NIHRDataInsights/HRCSData huggingface dataset:
Title: Towards targeting neutrophils in hepatocellular carcinoma
Funder: Cancer Research UK

Abstract: Background. Primary liver cancer is the 5th most common cancer worldwide and the 2nd and 7th major cause of cancer deaths in men and women respectively. Hepatocellular carcinoma (HCC) accounts for the majority of cases and its rising incidence is associated with the emergence of obesity-related non-alcoholic fatty liver disease. With recently published and new preliminary data the principal investigators (Mann, Reeves and Owens) have developed a new paradigm for the pathogenesis of HCC that implicates neutrophils as key inflammatory drivers of cancer inception and growth. Importantly, neutrophils have a highly dynamic phenotype and respond to factors in the disease microenvironment (e.g. TGFß) by transitioning between pro- and anti-tumour states. The goals for this research programme are to discover how neutrophil phenotype is influenced by HCC disease stage (and treatment), determine if neutrophil phenotype can be modulated for therapeutic benefit and illuminate the mechanisms by which neutrophils promote cancer in the diseased liver. In addition the applicants will collaborate with AstraZeneca to determine if small molecule modulators of neutrophil phenotype and function can suppress HCC and enhance anti-tumour immunity. Specific Aims: we will determine: (1) The phenotype and behavior of human neutrophils in association with HCC disease stage and how these characteristics influence response to treatment. (2) The role of reactive oxygen species and elastase as mediators of neutrophil-driven HCC. (3) The role of TGFß as a modulator of neutrophil phenotype and HCC growth and the potential of small molecule inhibitors of TGFß signaling to have therapeutic benefit. (4) If blocking CXCR2-mediated chemokine recruitment of neutrophils can suppress HCC and if small molecule inhibitors of CXCR2 can enhance anti-tumour immunity. Methods: Neutrophil phenotyping in HCC patients blood - using flow cytometry, functional assays and RNAseq - will be interpreted alongside patient and tumour characteristics, including response to treatment. Carcinogen, dietary and ageing models of HCC in mice will be combined with genetic deletions and small molecule inhibitors targeted to neutrophils to assess the role of reactive oxygen species, TGFß and CXCR2. Complementary in vitro studies will employ a unique liver bioreactor to study human neutrophil-liver signaling interactions that stimulate HCC in the context of chronic liver disease. How the results of the research will be used. This programme will generate new insights into the pathobiology of HCC, establish neutrophils as important cancer modulators and unlock new biomarker and therapeutic options to be exploited in collaboration with clinical and industrial collaborators.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/15/007: PLATO - PersonaLising Anal cancer radioTherapy dOse - incorporating ACT 3, ACT 4 and ACT 5 trials (supported by Stand Up To Cancer)
Funder: Cancer Research UK

Abstract: Background: Anal cancer is a rare disease but its incidence is rising rapidly. Approximately 1000 cases in the UK and 5,000 in the USA are diagnosed each year. The UK has a proven track record in performing phase III trials in this disease. We performed the largest phase III trial (of three) that determined concurrent Mitomycin C, 5 Fluorouracil and radiotherapy as a new standard of care. Three further phase III trials (ACT2 was the largest) concluded that neoadjuvant and maintenance chemotherapy did not improve cancer specific outcomes. Aims: A new generation of clinical trials is now required that optimises radiotherapy dose based on stratified risk assessment. PLATO is an integrated trial in which the most relevant clinical research questions are asked within three distinct risk strata. Methods: Three trials are proposed. ACT3 is a phase II study for the small minority of anal margin tumours suitable for local excision alone with selective lower dose involved field CRT for patients with deep or lateral margins = 1mm. ACT4 is a randomized phase II trial that compares standard CRT with reduced dose CRT in patients with T1-2 (up to 4cm) N0 disease. ACT5 is a seamless pilot, phase II and phase III trial that compares standard CRT with two radiotherapy dose escalation arms using a synchronous integrated boost. One of the two experimental arms will be selected for the phase III component of the study. How the results of this research will be used: The outcomes of the trials are likely to have a significant impact on clinical practice, future clinical trials, and influence both national and international guidelines. ACT3 will determine whether a strategy of surgery alone for patients with clear margins and low dose involved field CRT results for T1N0 anal margin tumours results in acceptably low rates of locoregional failure. ACT4 will determine whether dose de-escalation results in low rates of locoregional failure and reduced acute and late toxicity. ACT5 will determine whether, in locally advanced disease, dose escalation reduces locoregional failure with acceptable rates of acute and late toxicity. PLATO will provide valuable data across the locoregional disease spectrum for future imaging ,biomarker and radiobiology research with prospective high quality cancer outcome and patient reported late toxicity data for a range of defined radiotherapy dose fractionations.


Research activity codes: 6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Systematic functional characterization of somatic regulatory mutations driving estrogen receptor positive breast cancer progression
Funder: Cancer Research UK

Abstract: Background: The dramatic phenotypic changes that define most solid cancers are the consequences of profound transcriptional aberrations. Transcriptional anomalies are often ascribed to somatic changes (mutations) occurring in 2% of the human genome, i.e. protein-coding genes (oncogenes2 and/or onco-suppressor genes). However, an important paradigm shift has occurred in the last few years revealing the importance of non-coding regulatory DNA in coordinating transcription and cell identity. Conservative estimates indicate that regulatory regions account for nearly 50% of the genome where they are organized within defined 3D structures (topological associated domains: TADs). Regulatory regions are associated with precise epigenetic states involving histone modifications, chromatin accessibility and DNA methylation. Whole genome sequencing (WGS) data demonstrate that the majority of mutations occur in non-coding regions, however a critical question remains unsolved: what is the contribution of somatic regulatory mutations (SRMs) in altering the information stored at critical regulatory regions? Aims: This proposal is divided in three main aims (systematic characterization, evolutionary profile and functional manipulation of SRMs). Our first aim is to identify and prioritize SRMs targeting the regulatory landscape of ERa BCa patients. Our second aim is study how SRMs emerge and expand during cancer progression. Our last aim is to investigate the functional consequences of SRMs and how they can be exploited in the clinic. By aim3 we will have focused on 5-10 recurring functional SRMs. Methods: Using my epigenetic expertise, I have generated important preliminary data and developed a sensitive and cost-effective targeted strategy to identify potential SRMs drivers. My approach allows for longitudinal analysis of clinically treated patients to study tumor progression and the evolution of drug-resistance. The main hypothesis is that SRMs target regulatory regions and alter gene expression by: 1) altering TFs binding and epigenetic states of oncogenic regulatory regions 2) disrupting the binding sites of TFs involved in chromatin organization and insulation (CTCF). I will use ERa positive breast cancer (BCa) as a model considering that: 1- 97.4% of somatic mutations target non-coding DNA 2- ERa positive BCa is driven by a restricted number of enhancer specific TFs 3- ~3% of patients relapse each year with endocrine therapy resistant disease suggesting progressive tumor evolution. 4- I have access to the most appropriate longitudinal, patient-derived samples with extensive clinical annotations. Impact:- I will identify new potential drivers to improve personalized medicine in a cancer population with unmet need (metastatic BCa) using the most appropriate clinically annotated material.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Enhancer subversion and its role in the generation and maintenance of Acute Myeloid Leukaemia
Funder: Cancer Research UK

Abstract: Background. Cis-regulatory elements, such as enhancers, fine tune transcriptional activity and generate tissue specific gene expression patterns through three-dimensional interaction with gene promoters. There is growing evidence that activity of these elements is corrupted in cancer, with acute myeloid leukaemia (AML) an exemplar of this process. Studies in AML have demonstrated recurrent and frequent mutations in the trans-acting transcription factors, epigenetic regulators and structural proteins that regulate enhancers. Furthermore, structural chromosome rearrangements have been shown to recruit aberrant enhancer function to critical leukaemia genes. However, exactly how these enhancers are corrupted, the genes aberrantly expressed under their control and the identity of the trans-acting factors remain poorly understood. Aims. We will identify critical enhancers, the genes that they regulate and the trans-acting factors that control them. These critical nodes will then be assembled into regulatory networks and validated in functional experiments. We will look to establish common mechanisms of enhancer corruption and correlate these with specific mutational genotypes. These will inform the biology of AML, identify and validate potential therapeutic targets and, as we will use chemical inhibitors already in the clinic, will inform the mechanisms of action of some drugs. Methods. We will combine longitudinal studies in sophisticated mouse models of AML generated by combining common mutant alleles, allowing us to examine dynamic enhancer function prospectively. Using state-of-the-art genomic techniques (ChIP-Seq, ATAC-seq, RNA-Seq and promoter based Capture Hi-C), we will link the activation state of specific enhancers, their three-dimensional interaction and chromatin accessibility with gene expression and determine how this evolves with development of the disease. Using the same techniques in patients with AML we will also catalogue critical enhancer elements, leukaemia genes and regulatory trans-acting factors. We will functionally validate these elements singly and genome wide using CRISPR activation, CRISPR interference and chemical inhibition allowing us to assemble critical transcriptional networks across multiple AML genotypes. How the results of this research will be used. Taken all together, our work will provide a better understanding of the transcriptional rewiring that occurs with AML evolution and also to identify critical network nodes that are required to maintain leukaemia. These data will help us to better classify AML, and will further identify potential targets that might be therapeutically exploited to improve the dismal outcome in this aggressive disease. These studies will also have mechanistic and therapeutic implications beyond AML to inform biology and therapy in other cancers.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS
Title: CRUK/11/054:FOCUS 4 - Molecular selection of therapy in metastatic colorectal cancer: a molecularly stratified randomised controlled trial programme (supported by Stand Up To Cancer)(CA)
Funder: Cancer Research UK

Abstract: Background: Colorectal cancer is a heterogeneous disease where standard approaches to evaluation of novel therapies have frequently failed to make progress and prognosis in metastatic inoperable disease remains poor. Aims & Objectives: The aim of the study is to test rationally selected targeted drugs to detect if they have single agent or combined novel-novel activity as demonstrated by an increase in progression free survival in the chemotherapy free interval following first line chemotherapy in biomarker enriched subpopulations of patients with metastatic colorectal cancer. Methods: Patients’ tumours will be analysed for genetic mutations, mrna expression and immunohistochemistry for a panel of biomarkers and will be segregated into 5 cohorts: BRAF mutation; KRAS/NRAS mutation; EGFR dependant, DNA repair deficient and unclassified. Following 16 weeks first line therapy, patients with stable or responding disease on standard criteria will be randomised between active novel agent(s) and placebo in a maintenance strategy, using targeted therapies hypothesised to be effective within that biomarker selected population. The primary endpoint will be progression free survival from randomisation, with a shorter term endpoint for early stopping in the case of futility. How results will be used? To provide robust evidence of activity of the novel therapies in biomarker enriched populations; to further develop the biological categorisation and understanding of colorectal cancer; to prospectively validate certain biomarkers as predictive markers for the novel therapies under evaluation; to provide an environment within which novel agents may be rapidly tested in biomarker defined sub-populations of patients with metastatic colorectal cancer. To improve the outcome of patients with metastatic colorectal cancer by providing a greater understanding of the molecular diversity of the cancer and of its response to novel therapeutic approaches.


Research activity codes: 5.1 PHARMACEUTICALS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Bone Morphogenetic Protein signalling and stromal-epithelial interaction in intestinal inflammation and carcinogenesis.
Funder: Wellcome Trust

Abstract: The intestinal mucosa is a complex ecosystem and the epithelium has a dynamic relationship with underlying stroma. Key aspects of intestinal homeostasis and disease states, including inflammatory bowel disease and cancer are characterized by the interdependence of the epithelial and stromal compartments. Inter-compartmental cell-signalling pathways regulate intestinal epithelial cell fate determination in homeostasis, and transient perturbation of these networks is required in the physiological response to inflammation and injury. This promotes epithelial stem cell behaviour, cell proliferation and migration as part of a wound healing response. However, failure of restoration of homeostatic control in chronic inflammation, or pathological disruption of signalling can result in neoplasia initiation and progression. In resultant tumours, optimally selected somatic mutation spectra differ and reflect these variable influences on lesion pathogenesis. This proposal will explore these concepts using disruption in Bone Morphogenetic Protein signalling and it's pleiotrophic antagonist Gremlin1, as exemplars of the paradigm. Specific goals include: 1. Identifying stromal cell populations expressing Grem1 in intestinal regeneration and tumour desmoplasia. 2. Assess the functional role of BMP disruption in these conditions. 3. Using mouse models to test therapeutic manipulation of BMP signalling. 4. Using somatic mutation analysis to generate molecular biomarkers of Grem1 initiated tumourigenesis.

Lay abstract: Inflammation, wound repair and cancer are inextricably linked, to the extent that cancer is often described as the "wound that never heals". This is because many of the chemical message networks that restrain and control epithelial stem cell growth in health are deranged in both wound repair and cancer. In regeneration, temporary signalling disruption from wounding allows cells to divide to replace those lost. In cancer, permanent disruption of signalling pathways leads to unrestrained cell division, one of the key hallmarks of malignancy. This project focuses on a key signalling pathway called Bone Morphogenetic Protein (BMP). A team of gastroenterology scientists will use human tissue and state-of-the art biological models to explore how BMP signalling is temporarily disrupted during wound repair and to see how these important functions can be co-opted and corrupted by cancer. Goals include: 1. Identifying cells responsible for expression of BMP constituents in health, wounding and cancer. 2. To understand how this signalling pathway impacts upon wound repair and tumour growth 3. To test potential new drugs that affect BMP signalling. 4. To use characteristic mutation patterns to identify human tumours that originate from BMP disruption and see if they behave differently to other cancers.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Exploiting the effects of low mural cell beta3-integrin in the control of cancer progression, therapy resistance and metastasis
Funder: Cancer Research UK

Abstract: Resistance to therapy and cancer metastasis are the main causes of cancer related deaths. Identifying patients who have a high risk of progression and determining alternative strategies to treat them is required. It has become increasingly apparent that deciphering the molecular mechanisms that promote therapy resistance and metastasis at different stages of the disease will likely identify the most effective targets for the treatment of advanced cancers. Most of the research to date has focused on mechanisms intrinsic to tumour cells, but effective strategies are still a limited. Evidence indicates that cells that constitute tumour blood vessels, including supporting mural cells, can control these processes. Our laboratory is recognised for identifying the molecular control of cancer growth and therapy efficacy by tumour blood vessels. We have recently discovered that loss of mural-cell beta3-integrin promotes intracellular signalling pathways that stimulate paracrine signals to accelerate primary tumour growth without affecting vascularisation. Importantly, these data are clinically relevant. We show, in human cancers, from different stages of progression, that low mural beta3-integrin expression is associated not only with an increase in tumour burden but also with higher cancer stage, relapse rates and metastasis (Wong and Muñoz-Félix et al., Cell 2020). However, how mural beta3-integrin regulates cancer progression, therapy efficacy and metastasis is unknown. The studies proposed in our CRUK programme grant are directly relevant to improving our understanding of the mechanisms by which mural beta3-integrin regulates cancer progression, resistance to therapy and metastasis. The strength of this programme is underpinned by being designed in partnership with our co-investigators, a group of internationally recognised oncologists, pathologists and metastasis experts. Together we will determine whether low mural beta3-integrin expression identifies patients, of the same cancer stage, who are at high risk of progression and metastasis. We will exploit the fact that loss of mural beta3-integrin enhances signalling pathways in mural cells and associated malignant cells that, when targeted, might identify clinically relevant molecular vulnerabilities. We will validate putative mechanisms, in mural cells and malignant cells, that we have already discovered, and also identify new molecular players that will be tested functionally in mouse and in vitro models of cancer progression, therapy resistance and metastasis, with the ultimate aim of improving the control of cancer progression and metastasis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Cancer vulnerabilities
Funder: Cancer Research UK

Abstract: This programme focuses upon using genetic principles to identify and optimise precision medicine approaches to cancer. Despite a working understanding of the processes that drive tumourigenesis, targeted therapy approaches that exploit this information are either: (i) still not available for most patients; or (ii) are available but limited in their effectiveness by drug resistance. For example: --therapeutic approaches that target alterations in the FBXW7 or Cyclin E remain to be identified; --where a synthetic lethal approach has been clinically validated (PARP inhibitors or platinum-salts in patients with BRCA1/2 mutations), drug resistance caused by genetic reversion of BRCA1/2 limits overall efficacy; --precision medicine approaches that prevent, delay or target PARPi-resistant clones with reversions do not exist. Approach. We will use cell/molecular biology approaches, in vitro, ex vivo and in vivo model systems and take both hypothesis-driven and hypothesis-agnostic approaches, towards the following translational aims: Work Package 1: Can PARPi and platinum-salt resistance be prevented/delayed by novel drug-like DNA Polymerase Theta inhibitors that inhibit a DNA repair process that contributes to drug-resistance-causing BRCA1/2 reversion mutations? Work Package 2: Are some pathogenic BRCA1/2 mutations more likely to revert than others ? Can this information be used to predict the relative duration of response to PARPi/platinum-salts and/or direct the use of heightened surveillance approaches for detecting reversions by ctDNA; Work Package 3: Can we treat cancers with BRCA1/2 reversion mutations by targeting new therapeutic vulnerabilities that emerge upon reversion or by activating immune responses to neopeptides encoded by reversions? Work Package 4: Could ATR inhibitors be used to target hard-to-treat gynaecological cancers with PPP2R1A defects ? Work Package 5: Can synthetic lethal approaches that target FBXW7 or Cyclin E dysregulated cancers be identified that operate in the face of the extensive heterogeneity and plasticity seen in human cancers? How the research will be used. This work has overtly translational aims and therefore our intention is to use the information we generate to inform the design of new clinical trials, the interpretation of existing trials, the identification of new predictive biomarkers to be used in cancer treatment or the selection of new targets for drug discovery. Although this proposal will focus on DNA damage-and chromosome instability related biology and targets, much of what we learn will be relevant to other areas of cancer biology and the treatment of the disease in general.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS