Institute of Cancer Research

UKRI Gateway to Research · FY 2026 · 2026-07

Despite the recent advances in targeted treatments for cancer, a pervasive barrier for the cure or, at least sustained long-term therapeutic control of the disease, is the challenge of drug resistance. Clearly, there is an urgent and, as yet, unmet clinical need to identify novel and more effective approaches to anti-cancer drug sensitivity prediction and prioritisation, and deciphering cancer cells’ unique metabolic architecture and therapy-induced metabolic alterations could be a powerful tool towards this direction. Molecular heterogeneity, both within (intratumoral) and between (intertumoral) tumours significantly impacts treatment response and is a major contributor to drug resistance and therapy failure. Over the past few years my group has developed a multimodal pipeline to characterise the metabolic cartography of breast cancer comprising of Desorption Electrospray Ionization (DESI) mass spec imaging, and complemented with Imaging Mass Cytometry (IMC) for protein profiling to stratify the disease into eight metabolically-distinct regions (metabotypes) that are present both within and between tumours. High-throughput genetic characterisation of these metabotypes following spatial transcriptomics profiling revealed their association with clinically-relevant genetic signatures that are predictive of unique responses to targeted therapies. Here, we propose to use this innovative pipeline to establish a completely new way to prioritize and deploy drugs and synergistic drug combinations based entirely on the spatial metabolic cartography of cancer. In addition, we aim to develop a computational framework that integrates perturbation networks with flux balance analysis (FBA) to predict therapy-induced metabolic flux changes across cancers. We anticipate that this approach will identify context-specific vulnerabilities, thereby creating new opportunities for biomarker discovery and therapeutic intervention that could fundamentally change precision medicine.

UKRI Gateway to Research · FY 2026 · 2026-02

Patients with lung cancer (NSCLC) and head and neck cancer (HNSCC) are commonly treated with radiotherapy. Recent studies have shown that combining radiotherapy with immunotherapy improves outcomes for some patients. However, large patient groups do not respond to this combination treatment and the underlying causes for resistance are currently unknown.  My project aims to test how a protein called ART1 could cause cancers to resist treatment.  When cancer cells are stressed or die from cytotoxic treatments like radiotherapy, they release danger signals (ATP and NAD+) that alert the immune system and activate immune cells. These molecules act by binding to a receptor called P2X7R on immune cells which primes them to kill cancer cells. However, our recent work has shown that tumour cells can hijack this process by producing the ART1 protein. ART1 uses the NAD+ released in the tumour to modify the P2X7R on immune cells, resulting in their death instead of their activation. Our recent data shows that radiotherapy makes this process worse by promoting tumour cells to produce even more ART1. This shuts down the radiotherapy-induced immune response, causing the patient’s tumour to progress. Indeed, our analysis of tumours from NSCLC and HNSCC patients that did not respond to radiotherapy-immunotherapy treatment showed high ART1 and low P2X7R levels. We have developed an antibody that can block ART1 and reduce its immune suppressive effects. When we combined ART1 blockade with radiotherapy in mouse experiments, tumour growth reduced and more immune cells with P2X7R infiltrated the irradiated tumours. This suggests that targeting ART1 with drugs could improve the effects of combined radiotherapy immunotherapy treatment. We have also identified a potential novel role of another protein on immune cells, CD38. This enzyme breaksdown NAD+ in tumours, preventing ART1 from killing immune cells and allowing them to fight the tumours. This project has two main aims: First, to study how these three molecules, ART1, P2X7R, and CD38 interact, and are modified, in NSCLC and HNSCC patients undergoing radiotherapy or radiotherapy-immunotherapy.Our objectives for this aim are to understand their distribution in tumours and how they shape the immune response to cancer. Second, we will study  (1) the mechanisms of how ART1 in cancer cells disrupts P2X7R –signalling, using mice treated with radiotherapy and immunotherapy, and (2) whether blocking ART1 and encouraging CD38 at the same time can protect anti-tumour immune cells, boosting their signalling through P2X7R, and counteracting radiotherapy-induced immune resistance. In summary, there is an urgent need to combat therapy resistance and tumour recurrence in NSCLC and HNSCC patients. This study will take a novel approach to understanding how tumours avoid radiotherapy-induced immune attack, and test new strategies that can enhance its effectiveness. Ultimately, ART1-targeting drugs could be a way to make more patients with NSCLC and HNSCC respond better to radiotherapy-immunotherapy combinations, improving their quality of life and life expectancy. Our team combines expert tumour immunology and radiation biology researchers with clinicians specializing in radiotherapy and immunotherapy of HNSCC and NSCLC. Pursuing this project at the ICR, with its world-leading translational infrastructure, cutting-edge mouse modelling facility, and renowned drug discovery programme sets us up for successful completion of our aims and will allow us to build upon our findings to develop ART1-targeting drugs and bring them to patients.

UKRI Gateway to Research · FY 2026 · 2026-01

FIREDANSE will provide access to data from two of the UK’s leading cancer research institutions, the Royal Marsden NHS Foundation Trust and Imperial College Healthcare NHS Trust, using state-of-the-art technologies developed in Phase 1 of the DARE UK programme, demonstrating the possibility of linking patient biopsy images with other rich NHS data sources. This will allow future researchers to train artificial intelligence algorithms to answer more complex medical questions, make faster and better diagnoses, and contribute to alleviating the enormous pressure on hospital pathology services. Our cancer-patient grant co-leads have identified a strong need, from public and patients alike, for reassurance that any medical AI software has been thoroughly tested by hospital consultants, both during development and prior to roll-out in the clinic. There is huge concern about the possibility of AI “hallucinating” results, so patients want proper monitoring by human experts embedded in clinical AI programmes. However, there is a critical shortage worldwide of personnel with the qualifications needed to perform this essential role. A 2018 census conducted by the Royal College of Pathologists revealed that 97% of pathology departments were understaffed, with 78% having vacant consultant posts. We will adapt a highly successful app that we have previously created, running from a web browser on a consultant’s desktop, such that it will seamlessly and securely access deidentified pathology images and associated (synthetic) clinical data from both the Royal Marsden and Imperial College. The app will guide users through the process of entering their expert reviews, quickly gathering the information needed to train algorithms. This will make clinical studies spanning multiple hospitals work better or, when used for quality assurance of algorithms already in use, show whether the AI got it right or wrong. Prior to the DARE UK initiative, it was extremely challenging to guarantee the level of security and patient privacy required to link these data. To address well founded concerns that the public has about the way medical data could be misused, government policy mandates that most researchers will in future access data in ways like the ones being trialled in this project. FIREDANSE will engage members of the public by asking them about their top concerns, familiarising them with the subject area and language used, and facilitating discussions with AI scientists. We aim to promote a better understanding of both the ethics and practicalities of introducing AI into healthcare. Without “blinding participants with science”, we will strive to convey the complexities inherent in federating trusted research environments, whilst at the same time providing reassurance that the highest governance and technical standards are being adopted. An immediate test of the effectiveness of the materials we develop will come when, as part of the project, we use them to explain the privacy implications of the new architecture to information governance professionals (who are not IT specialists) at the partner organisations, and gain approval that the limited test service we will build is suitable for widespread use. This process will be strongly PPIE led/supervised, in indicated in WP1. In essence, the ethos of this project is captured by FIREDANSE or Balinese fire dance (https://youtu.be/fZc_RGX6TFA?feature=shared&t=234), which evokes the analogous interplays of data transiting between TREs and same high standards of performance that the project team will achieve to execute “safely” all the data movements needed for TRE federation.

UKRI Gateway to Research · FY 2025 · 2025-10

Adaptmet aims to develop an advanced training program encompassing the multifaceted aspects of metastasis adaptation mechanisms, intending to equip budding researchers with the necessary skills to emerge as leaders in this field. A robust mentoring and training strategy, coupled with cutting-edge methodologies and a diverse range of complementary soft skills, are crucial to this endeavour. These skills are imparted through local and network-wide events, fostering seamless research progression and nurturing successful career trajectories. Scientifically, Adaptmet addresses an unmet medical need by harnessing basic science to revolutionize drug development and, ultimately, enhance patient care. Specifically, scientific work packages (WPs) have been designed to approach metastasis from various functional perspectives. In order to metastasize, cancer cells must adeptly coordinate diverse cellular functions (Cell Fate - WP1). Additionally, understanding the intricate interactions between metastatic cells, the host immune system, and tissue stroma is pivotal (Environment - WP2). Crucial aspects such as the kinetics of metastasis and the mechanisms governing latency, particularly, remain inadequately understood (Latency - WP3). Clarifying this complexity, unravelling mechanisms underlying therapy failure, and identifying expansion pathways are central to defining novel therapeutic targets (Expansion - WP4). In essence, Adaptmet stands at the intersection of a rapidly evolving multidisciplinary domain, amalgamating distinct fields that often face challenges in mutual communication. The success of Adaptmet hinges upon robust partnerships, open exchange of ideas, state-ofthe-art methodologies and equipment, and the exploitation of synergistic opportunities among network members. This collaboration spans diverse perspectives, bridging gaps between different disciplines, thereby breaking down barriers and fostering interdisciplinary cohesion.

UKRI Gateway to Research · FY 2025 · 2025-08

DNA is known for its iconic double helix structure, but it can also form alternative, non-canonical structures like G-quadruplexes (G4s), intercalated motifs, and hairpins. These secondary structures are important because they play key roles in regulating processes like gene expression. However, they can also cause problems by interfering with fundamental processes such as DNA replication, leading to genomic instability. Cells produce specialized proteins called helicases to manage and unwind these secondary structures, but many questions remain unanswered about how these helicases function and which structures they target. This project addresses the challenge of accurately detecting DNA secondary structures across the entire genome in different biological contexts. Current methods for mapping these structures are either biased or have limited resolution. Our goal is to develop a new technique using nanopore sequencing, which will allow us to detect and map these structures at single-nucleotide resolution without the need for amplification or complex reagents. The technology we are developing, called Nanopore-Enabled Structure detection (NEST), exploits the fact that secondary structures cause DNA molecules to pause as they are threaded through nanopores, and employs machine learning to pinpoint the exact location of these secondary structures in our genome.   Our research has three main aims: Develop NEST using synthetic DNA and biological samples to reliably detect a wide range of secondary structures, starting with G4s. Map DNA structures in the absence of different helicases to understand how these helicases unwind G4s and how these structures are regulated during DNA replication. Investigate the role of the chromatin remodeller SMARCA4, which appears to protect cells from G4-induced DNA damage, especially in the context of cancer.   The results of this work have far-reaching potential applications. By better understanding the biology of DNA secondary structures, this research could lead to new therapeutic strategies for treating cancers and other diseases linked to genome instability. It could also provide insights into viral and bacterial genomes, offering new ways to combat infections. The development of NEST could become a valuable tool for the scientific community, enabling more accurate and widespread detection of these structures. This project aligns well with BBSRC’s long-term research priorities by advancing our understanding of fundamental molecular biology and contributing to new innovations in biotechnology and health.

UKRI Gateway to Research · FY 2025 · 2025-08

At the Institute of Cancer Research (ICR), many teams are focused on understanding how the immune system responds to standard cancer treatments—chemotherapy, radiotherapy, and immunotherapy—, as well as novel strategies, to improve patient outcomes. This research requires high-parameter flow cytometry to analyse immune cell populations, study the tumour microenvironment, and monitor tumour evolution and adaptation. However, the conventional flow cytometry systems currently available at the ICR can only analyse up to 29 parameters per experiment, while our studies require beyond 40 to distinguish different cell populations. Moreover, the commonly used reporter proteins in our preclinical studies, such as Kaede for cell trafficking and Tocky for TCR signalling dynamics, have broad emission spectra, further limiting the number of fluorochromes that can be studied. Additionally, highly autofluorescent samples cannot be analysed with our conventional system. Spectral flow cytometry overcomes these challenges by enabling the use of more markers in a single experiment (particularly important when patient and animal samples are  limited), improving data resolution between fluorophores with overlapping emission profiles, and subtracting autofluorescence to ensure higher data quality. We have identified SONY-ID7000 Spectral Cell Analyser as the best equipment to meet the needs of our researchers. This was decided based on its advanced technical features such as spectral unmixing algorithm, enhanced autofluorescence subtraction, modular capacity and fast acquisition times. These capabilities will allow ICR researchers to: expand the number of markers that can be used per experiment (only limited by fluorochrome availability) allowing us to characterise all the relevant subsets of cell populations and biomarkers. effectively remove autofluorescence, allowing the use of highly autofluorescent mouse and human samples. minimise the number of samples required per experiment, addressing a key challenge in preclinical and, particularly, clinical studies where patient blood volumes are often limited. decrease the time required for panel design, optimisation, data acquisition and analyses. enable the use less expensive conjugated antibodies, which was previously not possible. The equipment will be embedded in the ICR’s Flow Cytometry Core Facility, where it will be efficiently managed by our experienced Flow Cytometry Facility staff. The Facility, which currently operates at full capacity with six conventional flow cytometers, serves ~300 users across the ICR and has seen a three-fold increase in usage over the past three years. Due to restricted access and logistical challenges preventing us from using spectral analysers outside the ICR, there is a significant demand for this new system. Given the growing need for high-parameter analyses, and support from six ICR divisions for this application, we expect immediate full-capacity utilisation and seamless integration with our existing systems. The SONY-ID7000 will support a number of cutting-edge projects at the ICR, including: Characterising the functional immune response to radiotherapy (we have particular expertise and activity in radiotherapy-induced immune changes across pre-clinical models and patient samples), including advanced radiotherapy technologies. Evaluation of DNA repair inhibition combined with radiotherapy to sculpt the tumour-immune microenvironment. Multidimensional analysis of prostate cancer evolution in pre-clinical models. Longitudinal definition of tumour microenvironment in murine models of carcinogen-induced bladder cancer. Examining the impact of radiotherapy and immunotherapy on the metabolism of immune cells. Immunological response to radiotherapy treatment in patients in diverse tumour types. Overall, SONY-ID7000 is a vital piece of equipment that will transform our understanding of tumour evolution and immune response.

UKRI Gateway to Research · FY 2025 · 2025-07

The structural analysis of macromolecular complexes in situ, i.e. in the near-native cellular context, can yield unprecedented mechanistic insights into fundamental biological processes and is one of the most important frontiers in both structural and cell biology1. We present an application led by the Institute of Cancer Research (ICR), Imperial (ICL), Queen Mary University London (QMUL) and King’s College London (KCL) for instrumentation to generate electron-transparent cell and tissue samples for cryogenic electron tomography (cryo-ET), using cryogenic focused ion beam milling coupled with scanning electron microscopy (cryo-FIB-SEM)1. This equipment will open a critical bottleneck and meet the current and growing unmet demand for access in London where there is a large critical mass of bioscience researchers to realise the full potential of this technology for transformational scientific impact, training and exchange. This will complete the full provision of an accessible in situ structural biology pipeline. Cryo-ET has enabled the reconstruction of macromolecular assemblies within cellular context, recently advancing to resolutions comparable to in vitro single-particle cryo-EM in favourable cases2. Fluorescent and electron-dense molecular tagging methods enable specific proteins and nucleic acids to be tracked within cells and tissues, making it possible to study any macromolecular complex and rare events for electron imaging, not only the largest and most abundant targets. However, samples thicker than 200 nm are rarely electron transparent let alone amenable to high-resolution imaging by cryo-ET. Requirements for identifiable targets and super-thin samples have kept the majority of molecular machineries inaccessible in situ studies. Now the maturing ability to prepare electron-transparent sections anywhere in cells, tissues, and even small organisms by cryo-FIB-SEM has opened vast potential for new discoveries across cellular biology1. Cryo-FIB-SEM uses a narrow ion probe to mill thin lamellae left in plane or lifted out to specialised supports, an approach that has been refined in reliability and throughput3. The unique power of targeted cryo-ET lies in its ability to image structures of high and often insufficiently understood complexity, rendering these targets unsuitable for in vitro reconstitution and analysis by single-particle cryo-EM. Moreover, the cryo-FIB-SEM enables the combination, on a single sample, of cryo-fluorescence, serial block-face SEM4, and cryo-ET of thinned sections deep within cells or tissues, providing multimodal cellular context absent from in vitro studies. The cryo-FIB-SEM instrument will be installed at the ICR, co-located with a comprehensive setup for all stages of a state-of-the-art workflow, providing high impact at excellent value for money. The new instrument will be managed and supported by dedicated Research Technical Professionals who will train, support and collaborate with researchers across the pipeline. This partnership of ICR, ICL, QMUL and KCL builds on our successfully implemented London Consortium for Electron Microscopy (LonCEM), through which we have been collaborating since 2017 and operating a high-end cryo-electron microscope since 2019. The new cryo-FIB-SEM instrument will offer sustainable access to a game-changing technology, vital opportunities for scientific exchange, collaborative synergies across related research areas, and training. Research enabled by this equipment spans a wide range of fundamental discovery science with relevance to health and biotechnology over six research themes, run by a total of 50 Project Co-Leads: Cell Signalling; Eukaryotic Molecular Machines; Genome Integrity; Gene Expression; Healthy Ageing, Amyloids and Protein Misfolding; Microbiology, Host-Pathogen Interactions and Microbial Engineering. We aim to establish this as a major UK centre for in situ structural biology.

UKRI Gateway to Research · FY 2025 · 2025-06

Although the cells in our body possess distinct features, they all contain identical genetic material stored in DNA. The diversity of mammalian tissues is mediated by the unique set of active genes in each cell type. Such unique gene expression patterns are established by the regions of the DNA known as enhancers. Enhancers do not have a specific sequence code and are often located far away from the genes they control, making predicting their location difficult. Previous studies have found that certain chemical tags on histones, the proteins that package DNA, correlate with enhancer activity. We have used advanced computational methods (machine learning and explainable artificial intelligence) to predict the location of enhancers in flies, humans and mice based on the combinations of different histone modifications. We found that two such marks, H3K14ac and H3K18ac, are important for identifying enhancers. However, how these modifications contribute to the function of enhancers is currently unknown. To study the role of H3K14ac and H3K18ac in gene regulation, we will combine molecular and cell biology approaches with advanced computational analysis, merging expertise from two research institutions. Particularly, we plan to create mutant cell lines lacking H3K14ac and H3K18ac and use a range of advanced molecular techniques to understand how their loss affects enhancer function, gene expression, and genome organisation. In addition, our cellular assays will show how these modifications influence cell behaviour and allow us to link molecular and cellular changes mechanistically. To support these experiments, we will develop novel user-friendly artificial intelligence software to annotate and characterise enhancers in different cell types. With its unique focus on the understudied epigenetic modifications H3K14ac and H3K18ac in mammalian cells, this research project promises to provide new insights into gene expression regulation. Moreover, its methodological advancements will offer valuable and easily adaptable tools for researchers worldwide studying gene regulation and cellular differentiation.

UKRI Gateway to Research · FY 2025 · 2025-06

Cyclin B1/Cdk1 is both the regulatory hub and the trigger for cell division. Despite this crucial role, key aspects of cyclin B1/Cdk1 regulation have remained elusive due to the limitations of traditional biochemical studies. Recent technical advances mean we are now able to address these long-standing questions, and our work has revealed unsuspected regulatory steps in how the cell assembles the machinery to trigger mitosis. Here, we propose to apply gene editing, advanced cell imaging and proteomics to further our understanding of how the cell assembles the mitotic trigger, specifically: the regulation of cyclin B1-Cdk1 binding; and the how activating cyclin B1/Cdk1 moves it rapidly into the nucleus. The insights gained from this research will deepen our understanding of cell cycle mechanics and provide important implications for tissue morphogenesis and cancer biology.  

UKRI Gateway to Research · FY 2025 · 2025-05

Acute myeloid leukaemia (AML) is an aggressive blood cancer which prevents the production of normal, healthy blood cells and can therefore lead to severe anaemia, infections and bleeding. There are many different types of AML, but most have a very poor prognosis. AML most commonly affects older adults, but can occur in all age groups. It is usually treated with chemotherapy which kills most cancer cells, but the leukaemia stem cells (LSCs) from which these originate are often resistant. LSCs can restart production of the cancer cells which means that AML usually returns, or relapses. Furthermore, the older, less fit patients who constitute most cases are often unable to tolerate chemotherapy treatment. As a result, the prognosis is usually poor. Patients therefore urgently need new treatments that are tolerable yet capable of destroying LSCs to prevent relapse and lead to a long-lasting cure. This project aims to develop a new treatment for AML which could tackle this unmet need and improve patient survival.  Our team’s previous work suggests that activating a set of chemical processes called the hypoxia-inducible factor, or HIF, pathway, represents a promising strategy for killing AML cells, including LSCs. The HIF pathway is usually activated by cells in the body to cope with low oxygen levels and they switch a variety of different genes on and off. When oxygen levels are normal, the HIF pathway is inactivated by proteins called prolyl hydroxylase (PHD) and factor inhibiting HIF (FIH). Our team have developed a new drug, IOX5, that stops PHD from inactivating the HIF pathway. This drug was given to mice with AML and both improved their survival rate and killed LSCs, suggesting that it has the potential to prevent AML coming back. Additionally, it proved to be even more effective at killing leukaemia cells when given with venetoclax, an existing AML treatment often given to patients who are unfit for chemotherapy. These early results are promising, but to find out whether this potential treatment strategy works in humans with AML, clinical trials are needed. However, we need to answer several questions relating to HIF pathway activation before these can be planned. These represent the aims of this project, which are as follows: We need to understand against which AML types IOX5 and venetoclax work best, so we will test them against a variety of different human samples. We will determine whether stopping FIH in addition to PHD, which should reduce inactivation of the HIF pathway, also increases treatment effectiveness. We have a drug, DM-NOFD, which achieves this and early tests indicated that it enhances the effects of IOX5 and venetoclax. We will therefore test this triple combination on human samples to discover if it works better. We will investigate the way in which the HIF pathway targets AML, which may help us to identify potential side effects which could occur in a clinical trial and new treatment targets. We will determine the effects of these treatments on the production of normal blood cells, which is often inhibited by the therapies currently used and limits their tolerability. By improving understanding of HIF pathway activation and how it can best be utilised to treat AML, we hope to bring these treatments closer to clinical trial and potentially improve the cure rate for patients with this devastating disease.

UKRI Gateway to Research · FY 2025 · 2025-01

ADP-ribosyltransferases (ARTs), which catalyse a post-translational modification known as ADP-ribosylation, consuming nicotinamide adenine dinucleotide (NAD+), have emerged as important drug targets in a range of pathologies. The most prominent examples are the DNA damage sensors PARP1 and PARP2, targets of clinical PARP inhibitors in breast, ovarian and prostate cancer1,2. Yet, the actionable repertoire of ARTs extends to other family members. Tankyrase (TNKS, TNKS2) is a highly conserved, versatile ART which like PARP1/2 catalyses the attachment of chains of poly-ADP-ribsose (PAR) to substrates. Tankyrase controls a variety of physiological processes, including Wnt/beta-catenin signalling, Hippo signalling, telomere length regulation and glucose homeostasis, with disease links to cancer, diabetes, fibrosis, neurodegeneration and anti-viral responses3,4. Inhibition of Wnt/beta-catenin signalling, relevant to drug development efforts to target colorectal cancer, fibrosis and neurodegeneration, is largely attributable to the stabilisation of the tankyrase substrate AXIN1/2, a key negative regulator of the pathway5. Initial tankyrase inhibitor studies indicated a small therapeutic window, common for agents targeting the Wnt/beta-catenin pathway6,7. Whilst the mechanism of toxicity remained unclear, new compounds show much-reduced toxicity, rekindling drug development efforts8,9. Notwithstanding, our knowledge of tankyrase's regulation and mechanism of action still lags that of PARP1/2, which complicates the interpretation of inhibitor responses and limits further inhibitor development. Open questions include the mechanisms of tankyrase regulation by self-assembly into filaments and other inputs, the precise mechanistic impact of catalytic inhibitors, and the roles of catalytic vs. non-catalytic functions5,10. We have a long-standing interest in tankyrase, having revealed substrate binding and polymerisation mechanisms, catalysis-independent (scaffolding) functions and initial approaches to target these5,10-14. Our recent cryo-electron microscopy (cryo-EM) study revealed the architecture of part of the tankyrase filamentous polymer, providing important mechanistic clues10. As the substrate-binding modules were absent from this study, their contribution to tankyrase regulation, which our preliminary structural, biochemical, biophysical, genetic and proteomic studies point towards, remained unclear.

UKRI Gateway to Research · FY 2024 · 2024-08

Context: Patients with various kinds of cancer receive treatment involving radiotherapy and immunotherapy drugs called immune checkpoint blockers (ICB). Some patients can be cured with these treatments; sadly, for many patients these treatments do not work or their cancer may initially respond but then return. At this point their cancer is said to be resistant. One of the reasons for this resistance is that cancer cells turn off one of the ways in which cells die, a process called apoptosis. When this happens, there are limited treatment options for these patients. Therefore, novel medical solutions are needed to overcome apoptosis-resistance. Approach: We believe that by triggering an alternative way for cells to die called necroptosis, we can overcome the resistance to apoptosis. Necroptosis is a different way for cells to die, it is how the body gets rid of cells infected by pathogens such as viruses. So, if we develop treatments that promote necroptosis, this could both kill tumour cells that are resistant to apoptosis and stimulate the patient's immune system to mount a strong response against cancer cells, as if they were infected by a pathogen. This would make radiotherapy and ICB treatment more effective. Aims: The goal of the project is to discover and develop prototype drugs which cause depletion of a protein called RIPK1. Our work shows that this will induce cell death by necroptosis. RIPK1 blocks necroptosis and so is used by cancer cells to evade cell death and allow them to hide from the immune system during radiotherapy and ICB treatment. RIPK1 blocks necroptosis by scaffolding - forming physical contacts with other proteins. Drugs that just switch off the function of RIPK1 are known, but these do not prevent this scaffolding and therefore do not work. We therefore needed to find a way to deplete RIPK1 in cells, which will induce a strong immune response like that of a viral infection in combination with radiotherapy or ICB. Degraders are drug molecules that induce destruction of a protein by the cell's own "waste-disposal system", the proteasome. We have discovered degraders that cause RIPK1 depletion in human and mouse cancer cells. Injecting our prototype molecule R1-ICR-5 directly into the tumour in a mouse model of breast cancer improved the effectiveness of radiotherapy. This is an exciting breakthrough, and our goal is to improve this molecule to discover a drug that can be tested in patients. In this project, we will design, make, and test new improved RIPK1 degraders that can be dosed systemically rather than injecting directly into tumour. We will test our improved degraders in proof-of-concept studies in mouse models of different cancer types including breast, melanoma and head and neck cancer, in combination with radiotherapy as well as ICB. These experiments will provide further confidence that this is a viable approach for effective cancer treatment. Potential applications: By designing new prototype drugs and showing they are effective in mice, we will be in an excellent position to partner the project with a pharmaceutical company, so that we can continue developing this into a drug that can be tested in patients (clinical candidate).?Our aim is to progress our RIPK1 degrader into clinical trials and ultimately see it used as a combination treatment with radiation and ICB for cancer patients on the NHS and internationally.

UKRI Gateway to Research · FY 2024 · 2024-08

RNA splicing is a crucial phase in processing the genetic information. This process is carried out by complex particles known as spliceosomes, considered some of the most sophisticated cellular machines. During splicing, spliceosomes remove non-coding regions (introns) from RNA transcripts and then reconnect the coding regions (exons). This drastic "editing" ensures that the genetic information is accurately translated into proteins. Beyond catalyzing RNA splicing, spliceosomes can process specific sequences of intronic RNAs known as SNORD (small nucleolar RNA C/D box). These RNAs are vital in forming small nucleolar ribonucleoproteins (snoRNPs), which later play essential roles in the maturation of ribosomes. Spliceosomes can actively shape the SNORDs and induce their association with specific proteins to construct functional snoRNPs. For both RNA splicing and SNORD processing, spliceosomes employ a group of five proteins that form the intron-binding complex (IBC). Central to the IBC's functionality is one of its components - the RNA helicase Aquarius, which acts as a pivotal molecular motor. Our objectives are to deeply understand two areas: first, how the IBC promotes the restructuring of spliceosomes to initiate the splicing chemistry. Second, we aim to explore how the IBC coordinates the processing of SNORD sequences and splicing within spliceosomes. As the spliceosomes are very dynamic molecular machines, permanently modifying their composition and conformation, a key challenge is to find means of stalling them at precise stages, and then to resolve their 3D structure with cryogenic electron microscopy (cryo-EM). We will use advanced methodologies of cell cultivation in a bioreactor, proteomic mass-spectrometry, protein and RNA biochemistry, and cryo-EM. This integrative approach will enable us to reconstruct intermediate stages of spliceosomes, to dissect and visualize RNA splicing and SNORD processing at a molecular level. Positioned at the forefront of RNA biology and cryo-EM structural biology, this research aligns with the BBSRC's objective to maintain the UK's leadership in the "bio-revolution". It aims to enhance our fundamental understanding of biological systems through innovative ideas and impactful research, crucial for biotechnological advancements and an integrated understanding of health. Additionally, this project will contribute to nurturing and developing talented scientists, promoting a flourishing, innovative, and inclusive research culture.