NIHRDataInsights/HRCSData huggingface dataset:
Title: Generation and development of anti-DC-SIGN antibodies to treat follicular lymphoma
Funder: Cancer Research UK

Abstract: Background:Follicular lymphoma (FL) is amongst the most common lymphomas and incurable by conventional therapies. FL cells are characterised by the acquisition of mannosylated glycans in their B-Cell Receptor (BCR) antigen-binding site (BCR-Mann). This is a tumour-specific change not evident in normal B-cells, observed from an early stage in lymphomagenesis and maintained throughout the entire disease course including following transformation into diffuse large B-cell lymphoma. BCR-Mann is recognised by the carbohydrate-recognition-domain (CRD) of DC-SIGN expressed on macrophages (Mf), located close to proliferating tumour cells in FL. Engagement of the BCR-Mann by DC-SIGN results in long-term, low-level, antigen-independent growth/survival signals to FL cells. We can simulate the specific interaction between FL cells and Mfs via BCR-Mann:DC-SIGN binding, that can be inhibited by anti-DC-SIGN antibodies in vitro. However, current antibodies are internalised rapidly and may promote immunoregulatory signals in Mf favouring FL progression. Aims:To generate and validate a series of novel anti-DC-SIGN antibodies and constructs to provide long-term blockade of the BCR-Mann:DC-SIGN axis in FL, without compromising innate cell immunity. We will: 1) generate a series of new fully human anti-DC-SIGN mAb; 2) demonstrate their specificity for DC-SIGN, define their epitopes and biophysical properties; 3) assess their ability to block the BCR-Mann:DC-SIGN interface and internalise DC-SIGN; 4) identify the most effective reagent for clinical development; 5) perform preliminary toxicity and efficacy studies. Methods:We will use the proprietary Bioinvent phage display library to identify a series of Fab binding to the DC-SIGN CRD, characterising them with respect to fine epitope before assessing them in a series of assays to measure effects on Mf and FL cells. Specificity will be assessed using DC-SIGN-transfected cell lines or primary cells. Biophysical properties will be assessed using surface plasmon resonance, determining the affinity for DC-SIGN-Fc. We will employ endocytosis and cell clustering assays to assess BCR-Mann:DC-SIGN blocking capacity and identify the best blocking reagent while investigating back-signalling into Mf by immunoblot, flow cytometry and cytokine release. Preliminary toxicity studies will be performed in human DC-SIGN transgenic mice (hSIGNtg), while efficacy will be measured in hSIGNtg x NSG mice transplanted with BCR-Mann+ FL cell lines or primary human tumours. How the research will be used:This research will provide novel reagents capable of interfering with growth and survival of FL cells. The project is strengthened through the strong interaction between experts in antibody development (Cragg) and FL/BCR signalling (Forconi) who is well positioned to translate the findings into the clinic.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/15/073 SGXII: Three versus five years of adjuvant imatinib as treatment of patients with operable GIST with a high risk for recurrence: A randomised phase III study
Funder: Cancer Research UK

Abstract: BACKGROUND Three years of imatinib is considered the standard of adjuvant therapy for patients with operable high-risk GIST based on the findings of the SSGXVIII/AIO. Yet, many patients are still at a high risk of GIST recurrence after completion of 3 years of adjuvant imatinib, and might benefit from further adjuvant imatinib therapy. The risk of GIST recurrence after 3 years of adjuvant imatinib can be estimated using prognostic factors. Based on the analyses made on the SSGXVIII trial data, the most important factors that predict the risk of GIST recurrence in a patient population treated with 3 years of adjuvant imatinib are tumour mitotic count and tumour site. Patients with high tumour mitotic count and GIST located at non-gastric site have the greatest risk. Study hypothesis: Further 2 years of adjuvant imatinib may improve recurrence-free survival (RFS) of patients who are at a high risk of GIST recurrence despite completion of 3 years of adjuvant imatinib. INDICATION Patients treated with adjuvant imatinib for 3 years after complete surgical removal of high-risk GIST and who are considered to be at a high risk of GIST recurrence despite 3 years of adjuvant imatinib. END POINTS Primary: Recurrence-free survival (RFS) after randomisation. Secondary:Overall survival.GIST-specific survival. Adverse events. To evaluate tumour tissue and blood molecular markers in prediction of GIST recurrence. TRIAL DESIGN open-label, 2-arm, prospective, randomised, multicentre phase III trial. Patients diagnosed with GIST who have completed 3 years of adjuvant imatinib, who are free from GIST recurrence after 3 years of adjuvant imatinib, and who have a high risk of recurrence despite 3 years of adjuvant imatinib will be randomly allocated to one of the following 2 arms in a 1:1 ratio: A.to further 24 months of adjuvant imatinib (planned total duration of adjuvant imatinib 5 years) B.to stop imatinib (planned total duration of adjuvant imatinib 3 years) The study participants will be followed up for a minimum of 7 years post-randomisation or until death. NUMBER OF PATIENTS 300 patients, recruited across all European sites, to be randomised in 1:1 ratio, 150 to imatinib for further 24 months and 150 to stop imatinib. ASSESSMENTS OF EFFICACY Primary: RFS is defined by the time interval between the date of randomisation and the date of first detection of GIST recurrence or death, whichever occurs first. Secondary: Overall survival (the time period between the date of randomisation tand the date of death).


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Spatial regulation of core neurodevelopment transcription factors in human glioblastoma stem cells
Funder: Wellcome Trust

Abstract: The most common brain cancer, termed glioblastoma (GBM), is incurable and life expectancy is only ~14 months. The cells that drive GBM are trapped in a stem cell-like state and exploit pathways used by normal brain stem cells. GBM stem cell-like cells increase key factors (transcription factors) that are master regulators of brain stem cells, such as SOX2 and FOXG1, which bind to gene control regions called super-enhancers. Many critical genes that drive GBM exist as separate pieces of DNA rather than as part of the organized DNA structure in chromosomes, called extra-chromosomal DNA (ecDNA). This enables tumour cells to rapidly expand key regulators and may contain super-enhancer areas to switch important genes on. We predict that increased amounts of these transcription factors and their clustering at super-enhancers explains the locked-in stem cell state of GBM cells. This project aims to confirm that important gene drivers of GBM are found on ecDNA in GBM cells from patients. We will test which transcription factors stick to which enhancers to understand the combinations needed to switch on important genes. We will evaluate if these factors, enhancers and genes physically converge as condensates to make cancer cells ‘stuck’ in their stem cell-like state.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Exploiting Radiogenomics for Evaluating Intratumoural Heterogeneity and Therapy Response in Soft Tissue Sarcoma
Funder: Wellcome Trust

Abstract: Soft tissue sarcomas (STS) are a rare group of cancers that can develop throughout the body. There are over 100 subtypes, which often exhibit different tissue compositions across a single tumour. STS tumours therefore behave variably to treatment, and predicting patient response to pre-operative therapy is challenging. Advancements in MRI provide insight into the behaviour of tumours without needing an invasive biopsy. However, we lack research comparing MRI with tumour tissue to allow confidence in MRI interpretation. This project seeks to gain a better understanding of the differences seen in STS, and establish if imaging can reflect the underlying biology of these differences. I aim to match image-guided sampling of multiple regions of STS tumours with molecular analysis. The analysis will investigate the DNA, RNA and proteins within the tumour tissues and how this relates to MRI. We will assess whether integrating molecular and imaging data can improve our understanding of whether tumours are responding to treatment. My research will increase our understanding of the complex nature of STS and why distinct tumour regions behave differently. This will impact clinical practice by enhancing our ability to accurately measure and predict responses to pre-operative therapy and facilitate delivery of precision medicine.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: The effect of lipid-lowering agents and the dysregulated metabolism on the risk and progression of head and neck squamous cell carcinoma (HNSCC).
Funder: Wellcome Trust

Abstract: Background Drugs such as statins reduce blood cholesterol, but they may also lower the risk of getting certain cancers, however the evidence surrounding head and neck cancer is inconclusive. In addition, the mechanisms by which these drugs might prevent head and neck cancer requires further evaluation. Statins and similar drugs modify circulating blood factors such as cholesterol, hormones and metabolites which result in the exposure of cells to an environment that may alter the chances of a cancer developing. We want to determine whether such changes to the body’s metabolic environment also influences the likelihood of developing and dying from head and neck cancer. Research approach 1) Analyse large datasets of people with head and neck cancer, to determine if statins and similar drugs causally protect against cancer development and progression. 2) Explore how changes in cholesterol, hormones and metabolite levels might mechanistically prevent head and neck cancer using laboratory studies. 3) Identify potential drug targets for prevention or therapy in head and neck cancer. Impact This project will investigate the link between changes to the body’s cholesterol, hormones and metabolite levels and head and neck cancer. This could help inform targeted cancer screening, prevention and intervention for these patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Investigating the ageing phenotype in the bone marrow microenvironment: the role of macrophages in regulating normal and malignant haematopoiesis
Funder: Wellcome Trust

Abstract: Most people diagnosed with Acute Myeloid Leukaemia (AML) die of the disease because the available chemotherapy targeting AML cells cannot kill all the leukaemia cells in the bone marrow. In part, this is because the bone marrow environment promotes leukaemia growth and also provides protection from the drug treatment. It is hoped that future treatment strategies targeting the environment and the tumour (the soil and the seed) will lead to improved outcomes for patients. This project aims to understand the cancer-specific protective functions of the bone marrow with a view to identify new treatments in the future. We have recently discovered that AML cells cause senescence, the process of ageing of cells in which cells permanently stop dividing, in the bone marrow and that this supports the survival and growth of leukaemic cells. Senescence normally occurs with ageing and the fact that AML occurs most commonly in older people is consistent with the observation that the leukaemia thrives on converting the bone marrow microenvironment into a senescent environment. During this fellowship I plan to further investigate the impact ageing has on the bone marrow microenvironment and how this in turn impacts on tumour development.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Cellular and genetic landscape of transformed myeloproliferative neoplasms
Funder: Wellcome Trust

Abstract: This research project aims to understand how a group of slow cancers of the bone marrow - myeloproliferative neoplasms (MPN) - accelerate into a rapid and incurable leukaemia - advanced-phase MPN. This happens in up to one fifth of all MPN cases. Current treatments can allay symptoms but do not cure advanced-phase MPN. Patients' responses are short-lived, followed by relapse and very poor survival lasting weeks or a few months. We urgently need to understand how MPN cells progress to aggressive leukaemia, why they are so resistant to current treatment, and whether there are surface markers on the diseased cells that we could target with new drug therapies. Our research draws on patient samples from a clinical trial called the Phazar study. This study examined patients with advanced-phase MPN, who received treatment with two drugs, ruxolitinib and azacytidine. About 40% responded to these drugs, but almost all subsequently relapsed. Using state-of-the-art technologies to examine these patient samples, we are seeking to understand the disease biology of this type of leukaemia, how it evolves from the more benign chronic phase, and why some patients respond to the current standard of care while others do not.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: VERITAS: An international multicentre phase II randomised trial evaluating and comparing two intensification treatment strategies for metastatic neuroblastoma patients with a poor response to induction chemotherapy
Funder: Cancer Research UK

Abstract: Background Despite impressive improvements in survival there remain types of childhood cancer with very poor outcomes. High risk neuroblastoma (HR-NB) has an overall survival of only 40%, and the outcome for the very high risk patients who have an inadequate response to induction chemotherapy is extremely poor at less than 10%. These patients constitute 25% of HR disease and there is a need for novel treatment approaches for them. 131-I mIBG has been widely used as a targeted radiopharmaceutical with a response rate in relapsed and refractory disease of 32%. Preclinical data suggests that topoisomerase I inhibitors such as topotecan can synergistically radiosensitise to 131-I mIBG. This combination has been shown to be safe and effective in a significant number of patients across Europe. Tandem high dose therapy in this group of patients offers the possibility of improving survival, and the combination of high dose thiotepa with busulphan and melphalan (BuMel)has shown promising response in pilot studies. Aims VERITAS is an international randomised phase II study comparing two tandem high dose therapy regimes: topotecan with 131-I mIBG, and high dose thiotepa, both followed by conventional BuMel, and peripheral blood stem cell support to determine if one (or both) arms is able to produce 3 year event free survival (EFS)of at least 30% with acceptable toxicity. Methods VERITAS is an International Society of Paediatric Oncology Europe Neuroblastoma (SIOPEN) study and will be open in all SIOPEN countries. VERITAS will recruit 150 children with refractory HR-NB over a 5 years. After randomisation patients will receive three cycles of standard irinotecan and temozolomide chemotherapy before stem cell harvest. Both tandem high dose regimes will only be given at limited numbers of centres. The primary endpoint of the trial will be the 3 year EFS. Toxicity monitoring will be a secondary endpoint, and will inform the decision of which regimen to take forward if efficacy is similar between the two arms. How the results of this research will be used Lack of robust data on the best treatment for patients with very HR refractory neuroblastoma has hindered efforts to improve their currently poor survival. VERITAS will be the first study focussing on these refractory patients and is designed to reveal the potential benefit of intensified high dose therapy. If the anticipated therapeutic benefit is seen, with acceptable toxicity, then this strategy will move forward to randomised phase III trial.


Research activity codes: 6.1 PHARMACEUTICALS;6.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Developing a decision rule using existing blood test data to select primary care patients with non-specific symptoms for urgent cancer investigation.
Funder: Cancer Research UK

Abstract: Background One in two patients ultimately diagnosed with cancer present to primary care with non-specific symptoms, such as unexpected weight loss (UWL) or fatigue. They have longer times to diagnosis and are more likely to be diagnosed as an emergency or at an advanced stage. NHS Rapid Diagnostic Centres (RDCs) are being rolled out in England to urgently investigate this patient group. However, many patients with non-specific symptoms have a low risk of cancer and GPs need to select who to refer to RDCs. Preliminary research suggests routine blood tests may help differentiate those at higher risk from lower, which may prevent unnecessary referrals and improve the diagnostic yield of RDCs Aim • To optimise the selection of patients with non-specific symptoms for urgent cancer investigation using results from routine blood tests. Primary objective • To incorporate simple blood tests into decision rules to select primary care patients with non-specific symptoms for urgent cancer investigation. Secondary objectives • To extend existing research using blood tests to select patients with UWL for cancer investigation to other non-specific cancer symptoms. • To understand whether incorporating blood test change over time improves cancer prediction by: o adapting established monitoring methods to routinely collected serial blood test data. o receiving training in advanced statistical techniques (joint modelling) and data science (machine learning). • To develop an intervention to select patients with non-specific symptoms for urgent cancer investigation (in NHS RDCs) for future evaluation. Methods Routinely collected UK electronic health records data (CPRD AURUM) from primary care linked to cancer registry data (NCRAS) will be used to develop clinical prediction rules. The performance of models derived using static and serial blood test data, and using traditional statistical methods (logistic regression), advanced statistical methods (joint modelling), and machine learning will be compared using standard discrimination and calibration statistics and decision curve analysis. How the results of this research will be used The feasibility of using the decision rule developed during this fellowship will be subsequently trialled in the network of NHS RDC pathways. International collaboration will inform the decision rule’s development so that its feasibility may also be tested in other RDC-type pathways, such as the Welsh Single Cancer Pathway and Nordic Multidisciplinary Diagnostic Centres. The results will also be relevant to settings where GPs have direct access to invasive testing (such as in the US) or to patient self-referral to community based point-of-care testing.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: TRICON8B: Sample collection of ovarian cancer tissues, blood and plasma for translational research from patients participating in the Cancer Research UK/MRC ICON8B trial
Funder: Cancer Research UK

Abstract: BACKGROUND Ovarian carcinoma is the fourth most common cancer in women and the most lethal gynaecological malignancy. There are approximately 7000 new cases/yr in the UK with 1 in 50 women developing the disease over their lifetime. Most women present with advanced (FIGO stage III-IV) disease and despite multimodality treatment with debulking surgery and platinum-taxane chemotherapy (CT) administered on 3-weekly cycles, the majority of women relapse and die from their disease. The 5-year overall survival (OS) rate of ~30% has changed little in 30 years. MRC ICON8B is a randomised phase III trial designed to investigate whether outcomes can be improved for patients with high risk disease - for whom bevacizumab is increasingly being used - comparing 3 treatment regimens to evaluate the individual and combined contributions of bevacizumab and weekly dose-dense paclitaxel to improving the efficacy of treatment with a 3-weekly carboplatin backbone. ICON8B will recruit 1170 women with newly-diagnosed FIGO stage III-IV epithelial ovarian, primary peritoneal and fallopian tube cancer over 4 years. AIMS 1. Establish a comprehensive biobank comprising tumour tissue, blood and serial plasma samples associated with fully-annotated correlative clinical data within the ICON8B randomised trial. This will enable high-quality translational research in ovarian cancer, and will include a large collection of paired pre/post chemotherapy-exposure tumour tissue (from women undergoing delayed primary surgery). 2. Enable specific research on predictive markers of resistance and response to bevacizumab and dose-fractionated carboplatin-paclitaxel, and pharmacogenomics. 3. Provide a resource for other collaborative research projects. The feasibility and need for collections in ovarian cancer has been established by the ICON7 sample collection, which has attracted multiple applications for access from international research groups. METHODS Samples will be collected from consenting UK trial participants including: (i)pre-treatment FFPE tumour tissue plus an additional resection sample in patients undergoing delayed surgery; (ii)whole blood for DNA extraction; (iii)longitudinal plasma samples, enabling assessment of circulating biomarkers. Blood and plasma will be stored for future use; tissue microarrays will be constructed and cores for RNA/DNA extraction stored. HOW THE RESULTS OF THIS RESEARCH WILL BE USED Current proposals include use of FFPE and plasma to (i)investigate expression markers of sensitivity to bevacizumab in the context of dose-dense chemotherapy; (ii) validate plasma proteomic markers identified in ICON7. Genomic DNA will be used to test hypotheses surrounding germline determinants of prognosis, treatment-response and toxicity. International applications to access the sample resource will be invited.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS