how specific extracellular matrix/integrin adhesion complex (IAC) components regulate tumour-promoting processes such as cell cycle progression and accumulation of DNA damage. Our immediate objectives for the next five years are direct extensions of the current programme: 1. To define rigidity-sensing mechanisms operating at the plasma and nuclear membranes. 2. To determine how rigidity sensing is coupled to cell cycle control and accumulation of DNA damage. 3. To elucidate how rigidity sensing links to tumour progression in PDA. EXPERIMENTAL PLAN/METHODS We have established new techniques for global analyses of IACs using proximity labelling and mass spectrometry, and for three-dimensional culture of pancreatic organoids. We will build on these advances to define how variations in extracellular rigidity initiate signalling at IACs, elucidate the mechanisms that drive subsequent cell responses, and define how rigidity signalling connects to both the cell cycle machinery and activation of DNA damage responses. In parallel, we will determine the relationship between genetic aberrations in PDA and the response to tissue rigidity, elucidate the links between tumour cell differences in rigidity signalling and tumour progression, and identify common convergence points responsible for tumour cell adaptation to different rigidity environments. HOW THE RESULTS WILL BE USED The outcomes of the programme will: (a) advance our conceptual understanding of cell adhesion signalling in tumour progression/biology; (b) define optimal ways to disrupt tumour cell dependencies on adhesion signalling; and (c) develop line-of-sight for defining patient populations that would benefit (or not) from therapies targeting rigidity-sensing pathways. These findings will be relevant not only to PDA, but to other desmoplastic cancers.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/12/039: CaPP3 - a double blind randomised controlled dose inferiority trial of aspirin prevention in people with Lynch syndrome: high risk of cancer due to mutations in the mismatch repair genes (supported by Stand Up To Cancer)
Funder: Cancer Research UK

Abstract: Background: CAPP2 recruited worldwide 1009 people with the Lynch syndrome (LS) who are at high risk of hereditary cancer due to being carriers of mismatch repair gene defects; it showed, in a randomised placebo controlled trial format that 600mg daily aspirin for 2 years results in 63% reduction in colorectal cancer and similar reduction in other related cancers, apparent from 4 years (Burn et al Lancet 2011). It is important to establish whether this protective effect can be achieved with lower doses of aspirin and, consequently, fewer adverse events and to support translational studies of underlying mechanism. Aims: CaPP3 will be a double blind randomised dose inferiority trial (RCT) designed to compare the degree of cancer prevention resulting from three daily doses of enteric coated aspirin; 600mg, 300mg and 100mg. Methods:Recruits will be adults of 60 or under who have been shown to have a constitutional pathological variant in one of the mismatch repair genes (hMSH2, hMLH1, hMSH6 or PMS2), who are not known to be sensitive to aspirin. The UK regional genetics centres have identified approximately 6500 adult LS gene carriers (based on 2011 audits) and all are under 1 to 2 yearly followup colonoscopy. Gene carriers will be consented and blood/ saliva biobanking samples collected before blinded dose allocation via secure website: www.capp3.org, regular review and cancer registry data will be combined to assess impact on new cancers and adverse events related to medication for at least 5 years. Sample size calculation used CAPP2 observed “survival probability” for all Lynch related cancers and colorectal cancer: 0.889 and 0.949 after 5 years respectively. The null hypothesis is that 600 mg aspirin as active control is superior to the new treatments (300 mg and 100 mg aspirin). We have estimated that all Lynch syndrome cancers will be reduced by 50% using 600mg while 100mg will result in a 25% reduction. If 300mg results in a 30% reduction, the target would be to follow 1000 participants in each group. Parallel studies in other countries using the same randomisation are under development and will provide greater power. Application: This trial will establish a new international standard of care in hereditary cancer and inform the debate about more widespread use of aspirin to prevent cancer, especially in people with a personal or family history of cancer.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: CANCER AND NEOPLASMS
Title: Understanding the impact of telomere dysfunction on the evolving cancer genome
Funder: Cancer Research UK

Abstract: Background Telomere dysfunction and cellular crisis occur in early-stage lesions and cancers, across a broad range of tumour types, leading to genome-wide mutation and genomic complexity that generates the genetic variation required to facilitate clonal evolution and tumour progression. The purpose of this programme of work is to understand the mechanisms by which telomere dysfunction drives the evolution of the cancer genome and to identify ways to exploit this information for clinical benefit. Aims 1. Identifying genomic vulnerabilities to telomere fusion. Identification and characterisation of regions of the genome that are vulnerable to telomere fusion in crisis cells; understanding how telomere fusion is modulated in distinct epithelial cell lineages; dissecting cellular heterogeneity during crisis; characterising telomere to non-telomeric interactions. 2. Investigating the mechanism and impact of genomic catastrophe in crisis. Examining the genomic context in which telomere-induced genomic damage occurs, the mechanism of telomere-dependent chromothripsis and whether a telomere-driven crisis modulate the immunogenicity of cells. 3. Investigating DNA repair processing at telomeres and the impact on the escape from crisis. We have identified over 40 genes that influence a-NHEJ activity at human telomeres, we will investigate the role of these genes in processing of telomeric DSBs, the suppression or promotion of a-NHEJ activity and the impact this has across the genome. 4. Examining how telomere dysfunction impacts the cancer genome and how this can be exploited for patient benefit. We will use publicly available cancer genome data to detect signatures of telomeric mutation and examine the impact of telomere fusion in primary pre-neoplastic lesions. Based around our ability to detect mutation in single DNA-molecules, we will develop tools that have the potential to aid in clinical decision making and we will evaluate mechanisms to intervene in the process of telomere fusion and crisis. Methods We will utilise our single-molecule approaches to isolate and characterise telomere fusion events at the molecular level in human cells and combine these with high-throughput sequencing to characterise the impact of telomere fusion across the genome. Our bespoke bioinformatic pipelines will allow us to characterise genomic data for signatures of telomere-driven chromothripsis. How the results of this research will be used? We will use our understanding gained from this work, to provide new molecular markers of tumour progression and to exploit potential avenues for therapeutic intervention in the earliest stages of tumour development.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Alternative lengthening of telomeres: induction, maintenance and vulnerabilities
Funder: Wellcome Trust

Abstract: To maintain unlimited proliferative capacity, cancer cells must maintain their telomeres. ~85% of cancers achieve this by up-regulating telomerase, while the remaining ~15% of cancers employ the Alternative Lengthening of telomeres (ALT) pathway. Currently, there are no targeted treatments for ALT cancers, which have a poor prognosis and are universally aggressive. Insights into the mechanisms that promote/are essential for the ALT process may reveal vulnerabilities that could be exploited therapeutically. However, the lack of a cellular model that permits the induction of ALT has severely limited our ability to interrogate the underlying mechanisms. We have recently made a key discovery that Kaposi’s Sarcoma Herpes Virus (KSHV) infection triggers the stable acquisition of ALT. In this application, we will exploit KSHV to identify the host and virally encoded factors that are critical for ALT induction. Using PICh to interrogate the proteomic composition of telomeres, we have identified 703 proteins that are specifically enriched at ALT telomeres. We will perform a “703 ALT” CRISPR dropout screens to identify genes that modulate/are essential in ALT cancer cells but are dispensable in normal cells. Our proposal will expand our understanding of the ALT process and may identify critical vulnerabilities, which could be targeted therapeutically.

Lay abstract: To divide indefinitely, cancer cells must maintain their chromosome ends (called telomeres). Cancers solve this problem by either expressing an enzyme that lengthens telomeres or by recombining and copying telomeres by Alternative Lengthening of Telomeres (ALT). ALT cancers are very aggressive and there are currently no targeted treatments. Until recently, it was not possible to induce ALT in the laboratory. However, we discovered a virus, KSHV, which induces ALT as a means to copy its own DNA. We aim to exploit this finding to interrogate the mechanism of ALT induction. To discover factors essential for ALT, we have also identified proteins that are specifically enriched at ALT telomeres. We will screen these proteins to identify those that are essential for the survival of ALT cancers but are dispensable in normal cells. Our proposal will transform our understanding of the ALT mechanism and may reveal vulnerabilities that could be exploited therapeutically.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Single-cell cancer evolution in the clinic
Funder: Cancer Research UK

Abstract: Cancers adapt to therapy through a process of clonal evolution. Patients undergo multiple rounds of potentially highly toxic treatments, without a clear pre-emptive indication of efficacy. When the patient relapses, meaningful information to choose the most effective treatment is rarely available. There is therefore an unmet clinical need to develop tools, applicable to the clinic, to determine how cancer evolves under therapy. Accumulating evidence indicates that resistance to specific treatments entails recurrent evolutionary mechanisms. We argue that these recurrent mechanisms do not just beset a formidable hurdle for cancer therapy, but also represent a major Achille’s heel for cancer cells that could be exploited for novel therapeutic approaches. The recent introduction of single-cell genomics approaches has finally provided a mean for the comprehensive understanding of the evolutionary strategies exploited by cancer cells as a population. In particular, profiling rare, treatment-resistant subclones at single cell level is becoming feasible. In this proposal, we combine cancer evolution modelling, new single-cell approaches and novel microfluidic devices, as well as new data integration techniques, with the aim to provide a definitive single-cell portraits of tumor cells, before and after treatment. We propose to deliver tools and devices that could be promptly implemented in a clinical setting, to pre-emptively intercept resistance in individual cancer patients.


Research activity codes: 5.1 PHARMACEUTICALS;5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Improving outcome for patients with Poor Risk Acute Myeloid Leukaemia
Funder: Cancer Research UK

Abstract: Background: Acute Myeloid Leukaemia (AML) is characterised by the accumulation of immature cells called myeloblasts within the bone marrow, with patients presenting with symptoms of Bone Marrow Failure (BMF) and resultant sepsis or bleeding. It is the most common form of leukaemia in adults with seventy percent of patients dying from their disease, mostly within 12 months of diagnosis. Chromosomal abnormalities represent the best-established prognostic marker, dividing patients according to various outcome groups with poor or adverse patients comprising monosomies, chromosome 3 or 11q abnormalities or complex karyotypes, all of which have a dismal 10 year survival. We believe that improvements in care of this patient group will not be achieved by focussing on any single deregulated pathway or actionable mutation and we need instead to generate new knowledge on the mechanisms responsible for promoting and sustaining the pathophysiology of these leukaemia, and how these impact on both the bulk tumour, normal and leukaemic stem cell population. Aims: Our programme sets out to improve on existing treatments for patients with poor risk AML. Methods: This will be achieved by combining the efforts of 5 established UK groups into an unified programme of 4 interrelated work packages (WPs) that focus on new knowledge generation (WP4) through the integration of Genomic (WP1: WGS, RNA-seq) Cell Signalling (WP2: Proteomics and Drug testing) and stem cell profiling (WP3: CyTOF, normal HSC profiles) in a series of 50 poor risk AML patients. How the results of this research will be used: The results will provide new insight into the biology of poor risk disease, will inform our existing translational studies that include ‘targeting the phospho proteome’ and ‘reawakening normal stem cell function’, and will fuel new and innovative research projects based on our data integration WP. The programme will lead to new clinical trial activity in the area of poor risk disease and the capability to align patients to treatments based on their underlying biochemical profiles.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Structural and mechanistic understanding of UPR signal activation
Funder: Cancer Research UK

Abstract: The unfolded protein response (UPR) is an essential cell signaling system that detects the accumulation of misfolded proteins within the endoplasmic reticulum (ER) and initiates a cellular response in order to maintain homeostasis. These cellular responses include: transcriptional up regulation of UPR target genes, general cell translation attenuation, activation of ER associated degradation pathways (ERAD), and ER enlargement. However, failure to rectify the imbalance and to restore homeostasis, commits the cell to eliciting an apoptotic response. Although, recently there have been some advances in our knowledge relating to the molecular basis of UPR signaling, there still remains a lack of clear molecular/mechanistic understanding to how UPR signaling is induced and its subsequent propagation, hampering the effort to target UPR signaling for therapeutic intervention. In this current proposal, we aim to understand the fundamentally important mechanistic details of UPR signal induction, using a combination of structural biology, biochemistry, and cellular biology approaches in order to provide definitive insights into molecular basis of function.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Leeds Clinical Trials Unit core funding
Funder: Cancer Research UK

Abstract: Background : Cancer Research UK provides core funding for CTUs to support delivery of an innovative and practice changing clinical research portfolio. Aims : This application is for core funding support for the Leeds CTRU, University of Leeds. Methods: •The core funding support will enable ; Development of a portfolio of world leading clinical trials and associated translational research that will focus on new agent radiotherapy combinations (including immunotherapy) and advances in radiotherapy technology across a range of tumour sites • Strengthening and expansion of our role as the international leader in multiple myeloma and chronic lymphocytic leukaemia, leading national and international clinical trials, international meta analyses and associated translational research • Development and training of the next generation of clinical researchers and methodologists, to become the leaders of the future • Enabling further operational and methodological research to guide efficient and innovative trial design and delivery. How results will be used: The trials and associated translational research undertaken through the CRUK CTU will impact on the lives of patients on a global scale, will raise the profile of clinical trials research in cancer and provide a focus for CRUK branding and fundraising in the North of England.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS