NIHRDataInsights/HRCSData huggingface dataset:
Title: LuDO-N: A dose intense phase II trial of 177-Lutetium DOTATATE molecular radiotherapy in children with primary refractory or relapsed high-risk neuroblastoma.
Funder: Cancer Research UK

Abstract: LuDO-N: A dose intense phase II trial of 177-Lutetium DOTATATE molecular radiotherapy in children with primary refractory or relapsed high-risk neuroblastoma Background Neuroblastoma is a childhood cancer of unmet need. Despite genuine therapeutic advances, only about half of the children with metastatic high risk neuroblastoma will be cured of their cancer. The prognosis for those with refractory or relapsed disease is much worse, and at present very few survive. Among various options for treating relapsed and refractory disease is molecular radiotherapy. With these treatments, a vector molecule, which carries a radioactive isotope, links to a specific target on the cancer cell. As the radiopharmaceutical accumulates in the tumour, a high dose of radiotherapy is delivered. Different potential targets are expressed by neuroblastoma cells, the most widely used is the noradrenaline transporter, targeted by radio labelled meta-Iodobenzylguanidine for imaging and therapy. The somatostatin receptor is an alternative target, expressed by neuroblastoma cells and also by adult neuroendocrine cancers. Octreotide analogues bind with this receptor, and radio labelled compounds for imaging and therapy of neuroendocrine tumours are recognised as a standard and effective practice. Radio labelled somatostatin analogues have been tested previously in neuroblastoma, and based on that experience a new personalised and dose-intense administration schedule has been devised, which offers the prospect of more effective treatment. Aims This clinical trial will determine the response rate in children with refractory or relapsed metastatic high-risk neuroblastoma to a new, personalised, dose-intense schedule of the radio labelled somatostatin analogue, 177-Lutetium DOTATATE. The toxicity of treatment, the progression-free and overall survival rates will be determined. Sub-studies will correlate outcomes with tissue samples, imaging features, and the achieved radiation doses in tumours. Methods This is an international, multi-centre trial, already open and recruiting abroad. It is a two-stage single-arm non-randomised phase II evaluation of the efficacy and toxicity of this new 177-Lutetium DOTATATE administration schedule. Two administrations will be given two weeks apart, prescribed to a personalised whole body radiation dose of 2.4 Gy, rather than using a fixed administered activity. Fourteen patients will be enrolled in the first stage, and, subject to a good response rate with acceptable toxicity, a further ten in the second stage. How the results of this research will be used If this schedule is found to be effective, further research including combination treatments with other agents and randomised trials are planned.


Research activity codes: 6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Evaluating ethnic differences in blood markers of cancer in primary care
Funder: Cancer Research UK

Abstract: Background Ethnic minority groups in the UK have poorer cancer outcomes than British White groups. Improving cancer detection strategies for this population may boost UK cancer outcomes and reduce health inequality. The majority of cancers are diagnosed following consultation in primary care, where general practitioners have access to a range of blood tests used in the selection of patients for investigation for possible cancer. Despite evidence of differences in the reference ranges of common blood tests in different ethnic groups, research and guidance on these tests does not take ethnicity into account in setting thresholds for further investigation for suspected cancer. Research question Do blood test results used to identify possible cancer in primary care vary between people of different ethnic groups, in terms of their usefulness to predict cancer? Methods This cohort study will use English electronic primary care records linked to National Cancer Registration and Analysis Service data to determine the incidence of cancer in people of Black, White, Asian, Mixed, or Other ethnicities following one of the following abnormal blood test results in primary care: platelet count, haemoglobin/mean cell volume, cancer antigen 125 (Ca125), creatine reactive protein (CRP), and serum calcium. A series of five sub-cohorts will be derived, each comprising patients with one of these tests. The outcome measure will be incident cancer in the year following that test. Multi-level logistic regression models will be constructed for each sub-cohort, including an interaction term for ethnic group, which will indicate if the effect of the test result differs according to ethnicity. These models will allow us to estimate the positive predictive values for cancer for each ethnic group. How the results of this research will be used A key output from this piece of work will be positive predictive values for cancers, personalised to each ethnic group, for each laboratory test. Currently, standard laboratory reference ranges are applied to blood test results regardless of ethnicity. Our results will enable more precise estimates of cancer risk in patients with abnormal blood test results, which will contribute to better diagnosed work-up in primary care and better selection of patients for further investigation for suspected cancer. These results will be used to inform primary care cancer detection practice and policy. Current guidance can be updated following this study, such that clinical recommendations for general practitioners seeing patients with abnormal blood tests will take ethnic differences in cancer risk into account.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Exploratory & preclinical development & CRUKD/17/003 a Phase I first in human trial of AST-VAC2. Telomerase pulsed allogeneic Dendritic Cells for the immunotherapy of lung cancer (NSCLC)
Funder: Cancer Research UK

Abstract: AST-VAC2 is derived from human embryonic stem cells and has the phenotypic and functional properties of mature dendritic cells which are known to be the ?professional antigen presenting cells? of the immune system._x000D_ _x000D_ AST-VAC2:_x000D_ 1) expresses HLA Class I and II molecules and costimulatory proteins found on mature dendritic cells;_x000D_ 2) processes and presents antigen through both HLA Class I and II molecules;_x000D_ 3) is modified to express human telomerase, a known tumour antigen;_x000D_ 4) stimulates anti-telomerase specific T cells; and_x000D_ 5) functions after both cryopreservation and irradiation._x000D_ _x000D_ Therefore AST-VAC2 is expected to process and present telomerase antigen as an immunotherapy in vivo. Moreover, upon administration, AST-VAC2 will likely also induce allogeneic immune responses._x000D_ Induction of such allogeneic immune responses could be beneficial to the overall activity of AST-VAC2 by stimulating an ?adjuvant? effect and providing an environment to enhance indirect antigen presentation of the telomerase tumour antigen. Preclinical evidence of the functionality and activity of AST-VAC2 has been collected._x000D_ _x000D_ This application proposes to clinically test the safety and immunostimulatory activity of AST-VAC2 in two different patient populations with lung cancer. The first targeted population (cohorts 1 and 2) will be those patients with resected lung cancer that have no evidence of metastatic disease on imaging, having complete standard adjuvant therapy. The purpose is to evaluate the vaccine in a setting where patients? immune system is most likely to be normal or close to normal. At this point, subjects will not be receiving any other, standard therapy._x000D_ AST-VAC2 will be administered and the safety of AST-VAC2 along with immunological responses to telomerase and AST-VAC2 itself will be monitored._x000D_ Time to disease progression and survival data will be collected as part of the exploratory analyses, in the full recognition that the study will not be powered to make statistically significant observations._x000D_ The second setting (cohort 3) will be for patients with advanced lung cancer who are progressing after first line standard chemotherapy for advanced disease, but who have a good PS0/1. We propose this group as we will 1) to be able to assess immunogenicity in a less favourable clinical setting, 2) have an opportunity to assess intratumoral events in patients who are eligible for a re-biopsy and 3) have the chance to collect early data on clinical effects on the tumour.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Stromal rigidity as a driver of pancreatic cancer cell proliferation
Funder: Cancer Research UK

Abstract: BACKGROUND In pancreatic ductal adenocarcinoma, an extensive stromal reaction drives tumour progression and contributes to the lethality of the disease. An understanding of the causes of this desmoplastic response, and the consequent effects of a highly rigid stromal extracellular matrix on tumour cell phenotype, would therefore be a pivotal step in the quest to improve patient outcomes. Methods are now available to investigate force sensing in vivo, so it is timely to determine how stromal rigidity drives tumour proliferation. AIMS Three central hypotheses will be tested: 1. That the sensing of stromal rigidity originates at the adhesion nexus, the junctional structure that links cells to the extracellular matrix via integrin receptors. 2. That high stromal rigidity impedes the changes in cell architecture needed for accurate segregation of chromosomes during mitosis and that mechanical cues in the extracellular environment are linked to checkpoint-dependent control of the cell cycle. 3. That driver mutations in cancers lead to a rewiring of signalling networks, one outcome of which is evasion of these checkpoint control mechanisms. The desmoplastic response therefore forces proliferation under unfavourable circumstances and accelerates tumour progression. METHODS Our immediate objectives for the next five years will be to: 1. Define tumour-specific alterations in force-sensitive components of the adhesion nexus. 2. Determine the mechanisms whereby rigidity influences cell proliferation. We will build on our knowledge base of integrin-mediated adhesion and the specialist methodologies that we have pioneered to elucidate integrin function, and apply both to models of pancreatic adenocarcinoma. We will establish new techniques for global analyses of the adhesion nexus in three-dimensional pancreatic organoids (using proximity labelling and mass spectrometry) and define how variations in extracellular rigidity initiate signalling at this site to influence cell cycle progression. We will then determine the effects of perturbing candidate molecules in organoids and employ molecular cell biology approaches to pinpoint how the sensory mechanisms vary between wild type and tumour cells. HOW THE RESULTS WILL BE USED The outcomes of the programme will advance our understanding of cancer in two ways: by defining how the adhesive stromal microenvironment influences tumour cell proliferation, and by identifying potential clinical targets. In studies beyond the scope of this programme, perturbation of tumour cell-specific alterations in the rigidity-sensing process will be examined in relevant pre-clinical models. Agents that target the evasion of this sensory system could then be used to sensitise tumours to mitotic inhibitors or other chemotherapeutics.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Understanding Fc gamma receptors to improve antibody immunotherapy
Funder: Cancer Research UK

Abstract: Evidence from pre-clinical models and human trials indicate that almost all monoclonal antibodies (mAb) act by engaging FcgR, with the activatory to inhibitory (A:I) FcgR ratio dictating response. These observations indicate that unfavourable FcgR expression profiles can limit mAb-mediated immunotherapy for multiple mAb classes and underpin treatment resistance. These important insights suggest that a strategy of optimising FcgR expression will enhance mAb therapies. This phd will gain a better understanding of how FcgR are regulated, show how the tumour controls such expression and use this information to improve the potency of mAb therapeutics.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Pseudohypoxia-led identification of metabolic vulnerabilities in hypoxic tumours to improve patient outcomes
Funder: Cancer Research UK

Abstract: Studentship: Background The oncogene-driven expansion of a cancer creates regions of cells deficient in oxygen (hypoxia). These hypoxic cells represent a pernicious source of some of the most malignant cells within a tumour, and are highly resistant to conventional therapy resulting in poor patient outcomes. Survival of hypoxic cells requires significant metabolic adaptation. This, however, leads to a reduction in metabolic redundancy, revealing enzymes that become essential in these conditions that may represent therapeutic targets to selectively kill hypoxic cancer cells. However, it has been historically challenging to identify appropriate metabolic targets in hypoxia due to the complex nature of the changes that occur. Cancer-associated mutations in some metabolic enzymes lead to pseudohypoxia – a hypoxic cell phenotype observed in normoxic conditions. Pseudohypoxic cell models represent a reductionist system in which to identify novel metabolic targets for killing cells in ‘real’ hypoxia. Aims We have identified three metabolic enzymes in pseudohypoxic models that we will investigate as being specifically required for the survival of hypoxic cancer cells. The specific aims of this programme are therefore to: 1. Investigate pyruvate carboxylase (PC) as an essential enzyme in hypoxic cancer cells 2. Investigate the differential roles of proline synthetic enzymes in both normoxia and hypoxia, and determine whether PYCR1 is essential for hypoxic cell survival 3. Determine the relative roles of PCK1 and 2, and investigate PCK2 as a synthetic lethal target in hypoxic cancer cells Methods We will use a combination of 2D and 3D (spheroid) cell culture and orthotopic models of triple negative breast cancer and glioblastoma to investigate the three metabolic targets above. Stable inducible knockdown of each enzyme under investigation will be performed in cell lines before changes in the ability to support hypoxic cell viability are assessed in each model, as will be the metabolic consequences of hypoxia and loss of the enzyme. Changes in metabolism will be investigated by stable isotope tracer (13C)-based analysis using a unique method that combines information from mass spectrometry and NMR spectroscopy. How the results of this research will be used Hypoxia-mediated alterations in metabolism are largely uncharacterised, impeding forward progress of this field. Through a unique, integrated approach this programme of research will investigate novel metabolic pathways that are essential in hypoxic cells. Through this we hope to catalyse the development of novel agents to improve the outcomes of patients with some of the most difficult to treat cancers.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Full Duration Studentship - Accelerator Award A26815 "Single-cell cancer evolution in the clinic"
Funder: Cancer Research UK

Abstract: Studentship: Cancers adapt to therapy through a process of clonal evolution. Patients undergo multiple rounds of potentially highly toxic treatments, without a clear pre-emptive indication of efficacy. When the patient relapses, meaningful information to choose the most effective treatment is rarely available. There is therefore an unmet clinical need to develop tools, applicable to the clinic, to determine how cancer evolves under therapy. Accumulating evidence indicates that resistance to specific treatments entails recurrent evolutionary mechanisms. We argue that these recurrent mechanisms do not just beset a formidable hurdle for cancer therapy, but also represent a major Achille’s heel for cancer cells that could be exploited for novel therapeutic approaches. The recent introduction of single-cell genomics approaches has finally provided a mean for the comprehensive understanding of the evolutionary strategies exploited by cancer cells as a population. In particular, profiling rare, treatment-resistant subclones at single cell level is becoming feasible. In this proposal, we combine cancer evolution modelling, new single-cell approaches and novel microfluidic devices, as well as new data integration techniques, with the aim to provide a definitive single-cell portraits of tumor cells, before and after treatment. We propose to deliver tools and devices that could be promptly implemented in a clinical setting, to pre-emptively intercept resistance in individual cancer patients.


Research activity codes: 5.1 PHARMACEUTICALS;5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Local immunoradiotherapy (LIRT)
Funder: Cancer Research UK

Abstract: Immunotherapy has revolutionized the treatment approaches to many common cancers over the last decade, however combination strategies are required if the majority of cancer patients are to derive durable tumour control. In preclinical tumour models, radiotherapy (RT) has been shown to synergize with a variety immunotherapy approaches leading to better tumour control. Here RT not only leads to direct tumour cell death but is also able to promote a systemic anti-tumour immune response (abscopal effects). The ability of RT to induce a systemic immune response is rare and in order to induce systemic anti-tumour immune responses in the majority of tumours, combinations with immunomodulatory agents capable of overcoming the immunosuppressive tumour microenvironment are required. More recently, immuno-oncology (IO) agents of various types have been injected or delivered inside tumour lesions in a manner that is safe and active in preclinical models, as well as leading to encouraging results in clinical trials. Intra-tumoural approaches have the advantage of minimizing systemic exposure and toxicity, whilst potentially maximizing local efficacy in overcoming tumour induced immunosuppression. In this project, we propose to combine intra-tumoural administration of various IO agents in order to enhance therapeutic effects of immunotherapy against irradiated and non-irradiated tumour lesions. Such local radioimmunotherapy (LIRT) approaches will be tested using compounds that enhance immunogenicity of the irradiated lesion to turn it into an endogenous vaccine against cancer neoantigens shared by distant tumours. We will use agents that curtail the local immunosuppressive effects of radiotherapy as known to be chiefly mediated by TGFb and VEGF and involving a variety of immunosuppressive immune effector cells. The experimental plan will aim to test strategies in preclinical tumour models where the irradiated tumour will be injected with IO agent. These IO agents will include, but not be limited to, intra-tumoural injections of BO112, an experimental immunotherapy agent based on nanoplexed PolyI:C that mimics viral infection, inducing local cell death and pro-inflammatory effects to raise immunogenicity. The project will involve collaboration with the accelerator partners to provide incisive cellular and molecular analyses on mouse and human tissue samples in an exhaustive effort to understand the mechanisms behind both efficacy and failure with RT and IO combinations. The outputs of the project will include an enhanced understanding of the cellular and molecular immune functions accounting for efficacy and resistance leading directly to informing clinical trial design for the LIRT accelerator platform across the UK, Spain and Italy.


Research activity codes: 6.1 PHARMACEUTICALS;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Harnessing secondary data to assess youth uptake of e-cigarettes
Funder: Cancer Research UK

Abstract: E-cigarettes remain a controversial topic within the UK tobacco control community and their use by children and young people is a key issue. As many existing studies are cross-sectional, there is a need for more detailed consideration of range of factors associated with e-cigarette uptake, and currently available secondary data can provide timely answers to these questions. Aim To assess transitions into and out of e-cigarette use among young people in the UK. Specific objectives are to: 1. Estimate levels and patterns of transition into and out of e-cigarette and tobacco use among young people in the UK from 2015 – 2021 2. Assess pathways into and out of e-cigarette use, including income, parental and peer tobacco and e-cigarette use and social media use 3. Assess changes in sources of e-cigarettes in England between 2016 and 2020 4. Provide estimates of the number of children taking up and using e-cigarettes in local areas in the UK. Methodology We will address these questions with data from the Millennium Cohort Study (MCS) and the UK Household Longitudinal Study (UKHLS). The MCS and UKHLS will allow examination of individual-level trajectories into and out of e-cigarette use, as well as characterising which groups are most likely to follow these trajectories. We will use Markov models and latent class analysis to assess transition patterns and characterise patterns of use over time. We will use causal mediation methods to explore the role of a wide range of factors to include deprivation, family tobacco and e-cigarette use and social media use. We will also use the Smoking, Drinking and Drug Use (SDDU) survey, an annual survey of secondary school children and we will use similar methods to previous work from our group to provide estimates of young people taking up e-cigarettes at the local level. The SDDU will also allow examination of the main sources of e-cigarettes 2016-2020 using logistic or multinomial regression. Results Together these analyses will produce a comprehensive picture of e-cigarettes uptake among young people in the UK and strengthen the evidence base and recommendations for policy-makers considering e-cigarette use. Outputs will include academic publications on the stated objectives, alongside presentations at academic conferences. We will work with ASH to produce language summaries of findings for dissemination through the Smoke Free Action Coalition and hold focus groups with young people to refine dissemination messages.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: CANCER AND NEOPLASMS
Title: Potentiating immunotherapy from within the tumour microenvironment - Studentship
Funder: Cancer Research UK

Abstract: This studentship will explore the role of exosomes within the tumour microenvironment, specifically to assess how they influence the activity of oncolytic viruses, and whether they can be exploited to improve the ability of oncolytic viruses to spread from cell to cell within solid tumours. The student will initially characterise the exosomes produced by tumour cells and virus infected tumour cells, seeking to determine which virus proteins are entrapped within exosomes and the functional consequences of this. Finally we will seek opportunities to modify the viruses in order to exploit these pathways for improved therapeutic activity.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS