NIHRDataInsights/HRCSData huggingface dataset:
Title: CRUK/12/049: TIGER - Randomised phase III trial of intial salvage chemotherapy for patients with germ cell tumours
Funder: Cancer Research UK

Abstract: Background Germ cell tumours (GCT) represent the most common malignancy affecting adolescent and young adult men in both Europe and the United States. Early stage disease, which affects the majority of GCT patients, is nearly universally curable with local or short-course systemic therapy such that current efforts are focused on defining the least toxic means to achieve cure rather than improving efficacy. In contrast, up to 30% of patients with advanced GCT will not be cured with initial chemotherapy with or without surgery and therefore require salvage treatment. There is no international standard treatment in this setting and routine practice differs between countries. Aims The primary aim of this study is to compare the efficacy of conventional-dose chemotherapy (CDCT) using Paclitaxel, Ifosfamide, and Cisplatin (TIP) regimen with high-dose chemotherapy (HDCT) plus Autologous Stem Cell Transplant (ASCT) using Paclitaxel and Ifosfamide followed by high-dose carboplatin and etoposide (TI-CE) regimen as initial salvage treatment of patients with relapsed or refractory germ cell tumours (GCT). Methods This is an international collaborative group phase III randomised controlled trial coordinated in Europe by the European Group for Blood and Marrow Transplantation and in North America by The Alliance. 420 eligible patients will be stratified according to risk group and region (Europe or North America)and will be randomised (1:1) to receive either CDCT with TIP or HDCT with TI-CE. Patients will have regular follow up in line with routine practice for a minimum of four years. The primary endpoint is overall survival. Secondary endpoints include response rate, progression-free survival, toxicty and quality of life. How the results of the research will be used Due to a lack of a definitive randomised trial, it remains unclear whether sequential HDCT or CDCT represents the optimal initial salvage approach for patients with relapsed or refractory GCT. The international investigators believe this represents the most pressing question remaining for defining treatment standards and optimising outcomes and the results of this study will influence practice globally.


Research activity codes: 6.1 PHARMACEUTICALS;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Organ-on-a-chip model to investigate breast cancer bone metastases - full proposal
Funder: Cancer Research UK

Abstract: Background A common site for invasive ductal carcinomas (IDC) metastasis is bone, affecting about 70% of patients. Once metastasis to bone has occurred the five-year survival rate drops from 99% to 29%. How breast cancer metastasises to bone is poorly understood, partly because of the lack of appropriate models. Organ-on-a-chip technology is a new branch of bioengineering which may be used to accurately recapitulate bone metastasis by combining multiple cell types in a microfluidic chip with circulating media and physiological biomechanical forces. However a reliable breast cancer bone metastasis chip is currently not available. Aims The aim of this study is to develop an organ-on-a-chip model of bone metastasis in breast cancer and to use this to test the hypothesis that the interaction between cancer cells and osteocytes controls the metastatic niche and tumour development. We hypothesize that this process is regulated by physiological biomechanical loading of bone and osteocyte primary cilia. Methods In partnership with the company Emulate Inc., we will develop a specialised organ-on-a-chip model using microfluidic platform technology coupled with optimised biomechanical loading of the different bone cell types in co-culture with breast cancer cells maintained in a 3D matrix. We will characterise this new model and validate it against known chemotherapeutics in terms of phenotypic stability, cancer cell proliferation, migration and invasion and bone formation and remodelling. To test our hypothesis we will examine cancer cell behaviour with and without bone cells and mechanical loading. We will then quantify cancer cell behaviour following treatment with siRNA and pathway antagonists to disrupt osteocyte ciliogenesis and regulation by cancer cells within the chip. Finally we will test the effect of pharmaceutical regulation of osteocyte cilia to identify the potential of novel ciliotherapy for treatment of bone metastasis. How the results of this research will be used The project will deliver novel organ-on-a-chip technology for investigating bone metastasis in breast cancer and will be used here to examine the hypothesis that bone cells regulate metastasis in response to mechanical loading and modulated by changes in primary cilia. This is likely to be transferable to other cancers involving bone metastasis and may lead to novel ciliotherapies. The chip may also be modified for use with autologous cells making it suitable for personalised medicine therapies and will provide a scalable platform for testing new cancer therapeutics.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: CANCER AND NEOPLASMS
Title: Consumption of ultra-processed foods and cancer risk: comprehensive analysis across two large European Cohorts (UltraCan)
Funder: Cancer Research UK

Abstract: Background There is growing evidence linking the consumption of ultra-processed foods (UPF) to adverse health outcomes, including cancer. UPF are invariably obesogenic and are often characterized by higher energy density, lower nutritional quality and the presence of additives and contaminants derived from food packaging and compounds formed during production, processing, and storage. While mechanistic studies have indicated potential carcinogenic effects of specific components commonly found in UPF, epidemiological data linking the consumption of UPF to cancer risk are currently lacking. Aim To assess the associations between consumption of UPF and cancer risk at all anatomic sites using data from two large prospective cohorts, the UK Biobank and the European Prospective Investigation into Cancer and Nutrition (EPIC). Potential mechanisms and pathways will also be explored using existing biomarker data available within these cohorts. Methods A new classification system of foods based on the nature, extent and purpose of food processing rather than nutrient composition, termed NOVA, has been proposed to investigate the effect of food processing on disease outcomes. The NOVA ultra-processed food classification system has already been applied to data from the EPIC cohort and UK Biobank, the two largest cohorts in Europe (N~500,000 in EPIC and N~211,000 in UK Biobank). Dietary intakes were assessed using both 24-hour dietary assessment and detailed dietary questionnaires. These two large-scale complementary cohorts also comprise detailed information on lifestyle, anthropometry, medical history and a wealth of biomarker data. These valuable resources now offer an important opportunity to investigate associations between UPF intake and risk of site-specific cancers using multivariable Cox proportional hazard models adjusted for known risk factors. Further, the biological basis of the findings will be explored using mediation analyses in the UK Biobank and case-control studies embedded in EPIC and involving obesity/adiposity measures and biomarkers of potential mechanistic pathways. How the results of this research will be used The rapidly increasing consumption of ultra-processed foods in the UK and in most regions of the world is contributing to the ongoing obesity epidemic and may drive an increasing burden of cancer and other non-communicable diseases. The results of the proposed study will provide important, high quality data on the link between UPF and cancer. Such results will inform public health policy targeting product reformulation, taxation, and marketing restrictions on UPF products and the promotion of fresh or minimally processed foods.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: CANCER AND NEOPLASMS
Title: Peripheral T-cell Lymphoma: Early Detection By Mutation Analysis
Funder: Cancer Research UK

Abstract: Angioimmunoblastic T-cell lymphoma (AITL), peripheral T-cell lymphoma with T follicular helper phenotype (PTCL-TFH) and follicular T-cell lymphoma (FTCL) are a group of complex clinicopathological entities that are originated from T follicular helper cells. They are the most common T-cell lymphoma, together with PTCL not otherwise specified (NOS) accounting for 45% of all T-cell lymphomas. Despite the remarkable advances in therapy of B-cell lymphomas, patients with PTCL are still treated by chemotherapy alone, with a median three year survival merely ~30%. The poor clinical outcome is largely due to late diagnosis, often at an advanced stage of the disease, and also a lack of understanding of their early evolution and underlying molecular mechanisms. The diagnosis of AITL or more generally PTCL, particularly at its early stage, is a big challenge due to lack of specific clinical and histological features, paucity of neoplastic T-cells and prominent polymorphous inflammatory background even with the help of TCR gene clonality analysis. Repeat biopsies are often required to establish histological diagnosis. We hypothesize that the somatic genetic changes recently identified in overt PTCL are mostly likely present in the early “reactive” lesions and detection of these mutations will help to diagnosis PTCL early and improve their treatment outcome. Among the various genetic changes confined to the malignant T-cells in PTCL, RHOA, IDH2, CD28 and PLCG1 mutations are frequent, with RHOA mutation being the most frequent, occurring in 60% of cases. Mutations in these genes are highly clustered, with well-documented hotspots, and thus can be readily detected at a low allelic frequency with high confidence. We propose to investigate these mutations in reactive lymph node lesion and blood sample from patients with PTCL, and explore their utility in early lymphoma diagnosis. Specifically, we will address the following questions: 1) Can RHOA and related mutations be used for detection of early neoplastic lesion of peripheral T-cell lymphoma? 2) Can combined analysis of both RHOA mutation and TCR gene rearrangement improve the detection of early precursor lesion of PTCL? 3) Can RHOA and related mutations be used for detection of early neoplastic T-cell clone from peripheral blood lymphocyte and cell free DNA? 4) Can RHOA and related mutations be used for PTCL disease monitoring?


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Sample size considerations for oncology studies developing and validating clinical prediction models using machine learning for binary outcomes in low dimensional data settings
Funder: Cancer Research UK

Abstract: Background: Clinical prediction models (CPMs) are used to predict the probability of cancer patients’ current and future health status. They are used widely in healthcare and have potential to reduce disease burden, save money for the NHS, and improve patient care. Advancements in healthcare research, such as the availability of ‘big’ data and increasing computational power, has seen a proliferation of CPM models developed using machine-learning (ML) methods. ML methods offer greater modelling flexibility and the ability to model non-linear data and interactions. Though ML has shown promise in high dimensional settings (e.g., imaging), several systematic reviews have shown ML-based CPMs to be at high risk of bias in low dimensional oncology settings; developed using uninformed, too-small sample sizes, using inefficient data-splitting approaches to develop and internally test the CPM. Evidence-based guidance is needed for developing ML-based CPMs. Aims: The research aims of this study are to define and validate sample size criteria for studies developing and validating ML-based CPMs for binary outcomes in low dimensional oncology settings and to develop an interactive graphical user interface with worked examples. Methods: We will conduct a simulation study to define sample size requirements for five common ML techniques used to develop oncology CPMs: decision trees, random forests, gradient-boosting machines, support vector machines and neural networks. We will simulate data using realistic clinical prediction modelling scenarios. We will conduct resampling studies on lung, breast, and colon cancer to validate findings from the simulation study, using a real-world clinical cancer cohort, the Surveillance, Epidemiology, and End Results (SEER) Program. For both studies we will vary design factors, such as sample size and outcome rates, in a fully factorial method. A CPM will be developed for each scenario and its performance assessed using discrimination and calibration performance measures. We will assess hyperparameter tuning methods using cross-validation using default values, grid search or random search for hyperparameter tuning. We will use findings to develop an R Shiny app to create an interactive graphical user interface. How the results of this research will be used: We will develop formal sample size guidance, complemented with an R Shiny web app, for researchers developing and validating ML-based CPMs in oncology. The results will give model developers evidence-based guidance to better design their prediction modelling development and validation studies in oncology. Funders will benefit from better use of their resources and clear guidance for evaluating proposed studies.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: Anti-cancer potential of PI 3-kinase overactivation: a proof-of-concept investigation
Funder: Cancer Research UK

Abstract: BACKGROUND: The aberrant activation of PI 3-kinase (PI3K) signalling in cancer and inflammation has driven extensive PI3K pathway inhibitor drug development efforts. We now have generated pharmacological agents that directly activate PI3K signalling, by targeting the ubiquitously-expressed PI3Kα isoform, and found that these agends may hold therapeutic potential in tissue regeneration and – paradoxically – also in a cancer setting. Indeed, as part of our characterization of PI3Kα activators, we have found that PI3K overactivation in metabolically-stressed solid tumour cell lines can result in cell death, a phenomenon we have named PI3K overactivation-induced cell death (PI3K-OCD). This contrasts with PI3K-inhibitors which mainly stop cells from growing but do not kill the cancer cells. To use an analogy, if a cancer cell were a balloon full of air, a PI3K-activator would pump in extra air and make the balloon pop, while a PI3K-inhibitor would act by getting air out of the balloon, without destroying it. AIMS: Our 18-month-proposal aims to further validate the principle of PI3K-OCD as an anti-cancer strategy, using a combination of preclinical studies using genetic and pharmacological approaches of PI3Kα-activation. METHODS: cell- and mouse-based studies HOW THE RESULTS WILL BE USED: If the proposed target validation is successful, we will aim to (1) proceed with an more extensive a medicinal drug development programme to create PI3Kα activators with increased potency and drug-like characteristics, for use in preclinical efficacy and toxicology studies, and (2) undertake detailed mechanistic investigations to fully understand the underlying molecular mechanism of PI3K overactivation-induced cell death, to explore determinants of drug sensitivity as well as mechanism-based approaches and compounds for use of PI3Kα activators in combination therapy.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Radiopharmaceuticals and Molecular Imaging Group
Funder: Cancer Research UK

Abstract: We aim to develop new radioisotope-labelled compounds for the imaging of tumour biology Molecular imaging using the nuclear medicine imaging techniques of single photon emission computed tomography (SPECT) and positron emission tomography (PET) allows the visualisation and quantification of biological processes in tumour tissue in living organisms. The main advantage of these non-invasive techniques is that they can be performed repeatedly in the same subject, and that the same imaging methods are used in the clinic, which makes them easier to translate from the laboratory to patients in the clinic. Because of their exceptional selectivity and sensitivity, we are mostly interested in the use of antibodies, proteins and peptides, labelled with radionuclides, to target very specific aspects of tumour biology. Usually, molecular imaging targets are extracellular epitopes: cytokines, growth factors, or extracellular receptors. However, there is a mismatch between molecular imaging methods, which mostly target proteins or receptors on the outside of cancer cells, and cancer biology, where mostly intracellular events are studied. Therefore, one aim of the group is to develop novel methods to enable imaging of intracellular proteins, such as those involved in DNA damage repair signalling. Furthermore, increased awareness and the rolling out of screening programmes have had a significant impact on cancer survival, especially breast cancer. The earlier a cancer is detected, the better the chances for survival are. Another aim of the group is therefore to develop methods that would allow early detection of tumour tissue. We are evaluating the novel imaging agent developed in the group in models of breast and pancreatic cancer. http://www.radiationoncology.ox.ac.uk/research/bart-cornelissen


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Improving access to cancer screening among people with intellectual disabilities: development of a complex intervention
Funder: Cancer Research UK

Abstract: BACKGROUND Screening can reduce deaths from cancer if the people invited participate. The challenge is that often cancer screening programmes fail to sufficiently engage the most vulnerable, leading to persistent inequalities in uptake. Our recent analysis highlighted that uptake of bowel, breast and cervical cancer is substantially lower among people with intellectual disabilities. The potential impact of lower uptake is most evident with bowel cancer: people with intellectual disabilities are almost two and a half times more likely to die from bowel cancer which is more common in this population due to obesity, sedentary lifestyles, and higher levels of constipation. Cancer research among people with intellectual disabilities and other vulnerable groups is neglected and underfunded, and we need greater diversity in our approach as a research community. AIMS This proposal aims to improve access to bowel, breast and cervical cancer screening among people with intellectual disabilities through a rigorous process of co-design. METHODS In work package 1, we will conduct a systematic review to identify and describe the content of effective interventions to improve access to bowel, breast and cervical cancer screening for people with intellectual disabilities. In work package 2, we will interview up to 30 people with mild to moderate intellectual disabilities and up to 15 family carers of people with severe to profound intellectual disabilities, as well as 56 professional stakeholders in screening or supporting people with intellectual disabilities to investigate experiences of accessing bowel, breast and cervical screening and identify facilitators and barriers to participation. In work package 3, building on the systematic review and interview findings, we will conduct a participatory stakeholder workshop to develop recommendations on improving access to bowel, breast and cancer screening for people with intellectual disabilities. In work package 4, we will refine and test the acceptability of interventions to address low uptake of bowel screening among people with intellectual disabilities in further interviews and focus groups. HOW THE RESULTS OF THIS RESEARCH WILL BE USED Our vision is to catalyse a programme of research to improve access for people with intellectual disabilities across the cancer continuum: the current proposal represents a first, rigorous, evidence-based, multi-sectoral and co-design approach to improving access to cancer screening. We will take forward our recommendations in work package 3 to inform public health and government policies, and will seek further funding to rigorously test the effectiveness of acceptable interventions developed in work package 4.


Research activity codes: 4.3 INFLUENCES AND IMPACT
Health categories: CANCER AND NEOPLASMS
Title: Marie Curie Professor of Supportive and Palliative Medicine, Cardiff University
Funder: Marie Curie

Abstract: Professor Simon Noble was recently awarded a personal Chair at Cardiff University in recognition of his clinical research in the field of cancer associated thrombosis. There was a recognition of the need to ensure the Professor post was sustainable and afforded sufficient support to be able to deliver world leading research. Following external peer review, it was suggested that Marie Curie fund four academic sessions, on the condition that Cardiff University match funded them, thereby demonstrating a joint commitment to the post._x000D_ _x000D_ The aims of the post include to:_x000D_ ? Further develop and conduct high quality research on cancer associated thrombosis._x000D_ ? Develop research in other clinical areas of research priority as identified in the James Lind Alliance Research Priorities Report._x000D_ ? Take on leadership and management roles within the Marie Curie Research Centre._x000D_ ? Disseminate research outputs of the Research Centre._x000D_ ? Contribute to the strategy of the Research Centre, including succession planning and future research aspirations.

Lay abstract: This grant is an award to recognise the research of Professor Simon Noble who has been a clinical researcher in Cardiff University for fourteen years. For the past seven years he has been theme lead for thrombosis research (the study of blood clots) with a particular focus on how they affect people with cancer at the end of life. Professor Noble has recently been awarded a personal Chair (Professorship) by Cardiff University. This award will allow him to double the research time he undertakes and allow him to focus his research on matters pertaining to research priorities as identified by Marie Curie. It will also allow him to support the day to day running of the Marie Curie Research Centre, act as an ambassador for Marie Curie and further develop the organisation?s research successes on the world stage.

Research activity codes: 7.2 END OF LIFE CARE
Health categories: CANCER AND NEOPLASMS
Title: Precision immunovirotherapies: next generation oncolytics - Studentship
Funder: Cancer Research UK

Abstract: These two studentships, linked to the CRUK corresponding programme award entitled "Precision immunovirotherapies: next generation oncolytics" will: 1. Develop serum resistant precision virotherapies, capable of circumventing pre-existing anti-vector immunity in the patient population, and 2. Develop new technologies for the development of bespoke, receptor targeted virotherapies.


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