NIHRDataInsights/HRCSData huggingface dataset:
Title: How does RIF1 regulate DNA replication and cell recovery after chemotherapeutic replication inhibition?
Funder: Cancer Research UK

Abstract: BACKGROUND: Chromosome replication and maintenance are central for cell division, and derailment of these processes is a major cause of cancer. The protein RIF1 has emerged as a conserved regulator of chromosome maintenance, controlling DNA replication initiation and progression, and cellular survival after treatment with chemotherapeutic drugs that induce replication stress. Our work has uncovered how RIF1 controls DNA replication initiation, but its roles at replication forks and in orchestrating cellular recovery from replication stress remain unclear. To investigate these RIF1 functions and understand the repeated requirement for RIF1 during the cell cycle, we will continue our productive approach of first examining how RIF1 operates using the experimental power of yeast genetics, then following up our findings in human cells. AIMS & METHODS: The over-arching goal of this Programme is to understand how RIF1 safeguards DNA replication and ensures cellular recovery from interrupted replication. In human cells two different RIF1 splice variants have been identified, and we have discovered that only one of them can enable recovery from replication stress. RIF1 splice variant expression is reported to change during tumorigenesis, so uncovering the functional molecular distinction between the splice variants is important. Obstructing DNA replication is the major effective mechanism of many chemotherapeutic agents, so this work is especially relevant for cancer treatment. Our specific Aims are to:- (1) Understand how RIF1 is recruited to replication sites, and elucidate its role in protecting nascent DNA (2) Examine the consequences for genome stability when cells replicate their DNA in the absence of RIF1 (3) Establish why the longer of the two human RIF1 splice variants (‘RIF1-Long’), is specifically required to protect cells against replication-inhibiting chemotherapeutic agents, identifying in particular the BRCT domain protein with which RIF1-Long acts to mediate recovery (4) Investigate the differential expression of the human RIF1 splice variants in cancer, examining (in collaboration with clinical colleagues) whether the balance of RIF1-Long and RIF1-Short expression predicts tumour susceptibility to replication-inhibiting drugs OUTCOME & USE OF RESEARCH: Investigating how our mechanistic insights will improve cancer treatment is an integral part of this Research Programme. In particular we will examine whether the profile of RIF1 expression in tumours is predictive of chemotherapy response and can be used to optimise treatment regimes. More broadly, understanding the importance of RIF1 in chromosome maintenance will uncover mechanisms through which cells preserve their genome stability, revealing the causes of the genome instability that triggers carcinogenesis.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE
Title: Understanding replication-coupled DNA repair
Funder: Cancer Research UK

Abstract: Background Genome duplication is essential for the propagation of cellular organisms, yet errors that occur during DNA replication are a source of genomic instability and a central factor contributing to cancer. Normally, replication-coupled DNA repair mechanisms protect cells from genomic instability, but often these essential systems go wrong in cancer. We currently understand very little about the molecular mechanisms that underpin replication-coupled DNA repair and this remains a major conceptual barrier in defining the role that these pathways play in cancer. Furthermore, the complement of proteins that operate within these pathways is not fully known and it is highly likely that there are many unidentified factors in these pathways that would provide new avenues for therapeutic intervention in cancer. Aims I hypothesise that the dynamic regulation of ubiquitination by deubiquitinating enzymes (DUBs) is a key step in controlling replication-coupled DNA repair. Here, I will build on my previous work and exciting new discoveries to understand how DUB-dependent regulation of ubiquitin signalling underpins replication-coupled DNA repair. This will rely on three highly interrelated objectives that will allow me to discover how replication-coupled DNA repair mechanisms function in normal and cancer biology. 1. Discover how a novel putative DUB functions in DNA repair 2. Uncover how ubiquitination regulates replisome function in replication-coupled DNA repair 3. Understand how deubiquitination regulates a specialised replication-coupled DNA repair pathway. Methods To answer these important questions, I will use a combination of cellular and biochemical approaches, such as state-of-the-art mass spectrometry, CRISPR-Cas9-based genetic screening technology and advanced microscopy methodologies. Furthermore, I will generate novel genetic mouse models to allow me to answer my research questions in the context of a physiologically relevant model system. How the results of this research will be used Understanding the basic biology of replication-coupled DNA repair is fundamental to understanding how cancer cells are able to survive with increased amounts of genome instability and overcome treatment with chemotherapeutic drugs. In recent years, the ubiquitin system has become a prominent target for drug discovery to treat cancers, with DUBs emerging as druggable targets for cancer therapies. Therefore, the results of the work proposed here could be transformative, not only in terms of our understanding of replication-coupled DNA repair, but also for identifying novel therapeutic targets in cancer cells.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE
Title: Advancing the understanding and applications of mutational signatures
Funder: Cancer Research UK

Abstract: Cancer is the ultimate genetic disease. It is driven by mutation, and it drives further mutagenesis. Cancer sequencing experiments have permitted visualisation of in vivo mutagenesis, revealing patterns of mutation that arise in cells as they transform towards malignancy. These mutational signatures are informative of the DNA damage and DNA repair pathways that are active, or awry, in somatic cells. Today, we know of over 30 different mutational signatures in human cancers although the aetiologies of many of these signatures remain unknown. The research proposed here seeks to advance the field further through three main strands. First, can we gain insights into how mutations arise and influence cancer through innovations of analytical methods of mutational signatures? Beyond substitution signatures, a framework for mutational signatures of all classes of mutation will be developed. Additionally, how physiological processes like replication and transcription, and physical properties such as chromatin organisation and DNA secondary structures influence mutational signatures will be comprehensively explored to improve our understanding of mutagenesis through the genome. Second, can we accelerate the application of mutational signatures into the clinical setting? Although there have been huge advances in the academic analysis of genomic data, there remains a gap between developments like mutational signatures and clinical utility. I intend to bridge this gap by developing the computational tools that will allow us to make genomics simple and user-friendly, and engage with clinical and pharmaceutical counterparts to facilitate the translation of signature genomics into the clinic. Third, what are the mechanisms underlying the plethora of mutational signatures that have been identified in human cancer? Through analyses, it has been observed that some single gene defects consistently present not one, but multiple distinctive mutational signatures, sometimes of different classes of mutation (base substitution, indel and/or rearrangements). This provides an opportunity to understand how and why different patterns arise when the function of a single gene is abrogated. How DNA damage arises through the genome will be assessed in cell systems with different genetic backgrounds using bespoke DNA library preparations. To complement this, systematic knock-outs of essential components of compensatory repair pathways will be performed to see how they influence mutational signature behaviour in these different genetic backgrounds. Changes in resulting signatures will help us understand which repair mechanisms are critical to generating mutational signatures. (Cancer sites: Breast cancer, other cancers)


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE
Title: Understanding the cancer significance of the pRb-E2F network
Funder: Cancer Research UK

Abstract: The pRb-E2F pathway is a key point of control in the cell cycle, and loss of control of the pathway is regarded as a ‘hallmark’ of cancer. In the classical view, the retinoblastoma pRb tumour suppressor protein is a negative regulator of E2F transcription factors, which act as a transcriptional hub through which pRb exerts its impact on cell cycle progression. The temporal regulation of cyclin/CDK complexes leads to the phosphorylation of pRb, releasing E2F at the G1/S phase transition which enables E2F to drive the transcription of genes required for cell cycle progression. Our recent work has however uncovered new information which highlight the pRb-E2F axis as a regulator of a much larger cellular network, with wide mechanistic and biological impact. The goal of our programme is to clarify our evolving knowledge of the E2F network and its true biological relevance, and decipher its contextual ramifications for human cancer.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE
Title: Multi-modal clinical testing of prostate cancer patient plasma
Funder: Cancer Research UK

Abstract: Precision medicine in oncology requires broadly-applicable molecular characterisation of tumours. In contrast to tissue, liquid biopsies are minimally disruptive and can be obtained repeatedly, providing real-time molecular data. We aim to broaden the clinical utility of plasma analyses for risk stratification and treatment selection, monitoring and characterisation of resistance by increasing the amount and quality of information obtained. We have assembled a team that includes prostate cancer specific expertise on all key components (molecular, clinical, genomics, epigenetics, vesicles, liquid biopsies) and extends to multiple hospitals and clinical trial cohorts with the dual aim of ensuring both prospective enrollment of advanced prostate cancer patients to answer specific clinical questions and to result in up-and-running liquid biopsy tests at multiple institutions by end of the project. Approaches established will also have utility in plasma analyses in other cancer types. Our team will i) implement novel computational approaches and targeted design strategies to accurately quantitate commonly recurring point mutations and copy number changes, including mono- and bi-allelic deletions at low tumour purities; ii) integrate these genomic data with read-outs of methylation status and use clinically applicable approaches for exosome isolation and analyses to obtain information on mRNA and protein expression; iii) establish a cloud-based computational pipeline to enable standardized analysis across our network and with external collaborators; and iv) independently clinically qualify the multi-modal testing in plasma samples collected in multi-centre prostate cancer clinical trials representative of different stages in the disease spectrum.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE
Title: Molecular Mechanisms of the APC/C and Cell Cycle
Funder: Cancer Research UK

Abstract: Background The complex molecular and morphological changes intrinsic to the cell cycle mediate chromosome duplication and segregation, and cell growth and division. A critical regulator of the cell cycle is the anaphase-promoting complex (APC/C). The APC/C is a large multi-subunit E3 ubiquitin ligase that regulates progression through mitosis and entry into S phase. Its size reflects its complex functions and regulatory mechanisms. APC/C coordination of cell cycle progression is achieved through the temporal and spatial regulation of APC/C activity and substrate specificity. Regulation occurs through multiple mechanisms including reversible protein phosphorylation, the association of activator subunits and through the spindle assembly checkpoint (SAC). Disruption of these processes contributes to aneuploidy and cancer, whereas inhibitors that target the mitotic APC/C-Cdc20 would suppress cell proliferation. Aims Our research is aimed at understanding the structure and mechanism of the APC/C at a molecular and cellular level. Specifically we aim to provide insights to (i) how the APC/C targets specific protein ubiquitination and degradation in a cell cycle-dependent manner, (ii) how the APC/C is regulated by the SAC, and (iii) rationalize the development of APC/C inhibitors. Little is known of the precise spatial organization of the APC/C within the cell and how this changes and is controlled during the cell cycle. In further aims we seek to understand the specific intracellular location of the APC/C, and to understand its molecular structure in situ in the context of other cellular components and sub-structures including the mitotic spindle, kinetochores and centrosomes. This work will bridge information from molecular and cellular structure. Methods A key approach is to determine atomic resolution structures of reconstituted recombinant human APC/C complexes with substrates and regulators using single particle cryo-electron microscopy. This information is complemented and interpreted using a range of biochemical and biophysical methods, and protein crystallography and NMR. We will use super resolution light microscopy to investigate the intracellular locations of the APC/C, and are initiating studies using cryo-electron tomography to visualize cells at specific phases of the cell cycle to understand APC/C structures in situ. To achieve this, we will develop correlative cryo-light and electron microscopy. How the results of this research will be used The outcome of our research will be a better understanding of the APC/C at a molecular and cellular level. It will provide information for rational targeting of the APC/C for drug discovery and help explain the consequence of cancer mutations in APC/C genes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE
Title: Accessing the Druggable Genetic Programs Governed by Mammalian bHLH-PAS Transcription Factors
Funder: Wellcome Trust

Abstract: We have recently projected that the human bHLH-PAS proteins form a class of transcription factors with great therapeutic promise, and propose to subject this family to in-depth chemical and functional explorations. The sixteen members of this family are functionally non-redundant and have genetic links to cancers, metabolic syndromes, inflammatory diseases, and psychiatric conditions. They share common architectural features that include a conserved DNA-binding domain and dual PAS domains. Our specific aims are: 1. Identify chemical ligands for members of the human bHLH-PAS family. 2. Determine the ligand-dependent genomic signatures and cellular pathways governed by family members. 3. Probe the mechanisms by which chemical ligands manifest their activities through this family. These studies allow us to transition from having visualized their ligand binding properties to employing chemical tools for interrogating and manipulating their functional activities as transcription factors.

Lay abstract: Cells, tissues, and organs utilize sensory communication networks dependent on a variety of small-molecules and proteins that selectively recognize them. This form of signaling communication is typically reliant on the metabolic state inside the cell, or changes in the extracellular environment, both of which can alter the levels of small-molecule signals. The binding proteins must form adaptive physiological responses to meet those signals. This proposal explores a family of human gene regulating proteins, known as the bHLH-PAS transcription factors, whose three-dimensional architectures allow binding to small-molecules and to genomic sites for controlling gene expression. We seek to find the cellular small-molecules and synthetic drug-like compounds that can bind and modulate the activities of these proteins. Understanding how such signaling molecules interact with this protein family should provide entry points for future drug development in a variety of unmet human conditions including cancers, metabolic diseases, inflammatory diseases and psychiatric disorders.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE
Title: Imperial College of Science, Technology & Medicine and Manchester Biotech Limited
Funder: Innovate UK

Abstract: To open and enhance the market potential of hydrogels to the fields of mechanobiology and cancer. An experimental platform will be implemented for mechanobiology and cancer studies to test the suitability of these gels for anticancer drug delivery and commercial sales.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY);5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE
Title: A coordinated strategy to scale-up advanced therapies for patients in Manchester
Funder: Innovate UK

Abstract: "Advance Therapies are a new generation of treatments which use patients' cells as 'drug' to treat a variety of diseases. Although encouraging results have been reported, this technology is complex, expensive and currently only available to small numbers of patients. We have formed the Innovate Manchester Advanced Therapy Centre Hub (iMATCH); this is a group of collaborators who share a vision of working more efficiently together so we can offer Advanced Therapies to more children and adult patients with cancer and non-cancer diseases. iMATCH unites experts from The Christie NHS Foundation Trust and Manchester University NHS Foundation Trust, The University of Manchester and 9 businesses with specific expertise in different aspects of delivering Advanced Therapies. Our 9 commercial partners are; Cellular Therapeutics, Aptusclinical, Chaucer, Datatrial, Formedix, Asymptote, AstraZeneca, Agenus and The Christie Pathology Partnership. iMATCH will resolve the challenges and expand facilities to allow us to design and run larger clinical trials so that we can to treat greater numbers of patients within the NHS, safely and efficiently. We are going to focus on; * Coordinating patient cell collection * Processing and storage of those cells * Developing efficient systems to track samples from the patient, through manufacture and back to the patient * Ensure we have all the information we need, from each patient we treat, to know whether a clinical trial has been a success; this will include long term follow-up of patients These clinical trials are complex and challenging to run; it is important that we provide specific education for our doctors, nurses and the teams that support them. We want to define the education packages needed then offer this training to all Manchester-based partners, then any national and international teams. This will increase the use of Advanced Therapies world-wide. Manchester is an excellent choice for this investment by Innovate UK; we have a large population of 3.2 million people, two substantial hospital sites with existing experience offering these treatments to a variety of patients, a devolved Health Care System and an ability to draw together companies who can help us to overcome the complex challenges. Together we will improve patient outcomes."


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE
Title: Randomised controlled trial of Vinehealth digital health cancer solution: Covid-19 additional support
Funder: Innovate UK

Abstract: When cancer patients describe their experiences, they say: "\[information\] wasn't explained to me...you have to seek it out yourself", "it felt like they'd give you just enough information to go away with and then move on to the next patient", and "I didn't know what to expect when I went home". 99% of cancer care occurs in patients' homes. Patients only get information and advice from clinicians in short, infrequent appointments. Therefore, patients must learn for themselves how best to manage their health. But the information they need is spread out across many charities, websites and publications. Often, this information is inconsistent and confusing.[][0] Better information is also urgently needed by drug companies. Following recent regulatory changes, pharmaceutical companies must collect patient-reported information on safety and effectiveness of their cancer drugs. They are struggling to collect these data.[][1] Pharmaceutical companies, clinicians and charities understand this situation is unacceptable and worsens cancer outcomes but do not have the remit, resources or technical skills to collaborate effectively to improve it. As a small, experienced, credible and trusted technology company, Vinehealth meets the needs of patients and drug companies for better information; already leading this via partnerships across the fragmented cancer care ecosystem. Vinehealth's digital tools combine behavioural science and AI to improve cancer patient QoL, and collect patient-reported outcome (PRO) data that drug companies need. The platform is co-developed with patients, leading UK oncologists, all major UK cancer charities, and the most significant pharmaceutical companies. Vinehealth includes a patient-facing mobile app that delivers personalised information and support to enable cancer patients to better self-manage their medications, side-effects, symptoms and lifestyles, seamlessly integrating with smartphones and wearables. Patients can regularly enter PRO data to drive clinical research, inform clinical service re-design and provide pharma with crucial PRO data. PRO data can increase cancer survival up to 20%. Feasibility of the tool has been confirmed in UK's leading cancer centre (Royal Marsden). For commercial success, we must now finalise Vinehealth technical development and deliver a large randomised controlled trial over four NHS Trusts, generating robust evidence for Vinehealth's clinical and cost effectiveness in improving patient self-management and data collection. Technical work to prepare for the trial includes ensuring Vinehealth meets the NHS sites' data governance and interoperability requirements and further developing the platform for more personalised psychological support and broader PRO measures. [0]: https://paperpile.com/c/H8DKSw/hrbH [1]: https://paperpile.com/c/H8DKSw/HQom


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE