NIHRDataInsights/HRCSData huggingface dataset:
Title: Deciphering the genetic susceptibility of colorectal cancer
Funder: Cancer Research UK

Abstract: Background: Colorectal cancer (CRC), a major cause of cancer-related mortality, has a significant inherited basis. Deciphering inherited genetic susceptibility and understanding the mechanisms by which it impacts on carcinogenesis will inform our understanding of CRC biology. Aims: Our objectives are: (1) Define the allelic architecture of CRC and identify new predisposition alleles; (2) Decipher the functional basis of risk loci; improving our understanding of the regulatory hierarchies in tumorigenesis and highlighting critical mechanisms, which suggest novel therapeutic targets; (3) Perform genetic analyses to inform prevention and treatment outcome. Methods: We will: (1) Identify new risk alleles by genetic analyses of selected families and meta-analyses of new and existing GWAS datasets; (2) Link genetic susceptibility to CRC biology using a range of complementary genetic and functional assays – including in vitro reporter assays, progenitor model systems and analysis of tumour omics; (3) Identify modifiable risk factors through Mendelian Randomisation analysis of GWAS data and develop algorithms to optimise population screening programs for CRC by integrating genetic and lifestyle data. How the results of this research will be used: As well as providing a better understanding of cancer at a fundamental level, our work has two principle clinical benefits; Firstly, identifying those at increased risk and tailoring prevention or screening strategies and secondly identification of targets for anti-cancer therapy and chemoprevention.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Transforming the screening, diagnosis and treatment of prostate cancer
Funder: Wellcome Trust

Abstract: My proposal aims to deliver answers on 4 potentially paradigm-shifting research questions in prostate cancer. First, our current diagnostic strategy involves using inaccurate transrectal-biopsy which provides poor cancer risk stratification. By using accurate tests, such as MRI, mapping-biopsies and MRI-targeted biopsy used in unique patient cohorts, I aim to redefine the risk groups that we currently use to ensure better treatment allocation. Second, prostate cancer screening is not recommended since serum PSA testing followed by transrectal-biopsy is unable to accurately differentiate between men with or without clinically significant prostate cancer. I will test whether MRI might be used as a screening test in the high-risk African/African-Carbbean population. Third, the treatment of metastatic prostate cancer is based on systemic therapy. There is evidence that treating the tumour inside the prostate might be of benefit. I aim to test whether a randomised trial of local prostate ablation, with or without a vaccine, compared to standard-of-care, is feasible and acceptable, and also measure adverse events and side-effects. Finally, surgical RCTs are difficult due to strong preferences and often an inability to blind allocation. I aim to test the feasibility and acceptability of a novel comparative trial design in a surgical setting.

Lay abstract: My proposal involves tackling four problems to improve the screening, diagnosis and treatment of prostate cancer. ONE. At the moment we diagnose prostate cancer using a rectal examination and a biopsy test that are inaccurate. My previous research has shown that using MRI scans and MRI-guided biopsies can more accurately find out how aggressive a cancer is, so my work will involve redefining risk using these accurate tests. TWO. At present, screening for prostate cancer is not recommended in the UK because the PSA blood test that is used to screen for prostate cancer is not specific to important cancer that needs treatment. I will test whether MRI might be used as a screening test in men at high risk. THREE. Currently, we treat advanced prostate cancer with medication alone. I want to test whether heat-based treatments can be used to successfully treat the main prostate tumour compared to current care. FOUR. Randomised controlled trials in surgery are difficult. This is a bad thing for future patients because improvements in treatments may not get to clinic. I will try a new way of running randomised surgical trials.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Integrated Analysis in Mouse and Man for Early Detection of Mesothelioma: IAMMED-Meso
Funder: Cancer Research UK

Abstract: Background Mesothelioma is a devastating cancer with extremely poor prognosis (5-year survival <​8%). This disease is caused by inhaled exposure to asbestos, or similar biopersistent fibres, which may have occurred 30-40 years prior to onset of clinical symptoms. Malignancy is accordingly preceded by decades of chronic inflammation. Diagnosis of malignant mesothelioma is hampered by the cancer’s diffuse growth pattern and an inability of available diagnostic techniques to reliably distinguish between benign inflammation and malignancy. Moreover, because only 12-15% of patients that present with symptoms of pleural inflammation develop mesothelioma within 2 years, international guidelines mandate observation, rather than therapeutic intervention, for patients whose biopsies show no signs of invasive disease. This “watch and wait” approach thus prevents immediate treatment of patients with early-stage disease that may be at high risk of developing mesothelioma, or indeed those where mesothelioma was missed at initial biopsy. Recent therapeutic advances have shown significant survival benefit in patients with malignant disease and could be deployed earlier in the patients’ journey if definitive diagnostic tools are developed to reliably differentiate low-risk inflammation from high-risk pre-malignancy. Aims 1) Identify features that distinguish high-risk pre-malignant disease from truly benign pleural inflammation at low risk of progression to mesothelioma 2) Determine how pleural effusion relates to disease progression 3) Functionally validate our findings in pre-clinical models of pre-malignant disease Methods Our programme will combine temporal analysis of new mouse models with analysis of longitudinally-paired tissue samples (biopsy and fluid) from patients that progress from benign inflammatory disease to malignant mesothelioma, available to us through the CRUK-funded Accelerator PREDICT-Meso. The proposal is divided into 3 work packages that will address the molecular and cellular characteristics that distinguish between a) benign inflammation at low risk and b) seemingly benign inflammation at high risk of progression to mesothelioma. WP1 will focus on the solid tissue component of evolving disease; WP2 on the liquid pleural effusion component; WP3 on functional validation in ex-vivo and in-vivo models of progression to malignancy. Results will be used to identify definitive biomarkers to improve diagnostic accuracy and advance early detection of high-risk pre-malignant disease. These will first be disseminated within existing clinical research networks constituting the PREDICT-Meso consortium and AUK/BLF mesothelioma research network, then internationally through iMIG. Biotech will be recruited to exploit our findings for development of new clinical diagnostics.


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: REPLICATION, REPAIR AND RESISTANCE IN BRCA1/2-DEFICIENT CELLS AND TUMOURS
Funder: Cancer Research UK

Abstract: Germline heterozygous mutations in BRCA1 or BRCA2 genes predispose affected individuals to several types of cancer, including breast, ovarian, prostate and pancreatic. Moreover, triple-negative breast cancers associated with one of the most aggressive forms of the disease are significantly enriched in mutations in these genes. At the molecular level, BRCA1 and BRCA2 proteins have essential roles in DNA replication and in DNA repair by homologous recombination, both vital for the maintenance of genome integrity. Consequently, cells with compromised BRCA1/2 function accumulate stalled replication forks, which leads to replication-associated DNA damage and genomic instability, a signature of BRCA1/2-mutated cells and tumours. The molecular aetiology of the DNA replication and repair defects triggered by BRCA1 or BRCA2 inactivation has never been fully elucidated. In the next quinquennium, work in my laboratory will aim to unravel the mechanisms underlying replication failure in BRCA1/2-deficient cells and develop tools to observe these unfolding. Understanding which types of aberrations lead to replication fork stalling will explain how replication-associated DNA damage occurs. Our hypothesis is that BRCA1 and BRCA2 are required for the replication of certain parts of the genome, which are intrinsically prone to replication fork stalling. In the absence of BRCA1 or BRCA2, forks stalled at these sites fail to restart, leading to DNA damage. Repair of these lesions via error-prone pathways triggers chromosome alterations (e.g. insertions, deletions, translocations) which pose a threat to genome integrity and, in the long term, promote tumorigenesis. Here we propose to use the high-resolution EdU-seq technology to map the genomic sites where replication forks stall, upon acute BRCA1 or BRCA2 inactivation. We will subsequently investigate whether chromosome alterations emerge at these sites following long-term, chronic BRCA1/2 inactivation and whether they overlap with alterations identified in BRCA1- or BRCA2-mutated tumours. Furthermore, we will study how replication and repair at fork-stalling genomic loci are affected by PARP inhibitors and G-quadruplex ligands, both known to selectively kill BRCA1/2-deficient tumours. We will focus on understanding how aberrations associated with resistance to these drugs arise and will develop methods to counteract it. These approaches will improve our understanding of the nature and causes of genomic instability associated with BRCA1/2 inactivation in cancer. The mechanistic insights emerging from this work can in the long term be exploited for the design of novel therapeutic strategies to target tumours with compromised BRCA1/2 function and, more broadly, defective in homologous recombination repair.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: ER-phagy networks in cancer
Funder: Cancer Research UK

Abstract: Background Aberrant endoplasmic reticulum function supports growth of many cancers. Preliminary data obtained by my laboratory shows that disruption of ER-phagy, the selective degradation of ER by the autophagy pathway, may underpin this. ER-phagy disruption may drive tumour growth and create novel molecular dependencies of the tumour, thus presenting new therapeutic opportunities. Aims The molecular players and functional consequences of ER-phagy are opaque in cancer. Identifying these presents an outstanding opportunity to uncover novel cancer biology and new therapeutic opportunities. In particular, I propose pancreatic cancer as a promising initial test case. I will map the molecular network underpinning ER-phagy here, and test the mechanisms via which it regulates tumour cell phenotypes. I will use this information to identify molecules from within the network as new rational therapeutic targets, assessing these in preclinical models of cancer and human clinical datasets. Methods (A) Proximity proteomic screening approaches using APEX2 and TurboID fusions of CCPG1 in pancreatic cancer cell cultures and organoids, followed by focused secondary functional screening by CRISPR/Cas9 and cDNA expression, will identify novel ER-phagy network members. (B) Pancreatic cancer cell and organoid models will be used to probe network members' mechanistic influence on cancer cell biology, using cellular genetic techniques. I will test probable functions of ER-phagy (ER structural alterations, consequent effects on signalling, ER proteostasis and secreted factor production) via hypothesis- and data-driven discovery (ER proteome profiling, secretome profiling, RNA-seq). I will perform initial analyses on the influence of these mechanisms on tumourigenesis, via implantation of cells and organoids into mouse pancreata. (C) Key nodes in the emergent ER-phagy network (A), or molecules that transmit the mechanistic effects thereof (B), that also fit criteria for potential therapeutic targets, including disruption in human cancer, will be tested in genetically-engineered mouse models of cancer. This will enable validation as translatable therapeutic targets. (D) Molecular signatures composed of ER-phagy network members and outputs will be mapped onto human clinical samples via bioinformatic analysis of TCGA data, and analysis of pancreatic biobank samples by immunohistochemistry. These studies will determine how tumours might be stratified for potential intervention within the ER-phagy network. The analyses will also be extended to other cancer types, in order to determine more broadly the potential for therapeutic targeting of ER-phagy. Results This research will illuminate previously unknown aberrant events in cancer and provide a menu of novel therapeutic targets for translation in my future work.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Early Cancer Research Initiative Network on MBL (ECRIN-M3)
Funder: Cancer Research UK

Abstract: Background. Despite recent advances, CLL remains incurable. By far, CLL is the most frequent leukaemia in adults in the Western world. Every CLL is preceded by a pre-malignant state termed monoclonal B-cell lymphocytosis (MBL), which affects 3-14% of adults 40y. MBL shows (low rate) progression and is associated with immunodeficiency and premature death caused by infection and other cancers. However, predictive markers for immunodeficiency, progression and transformation to CLL are still lacking. Aims. To create a unique Research Network and Platform (ECRIN-M) that will develop and facilitate access to (new) resources and tools essential for early diagnosis of B-cell leukaemia and prevention of premature death and malignant transformation. Methods. The ECRIN-M3 programme will be delivered through 6 work packages (WP). The tasks are: 1) Project management (WP1); 2) Developing unique resources and innovative, essential tools, including genomics data management platform (WP2), biobank of plasma, purified tumour cells, normal cells and their sub-components (WP2), and detailed bulk and single-cell genetic and transcriptomic maps of tumour B-cells and immune profiles of MBL subjects from the general population and CLL patients (WP2); 3) Facilitating access to these resources to MBL-CLL researchers and the broader cancer community (WP2); 4) Designing, validating and applying innovative, minimally-invasive diagnostic screening assays for MBL, suitable for cost-effective nation-wide diagnostic screening programmes (WP3); 5) Accelerating generation of knowledge key for better understanding the role of immune dysregulation and the molecular and cellular mechanisms (WP4) and signalling pathways (WP5) involved in progression of MBL and transformation to CLL; and 6) Translating this knowledge into improved early diagnosis, risk stratification and prevention of death, progression and malignant MBL transformation, including dissemination and exploitation of the results of the programme (WP6). In order to accelerate validation of the potential (clinical) relevance of the results of the project across other cancer types, two additional B-cell tumour models will also be targeted in this proposal: the MGUS-MM and MZL-like MBL-MZL models. These activities will be undertaken by the new ECRIN-M3 Network that integrates and synergises efforts of 14 research groups from 4 leading institutions in Europe (as well as in Africa and South-America) on MBL. How the results of this project will be used. This Accelerator programme should set the basis for evaluation of feasibility of nation-wide early leukaemia diagnostic screening and prevention programs. Ultimately, the new platform, tools and knowledge gained will also benefit the larger cancer community.


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: Mechanisms underpinning distinct manifestations of Homologous Recombination deficiency in cancer
Funder: Cancer Research UK

Abstract: BACKGROUND: In Homologous Recombination Deficient (HRD) pre-cancerous lesions, the switch to error-prone non-homologous end joining (NHEJ) pathways for the repair of DNA double-strand breaks (DSBs) leads to chromosomal aberrations associated with the onset of tumorigenesis. My group has pioneered the mechanistic delineation of a specialised branch of the NHEJ pathway governed by 53BP1 that causes genomic instability in BRCA1-associated HRD cancer. However, NHEJ is also toxic in cancers with pathological ATM mutations, yet in this case the distinct classical-NHEJ (c-NHEJ) pathway is responsible. Thus, ATM and BRCA1 counteract the threat that different branches of the NHEJ pathway pose to chromosome replication, yet the mechanisms explaining this context specific interplay between different HR proteins and NHEJ mechanisms remain unknown. AIMS: The overall goal is to elucidate the context specific activities mediated by vital HR and NHEJ proteins, to understand the interplay between HR and NHEJ pathways, its dysregulation in cancer, and identify weaknesses to exploit with therapeutics. We will also test a hypothesis that the independent and synergistic functions of ATM and BRCA1 in HR can be explained by their roles in protecting structurally different replication-associated DNA lesions against distinct DNA-structure-specific NHEJ pathways. This involves: 1. Defining the pro-HR and anti-NHEJ mechanisms underpinning BRCA1-mediated tumour suppression. 2. Ascertaining the separate contributions of context-specific NHEJ activities to BRCA1-associated tumourigenesis. 3. Understanding the complementary DSB repair activities of BRCA1 and ATM during HR and NHEJ suppression. 4. Defining the endogenous DSB sources in BRCA1- and ATM-deficient cancer cells, and origins of those inflicted during anti-cancer therapy. METHODS: To identify DNA repair protein complexes, their activities and their DNA substrates, we will leverage our expertise and unique complement of cellular tools and animal models. Quantitative mass-spectrometry, high-content imaging, and cellular assays will provide indices of DNA repair proficiency, developmental and tumour studies will provide important (patho)physiological context, and whole genome sequencing will assign HRD-associated mutation signatures to repair mechanisms. We will also generate new reporter systems and implement DSB-sequencing to understand the origins of endogenous and drug induced DNA lesions in HRD cancer. USE OF RESULTS: Define why HRD manifests differently in BRCA1 and ATM mutated cancers and confers different sensitivities to HRD-targeting therapies. Understanding these differences aims to define how ATM-BRCA1 synergy might be better exploited in therapies and ensure that appropriate HRD-targeting drugs are matched with patient groups most likely to benefit.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Targeting Cancer Pain
Funder: Cancer Research UK

Abstract: Background Cancer treatments are proving increasingly successful, with dramatically prolonged survival times. The vision of CRUK that three in four people diagnosed with cancer will live at least 10 years by 2034 seems achievable. However, the quality of life whilst living with cancer can be significantly affected by pain, in particular debilitating bone pain associated with metastases in prostate, breast, lung and other cancers. Cancer pain is driven by sensory neurons. We propose to exploit dramatic recent advances in sensory neurobiology to develop new approaches to treat cancer pain. Aims We will define the subsets of sensory neurons that drive cancer pain and chemotherapy- associated pain in male and female mice. We will test the effect of killing or silencing these neurons on cancer pain behaviour. We will explore mechanistic insights from the study of these neurons to evaluate and select new analgesic targets. We will exploit biological and pharmacological approaches to identify successful analgesic methods that are attractive for clinical translation. Methods We will use bone pain cancer models in mice to identify sets of sensory neurons that innervate bone by back-labelling the neurons. We will use genetically encoded calcium indicators that signal neuronal activity (GCaMP) to find the neurons that are activated during cancer or chemotherapy associated pain in live mice. We have a repertoire of sensory neuron Cre-recombinase mice that include all sets of sensory neurons and flexed reporter mice including tomato, diphtheria toxin, chemogenetic silencers and GCaMP driven by sensory neuron-specific promoters. We will thus be able to examine the effect of killing the neurons with diphtheria toxin, or silencing those using pharmacologically selective actuator modules (PSAMs). This uses a mutated chloride channel that is activated by the drug Varenicline. Identifying key sets of neurons involved in cancer pain then allows us to transcriptionally profile the changes that occur and identify potentially interesting analgesic drug targets. We will also explore some new approaches to treating pain that have yet to be assessed in cancer pain and compare their efficacy with new targets we identify, in order to provide a strong rationale for translational studies. How the results of the research will be used? We have shown that cancer pain has unique facets, and the sensory neuron subsets involved are conserved between mice and primates. Therefore, successful approaches to treat cancer pain in our model systems should be clinically translatable.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: CANCER AND NEOPLASMS