NIHRDataInsights/HRCSData huggingface dataset:
Title: Imaging the Redox Microenvironment to Predict Tumour Resistance to Therapy
Funder: Wellcome Trust

Abstract: The majority of lung cancer deaths result from ineffective treatment of late-stage disease. Currently, there is no satisfactory way to identify patients that will not respond to standard-of-care treatments. Positron emission tomography (PET) imaging offers a potential solution to this clinical problem through the non-invasive assessment of molecular processes that underpin therapy-resistance. The identification of cancer patients that are refractory to treatment will allow the selection of second-line therapies that have the potential to improve patient response and survival. For this SRF, I will develop novel PET radiotracers to predict therapy resistance in mouse models of non-small cell lung cancer. These radiotracers will non-invasively image the aberrant activity of key antioxidant pathways that are causal to therapy resistance. Specifically, I will use structure-activity relationships and in vivo imaging to design highly-specific radiotracers for the cancer stem cell marker, aldehyde dehydrogenase 1A1; nuclear factor erythroid 2-related factor 2, the master regulator of the antioxidant response; and de novo glutathione synthesis. Our library of redox radiotracers will subsequently be used to detect drug resistance in syngeneic, isogenic and patient-derived models of lung cancer. Finally, I will use the radiotracers developed in this programme to assess response to immunotherapy in drug-resistant lung cancer.

Lay abstract: Drug resistance is one of the most pressing issues facing lung cancer patients today. Whilst chemotherapy may work at first, the treatment frequently becomes ineffective due to the cancer developing resistance to these drugs. At present, there is no way for doctors to accurately know when this treatment stops working. If this was known, different treatments can be given that may prolong the patient’s life. There is therefore a critical need to develop new ways to identify patients that may benefit from this ‘personalised’ treatment plan. Building on extensive, supportive preliminary data, I will develop new medical imaging tests to detect drug resistance in lung cancer. We want to ask the following important questions: 1. Can we use imaging to distinguish drug-sensitive from drug-resistant tumours before any drug is given? 2. Can the same imaging test be used to monitor whether new treatments are working after they are administered?

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Inequalities in cancer outcomes
Funder: Cancer Research UK

Abstract: Background Despite the implementation of successive comprehensive cancer policy initiatives, cancer survival in England remains lower than in most comparably wealthy countries, and wide sociodemographic inequalities in cancer survival persist. These initiatives have largely emphasised the importance played by individual (tumour and patient) characteristics on these inequalities. We have however shown that patient characteristics (e.g. comorbidities) explained little of the sociodemographic inequalities in cancer care and survival. We have also shown that inequalities exist even on a stage-by-stage basis and that more advanced tumour stage caused only part of these inequalities. The question now is how to address these inequalities. Aims Our ultimate aim is to reduce these inequalities. Through a series of projects, we will focus on the multidimensional interplay between the (sociodemographic and clinical) characteristics of the patients and the healthcare system components. Methods The overarching strategy of each project includes three steps. In step 1 we will finalise process maps to visualise the interplay between patient characteristics and the healthcare system components, potentially leading to inequalities in cancer outcomes. Developed in collaboration with stakeholders and patient representatives, each map will underline the causal structure for the further analyses and identify promising policy interventions to reduce the inequalities. Step 2 will describe the patient-system interplay of interest associated with these inequalities. We will quantify, at population level, the impact on cancer outcomes of potentially differential availability of healthcare system component resources, according to sociodemographic characteristics of the population, applying methods accounting for clustering. Step 3 will (i) examine simultaneously the effect of system-level components and patient characteristics on the cancer outcomes, and (ii) evaluate (hypothetical and actual) interventions aimed at reducing inequalities, according to various plausible scenarios. Together with health economists, we will conduct economic evaluations of these interventions which incorporate the equity dimension. As the analyses are based on observational (i.e. non-randomised) data (cancer registry data linked to population-based electronic health records and system-level data), we will apply and develop new advanced methodology, in particular from the causal inference framework to estimate causal associations in Step 3. How the results of this research will be used Understanding the patient-system interplay along the cancer patient pathway and its role on inequalities in outcomes will inform the development of interventions and policies for ensuring that all patients benefit from improvements in cancer care, regardless of their sociodemographic background.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: CANCER AND NEOPLASMS
Title: Dissecting the biochemical and cellular functions of SOX proteins in glioblastoma
Funder: Cancer Research UK

Abstract: Background Glioblastoma (GBM) is an aggressive brain cancer. The transcription factor SOX2 is often amplified or has elevated expression in GBM where it limits terminal differentiation and forms part of the core ‘stemness’ gene regulatory network. Despite its clear role as an oncogene in GBM and other carcinomas, SOX proteins are considered undruggable based on their biochemical features. Therefore, new insights into biochemical mechanisms of activity and regulation are urgently needed to provide new avenues for targeted therapies. Our pilot data indicates that SOX2 operates as a pioneer transcription factor upstream of other SOX factors. We have also uncovered unanticipated regulatory controls that likely explain SOX2 oncogenic activity. Aims We aim to gain a deep understanding of the biochemical and cellular mechanisms through which SOX proteins operate, and thereby identify novel molecular vulnerabilities that can be targeted therapeutically. In WP1 we will define and characterise the functional enhancers underpinning GBM – particularly those within amplified ecDNAs. We will determine the dynamic spatiotemporal regulation of SOX2 in sub-nuclear compartments (e.g., transcriptional hubs). In WP2, we will explore the mechanisms underlying biochemical cooperativity between SOX factors. In WP3, we will determine whether the activity of SOX2 is regulated by post-translational modifications and how this supports its oncogenic activity. Methods We will focus on patient-derived GBM stem cell models and human foetal neural stem cells engineered with key GBM driver mutations. We have already generated knock-in fusion reporter cells for relevant markers. In WP1 we will characterise enhancers using CRISPR, single cell RNA-seq/ATAC-seq profiling and super-resolution imaging of fusion reporters. In WP2 and WP3, we will determine how SOX factor influence nucleosome remodelling and dissect biochemical mechanisms using cell free and genomics approaches. How the results of this research will be used Our results will be used to guide new strategies for therapeutic targeting of cancer-acquired vulnerabilities triggered by excessive SOX activity. Small molecules, biotherapeutics, or advanced therapies, may be developed to target the biochemical mechanisms uncovered in WP2 and WP3. As elevated SOX proteins are features of many diverse solid tumours, our findings will have broader impact, enabling elucidation of mechanisms of transcriptional deregulation across solid cancers.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Exploiting adhesion protein networks in glioblastoma
Funder: Cancer Research UK

Abstract: Background: Whatever the mutational status and burden in glioblastoma (GBM), a cancer type of huge unmet medical need, invasive tumour cells must have intrinsic and extrinsic biological requirements (vulnerabilities) required for adhesion, invasive migration, evasion of anti-tumour immunity, survival and growth. Our recent work identified tyrosine kinases and adaptor/scaffold proteins that are actin and adhesion modulators. These lie at the heart of cancer cell pathways controlling integrin adhesions, actin dynamics, cancer cell polarization, directional migration and invasion. We also discovered a new way by which one classical adhesion protein, Focal Adhesion Kinase (FAK), promotes downstream responses from the nucleus, regulating chemokine expression, the tumour microenvironment and evasion of anti-tumour immunity. Aims: We will use new mouse and human glioblastoma (GBM) cellular models, including Glioma Neural Stem (GNS) cells derived from patients. These are being generated and characterised routinely as part of our CRUK Glioma Accelerator grant (joint with UCL). We will identify core adhesion proteins and their interaction partners that control cancer cell phenotypes and devise genetic and/or chemical strategies to intervene. Methods; our future work: • We will combine quantitative interaction proteomics and protein informatics to determine how adhesion protein complexes differ between GNS cells and their normal Neural Stem (NS) cell counterparts; • We will use CRISPR/Cas9-mediated genome-editing to interrogate key adhesion protein complexes (kinases and scaffold proteins) to determine how they contribute to GBM biology; • We will study the intrinsic behaviour of GNS cells and their responses to genetically interfering with adhesion proteins. We will also address how they influence the host immune cell infiltrate and functionality, and the structure of the microenvironment; • Finally, we will perform focussed chemical-genetic, high-content phenotypic screens to identify co-targeting strategies with potential therapeutic value, as we have done successfully for FAK. How the results of the research will be used: New understanding; we will identify core adhesion proteins that are ‘differently connected’ in physiologically-relevant GNS cell models, and determine which of these, or their proximal binding partners, control GBM phenotypes in vitro and in vivo. New translational opportunities; we will devise chemical-genetic co-targeting strategies to collapse the robustness of adhesion protein networks that control cancer cell survival, growth, invasion and/or anti-tumour immunity. We will make early translational gains by using existing pharmacological agents (where these are available), or chemical entities being developed against enzyme targets in adhesion protein complexes important for the biological properties of GBM.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS
Title: Developing immunostimulatory antibodies to deliver agonism without toxicity
Funder: Cancer Research UK

Abstract: • Background Monoclonal antibodies (mAb) targeting immune checkpoints such as CTLA-4 and PD-1/PD-L1 have transformed therapy for some types of cancer in a proportion of patients. Despite these advances, the majority of patients have tumours which are resistant to this form of immunotherapy. Recent studies suggest that most tumours which respond to checkpoint therapy display a ‘hot’ T-cell rich signature. Immunostimulatory antibodies (ISA) targeting TNF receptor superfamily members are capable of activating immune cells to deliver enhanced T cell priming, expansion, secretion of inflammatory cytokines and tumour cell killing. Notably, ISA synergise with checkpoint mAb to improve anti-tumour responses in preclinical models. To date clinical development of ISA has been hindered by two key issues. First, their activity on human cells has been variable, with only a minority demonstrating potent immunostimulation, in contrast to their more active murine counterparts. Secondly, severe adverse events are frequently seen with strong ISA agonists, necessitating new approaches to mitigate these effects. In the last five years, we have made important advances in understanding how to generate potent ISA that operate through either FcgR-dependent or -independent mechanisms. We are now ideally-placed to bring this understanding to bear on a range of existing and new targets to deliver next-generation ISA for clinical application. • Aims 1) Optimise human ISA to deliver agonism with and without FcgR cross-linking. 2) Develop novel ‘conditional’ ISA formats that mitigate adverse events 3) Evaluate a new class of ISA that promote lymphocyte recruitment to tumours • Methods The programme will benefit from interactions with structural biologists, experts in antibody engineering as well as specialists in receptor biology and tumour microenvironment. A unique panel of transgenic and humanised mouse models will allow appropriate evaluation of newly developed agents. By combining techniques, including X-ray crystallography, SAXS and molecular dynamics together with protein engineering we will define the relationship between key mAb properties (affinity, hinge-rigidity, epitope) and immunostimulatory activity. Furthermore, we will develop novel mAb formats and ISA against new targets to minimise adverse events associated with conventional ISA and improve T cell access to tumours. • How the results of this research will be used This programme will generate deeper mechanistic understanding of ISA, specifically detailing the factors which determine potency and toxicity in existing and new formats. We will apply this knowledge to generate new optimised ISA for clinical testing that could extend the benefit of immunotherapy to more people with cancer.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Deciphering the Immune and Neoantigen Landscape In NSCLC and Their Relevance to Cancer Immunotherapy
Funder: Cancer Research UK

Abstract: Non Small Cell Lung Cancer (NSCLC) is one of the largest causes of cancer-related deaths worldwide, and hence considered a cancer of unmet need by CRUK and primary target for the evaluation of novel therapies. Whilst recent clinical trials have underscored the potency of approaches mobilising the immune system to treat cancer, clinical responses are still limited to a fraction of treated patients, underscoring the relevance of studies aiming to understand the mechanism underpinning response and resistance to therapeutic intervention. With particular relevance to NSCLC, antibodies blocking Program Death-1 (PD-1), an immune-modulatory receptor expressed on T cells, have yielded promising clinical results. Furthermore, the neoantigen burden of tumours has been associated to positive responses, attributed to the ability of the immune system to recognised mutated self. Remarkably, little is still known about the in vivo crosstalk of cancerous and immune cells in NSCLC and even less about the immune-regulatory pathways controlling the function of neoantigen-reactive T cells within the lung microenvironment. Using samples for NSCLC patients and mouse models of cancer we propose a translational research program aiming to understand and target the mechanism affecting the recognition of lung cancer cells by the immune system and the regulation of such responses within the lung microenvironment. This research plan will shed light on mechanism of response and resistance to immunotherapy and provide new targets and rational for the development of future therapies against lung cancer.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: SMART Experimental Cancer Medicine Trials eNABLED
Funder: Cancer Research UK

Abstract: Background Clinical Research lags behind many industries in using digital technology to drive faster and smarter decisions. Phase 1/Experimental Medicine trials in particular would benefit from digitisation. In this “learning” phase of development these trials frequently require in-flight adaptation which would benefit from near-real time data capture and visualisation to drive faster and smarter decisions. Phase 1 colleagues particularly in Asia are making significant strides to digitise experimental cancer medicine trials. Sponsors are willing to pay a premium in Phase 1 for near-real time access to patient data, with the benefit this yields in faster and smarter iterative decisions that adapt the study population, drug posology, combination agent and predictive/pharmacodynamic biomarker thereby providing the investigational medicinal product the best chance of success. Aims 1.Scientific: Through the digitisation of experimental cancer medicine trials, the translatability of pre-clinical observations to clinical trials will increase by reducing false-negatives arising from insensitive experimental methodology 2.Capability/Infrastructure: To remain a competitive experimental medicine network in Europe to sponsors whose key driver in Phase 1 is to have near-real time access to data from patients recruited and to hypothesis generate and test from the emerging clinical trial dataset Methods A network of Experimental Cancer Medicine Centres in Spain, Italy and UK and coordinated nationally, will develop and test digital methods to •acquire per-protocolled assessments in hospital •push per-protocolled assessments into patient’s homes •determine if continuous monitoring of patients provides more informative data •enable investigators to be automatically alerted to emerging safety signals, and find trials matching the patient’s molecular and clinical characteristics •enable sponsors (both academic and commercial) to iteratively hypothesis generate and test on the emerging dataset •provide patients the opportunity to become co-researchers by access to their own data How the results of this research will be used Successful digital methods of proven utility will be accessed through open-source software by all participating centre 1.Providing investigators and sponsors near-real time access to more complete and less error-prone patient datasets in a format of intuitive visualisations and alerts to safety signals 2.Enabling patients (whose average survival is 6 months) flexibility to provide per-protocolled assessments from home, and to review their own data in the context of the trial as a whole 3.Upskilling the EU network of Phase 1 centres to conduct the increasing number of clinical trials appraising new digital technologies (devices); to be the go-to place for conducting such trials


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: CANCER AND NEOPLASMS
Title: Augmented Response of vOlatile bioMarkers to detect oesophagogastric Adenocarcinoma (AROMA)
Funder: Cancer Research UK

Abstract: BACKGROUND: Oesophagogastric cancers have low survival rates. Patients with early oesophagogastric cancer often have non-specific symptoms that can be associated either with cancer or more often a common non-cancerous condition. These patients are not eligible for referral for investigation under existing guidelines. We intend to develop a breath test for the detection of oesophagogastric cancer. The breath test detects volatile organic compounds (VOCs) which are small molecules, that could be detected at the gas phase at room temperature. Our research has found that breath testing has promising results in the detection of oesophagogastric cancer. The test is simple, non-invasive and acceptable to patients. AIMS: i. To confirm the identity and source of VOCs associated with oesophagogastric cancer ii. To improve the accuracy of the test by giving patients simple nutrients that will increase VOCs production iii. To establish the accuracy of the test in symptomatic patients iv. To understand the benefits of the test for both patients and the health service METHODS Source of VOCs in oesophagogastric cancer We will collect samples from patients with oesophagogastric cancer to study how VOCs are made by the cancer. We will find out if gut bacteria that are linked to the cancer affect the types of VOCs that are produced. Stimulated VOC production for enhanced cancer detection We will test if adding simple nutrients such as sugars and fats make either the cancer or their associated bacteria produce more VOCs. This will help us to improve how well our breath test works in later clinical trials. Multicentre trial We will determine the test performance in 5400 patients who have been referred for endoscopy because they have symptoms that may be associated with oesophagogastric cancer. Understanding the benefits of the test We will talk to patients and stakeholders to find out what they feel about the use of a breath test for cancer detection. The cost benefits of the test to the health service will be determined. HOW THE RESULTS WILL BE USED The breath test will be offered to patients with non-specific symptoms of oesophagogastric cancer and will help doctors determine which patients would benefit from a referral for an endoscopy. The breath test will mean that patients have faster access to a simple and accurate method of identifying oesophagogastric cancer that will lead to earlier treatment and improved survival. Healthcare services will benefit from a more cost-effect pathway for oesophagogastric cancer diagnosis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS