NIHRDataInsights/HRCSData huggingface dataset:
Title: Understanding and boosting T-cell transfer therapy in cancer with immunostimulatory antibodies
Funder: Cancer Research UK

Abstract: Background_x000D_ The success of monoclonal antibodies (mAbs) such as rituximab has shown the feasibility of immunotherapy for cancer treatment. Unfortunately a prominent limitation of passive mAbs like rituximab is that their efficacy as a single agent is relatively weak and their effects short-lived due to a lack of generation of immunologic memory. T-cell transfer therapy can potentially overcome these limitations and long-term remissions have been demonstrated in the treatment of melanoma and viral-induced B-cell lymphomas. Whilst this approach is rapidly gaining momentum, its progress is still being hindered by the lack or, or selection of appropriate tumour-specific targets, and the problems associated with in vitro expansion and in vivo functional maintenance of the transferred cells. Recent work by our collaborators in Stanford indicates that T-cell therapy can be enhanced by CpG-based vaccination. This approach negates the need and logistical difficulties of selecting anti-tumour T-cells. Such a manoeuvre has entered clinical trial testing and clinical benefit has been observed in a small cohort of patients._x000D_ _x000D_ Aims_x000D_ The project aims to augment CpG-based vaccination/T-cell transfer therapy by using novel immunostimulatory mAbs to T-cell co-receptors of the tumour necrosis factor receptor superfamily (4-1BB and OX40)._x000D_ _x000D_ It also aims to dissect the underlying mechanisms of this approach and facilitate the development of these mAbs for clinical use. _x000D_ _x000D_ Methods_x000D_ A syngeneic and spontaneously-developing tumour mouse model (Eu myc) will be employed to enable the study of host T-cell responses to tumour development and the means by which tumour tolerance can be surmounted using T-cell transfer therapy. _x000D_ _x000D_ These mice will be cross-bred with transgenic mice bearing human 4-1BB or OX40 receptors to allow the in vitro and in vivo testing of newly characterised human immunostimulatory mAbs to these targets._x000D_ _x000D_ The ability of the immunostimulatory mAbs to similarly stimulate proliferation and function of T-cells from lymphoma patients will also be examined._x000D_ _x000D_ How the results of this research will be used_x000D_ The data generated should guide the development of these new immunostimulatory mAbs for clinical trial testing in the context of T-cell transfer therapy.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Developing potential therapeutic targets in the Wnt signalling pathway
Funder: Cancer Research UK

Abstract: Developing potential therapeutic targets in the Wnt signalling pathway Hyperactivation of Wnt/ß-catenin signalling has been linked to a wide range of cancers. Most notably, the majority of colorectal cancers are due to mutational inactivation of the Adenomatous polyposis coli (APC) tumour suppressor, a negative regulator of ß-catenin, or to activating ('oncogenic') mutations in ß-catenin itself, a key effector of the canonical Wnt signalling pathway. Oncogenic ß-catenin mutations are also common in other types of cancer. In normal development and tissues, the Wnt/ß-catenin pathway plays important roles in controlling cell proliferation and differentiation, including the stem cell compartment in the intestine. Despite the importance of this pathway in cancer, developing small molecule inhibitors of oncogenic ß-catenin signalling remains a major challenge, due to the scarcity of ‘druggable’ targets in the downstream part of the Wnt/ß-catenin pathway. The aim of this research proposal is to discover new regulators of Wnt/ß-catenin signalling, and to develop their potential as therapeutic targets in cancer, through understanding their molecular properties and regulatory interactions with this important cancer pathway. The primary focus will be on the emerging roles of non-canonical ubiquitin in the control of Wnt/ß-catenin signalling, as revealed by the Trabid de-ubiquitylase and its associated E3 ligases whose roles in modulating the stability and activity of ß-catenin we plan to study. We shall also design and conduct new screens to discover small-molecule inhibitors that destabilise oncogenic ß-catenin, directly or indirectly, aiming to consolidate the proof-of-concept of the 'druggability' of this formidable molecule.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: The role of tumour vitamin D receptor expression, vitamin D related genetic variation and vitamin D supplement use in colorectal cancer survival
Funder: Cancer Research UK

Abstract: Background: Vitamin D has known anti-carcinogenic actions and has been shown to reduce colorectal cancer development. However, more observational evidence is required before randomised controlled trials of vitamin D supplementation for secondary cancer prevention are implemented. Genetic and tissue markers of vitamin D exposure also show promise in predicting progression and survival of colorectal cancer patients, but have yet to be fully explored in a UK population. Aims: The aims of the proposed research are to use a number of approaches to investigate the role of vitamin D in colorectal cancer progression and survival: 1. Conduct a systematic review of the existing literature on vitamin D intake (dietary and supplementation) and status (blood levels), colonic vitamin D receptor expression (tumour and normal tissue) and vitamin D related gene variation, with respect to colorectal cancer progression and survival. 2. Investigate the association between tissue vitamin D receptor expression (both normal colonic and tumour tissue) and colon cancer progression and survival in a large population-based cohort of colon cancer patients. 3. Evaluate the frequency of genetic polymorphisms of the vitamin D receptor (Vdr) and the vitamin D binding protein (VDBP) in colon cancer patients and investigate their association with cancer progression and survival. Methods Medline, EMBASE, Web of Science and Cochrane databases will be systematically searched using an appropriate search strategy developed to identify all relevant studies examining the measures of vitamin D exposure/status and colorectal cancer progression/survival. The prognostic value of Vdr expression in colon tumour tissue and normal colonic mucosa and genetic polymorphisms of the Vdr and VDBP genes will be studied in a large population representative sample of colon cancer patients from Northern Ireland. How the results of this research will be used The findings of this research will provide insight regarding mechanisms involved in colorectal cancer progression. It will elucidate the role that markers of vitamin D metabolism play in predicting the progression of this cancer and may provide sufficient evidence to justify trials of vitamin D supplementation in colorectal cancer patients. Therefore, it has the potential to provide new opportunities for the secondary prevention of, and improved survival from, colorectal cancer.


Research activity codes: 4.4 POPULATION SCREENING
Health categories: CANCER AND NEOPLASMS
Title: Analysis of alternative splicing in prostate cancer metastasis regulated by the RNA-binding proteins Sam68 and hnRNP A2/B1
Funder: Cancer Research UK

Abstract: Many men with prostate cancer (PCa), the second leading cause of male cancer-related deaths, have “incurable” (locally-advanced/metastatic) disease at diagnosis and a poor prognosis despite treatment. This observation may be due, in part, to a functional complexity of the cancer cell transcriptome primarily as a result of alternative mRNA isoforms, fusion transcripts, and non-coding RNAs. In addition to expression changes, metastasis may be mediated by structurally/functionally differing protein isoforms produced by alternative pre-mRNA splicing (AS), controlled by RNA-binding proteins (RBPs). Our and others’ work has implicated interacting-RBPs Sam68 and hnRNP A2/B1 in PCa, epithelial-mesenchymal transition (EMT), and metastasis. We are examining the role of Sam68 and hnRNP A2/B1 in EMT and metastasis using PCa cell lines, pre-clinical models, and primary tumours and metastases from patients with PCa. In particular, we are interested to know how changes in expression of Sam68 and hnRNP A2/B1 proteins affect the cancer cell transcriptome during PCa progression. Our work uses next generation sequencing (NGS), and will enumerate RBP target mRNA isoforms in PCa metastasis, furthering our understanding of RBP-driven metastasis. We hope that mRNA targets identified in this study will help to delineate therapeutic strategies for “incurable” PCa in clinical trials.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.4 POPULATION SCREENING
Health categories: CANCER AND NEOPLASMS
Title: Vitamin D regulation of growth control biomarkers in human colon and colorectal cancer (CRC)
Funder: Cancer Research UK

Abstract: Background – High serum levels of the vitamin D (Vit-D) metabolite 25(OH)D strongly protect against colorectal cancer (CRC) but inconsistent tumour responses and lack of suitable surrogate endpoint biomarkers (SEBs) impede treatment or chemoprevention strategies. Recent Vit-D biology discoveries provide ideal SEBs for assessment of Vit-D cancer control. For example, serum 25(OH)D is converted by CYP27B1 to active 1,25(OH)2D3 in colonic epithelium. Local accumulation of 1,25(OH)2D3 activates vitamin D receptor (VDR)-dependent and -independent signals that converge on functionally antagonistic E-cadherin (E-Cad) and osteopontin (OPN)-CD44 growth pathways. Catabolism of 1,25(OH)2D3 is initiated by CYP24A1. Serum 25(OH)D thus represents a pharmacokinetic (Pk) biomarker of Vit-D exposure while CYP27B1, VDR and CYP24A1 provide pharmacodynamic (PDyn) SEBs of Vit-D engagement with the colonic Vit-D endocrine system. E-Cad and OPN-CD44 represent Vit-D responsive surrogate growth control (SGc) SEBs. While Vit-D engagement with CYP27B1 is a key rate limiting step, Pk, PDyn and SGc SEBs in combination reflect the overall status of Vit-D growth regulation. We hypothesize that cancer-suppressive serum 25(OH)D levels influence growth biomarkers in human colon and CRC. This hypothesis will be tested in a double blind placebo controlled randomized clinical trial (RCT) of oral Vit-D3 against Pk, PDyn and SGc SEBs in CRC patients. The predictive power of SEBs will be assessed against independent prognostic markers. Because K-Ras mutation may influence Vit-D growth control, associations between CRC K-Ras genotype and SEB responses will be investigated. Aims The primary study objective will assess (i) Effects of cancer-suppressive 25(OH)D serum levels on colonic CYP27B1 expression Secondary objectives will assess (i) Expression, interrelationships and treatment effects on SEBs in normal mucosa (ii) SEB responses in CRC vs normal mucosa (iii) SEB associations with histopathological CRC prognostic factors (iv) Associations between CRC K-Ras genotype and SEB responses Methods – The study design involves a “Run-In” for quality control then a RCT of oral cholecalciferol tested against Pk, PDyn and SGc SEBs in CRC patients. SEB prognostic relevance and gene-phenotype correlations will be assessed against CRC histopathological factors. Effects of the K-Ras genotype on Vit-D growth signalling will be investigated for hypothesis generation. The study is powered for the primary objective, follows Good Clinical Practice guidelines and CR-UK biomarker quality control recommendations. Use of research results - This project may validate SEBs to identify Vit-D responsive CRC subsets and aid clinical translation of experimental and population evidence of Vit-D cancer control.


Research activity codes: 4.4 POPULATION SCREENING
Health categories: CANCER AND NEOPLASMS
Title: Identification and characterisation of novel, small molecule inhibitors of TDP1 by fragment screening
Funder: Cancer Research UK

Abstract: Background Topoisomerases regulate DNA topology and are fundamental to many aspects of chromosome metabolism. Topoisomerase-1-poisons (topotecan, irinotecan) are used in the treatment of lung, ovarian, and colorectal cancers; however, tumour drug resistance is common, limiting the clinical efficacy of this type of therapy. One potential cause of tumour drug resistance could be the over-expression of activities that repair Topoisomerase-1 (Top1)-linked DNA breaks, such as tyrosyl DNA phosphodiesterase 1 (TDP1) which can cleave the Top1 peptide from DNA termini. Data from in house studies suggest that TDP1 expression or activity may directly correlate with the tumour cell response to Top1 poisons and so TDP1 activity in tumours may determine the extent of response to Top1 poisons. Importantly, data mining suggests that expression of TDP1 varies greatly in cancer cell lines and primary tumours. We propose that a TDP1 inhibitor could have broad clinical utility as both a single agent in tumour genetic/epigenetic backgrounds sensitive to TDP1 inhibition and also as a combination agent with established Top1 poisons. Aims Identification of novel small molecule hit series as TDP1 inhibitors with evidence for cellular modulation of TDP1 and confidence of suitability for lead optimisation. Methods Biophysical screening techniques (thermal shift, NMR, X-ray crysallography) will be used to identify low molecular weight molecules that bind to TDP1. Medicinal chemistry driven optimisation of these compounds will improve binding potency, to be evaluated in our biochemical assays (TDP-1 activity assay, Alkaline Comet and Clonogenic Survival assays). Mode of action work will focus on mechanisms of enzyme inhibition, characterisation of binding sites and evaluation of cellular markers. Access to a well annotated clinical sample collection will allow evaluation of TDP1 inhibitors vs. clinical samples (e.g. colorectal, breast, lung, and head-and-neck). How the results of this research will be used The results from this research will initiate a lead optimisation program to identify a pre-clinical candidate molecule. Such molecules would allow exploration of the translational and therapeutic relevance of TDP1 and its impact on Top1 function.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Freedom From Tobacco: the next stage for tobacco control in Scotland
Funder: Cancer Research UK

Abstract: Background: The Scottish Government was elected in May 2011 with a manifesto commitment to develop a new tobacco control strategy for Scotland. In office the Public Health Minister has reiterated the commitment and the strategy development process is now underway and expected to be completed in the first half of 2012. Funding from Cancer Research UK has enabled ASH Scotland to play a pivotal role in creating the political space for this new strategy and develop a comprehensive framework for this next phase of tobacco control delivery. In this proposal we set out a plan of work to ensure that the new strategy translates into sustained and effective tobacco control work across Scotland. Objectives: 1) To sustain political momentum in Scotland following the publication of the strategy and impress upon Scottish political audiences that tobacco control remains an urgent focus for action; 2) To create an environment where fewer young people in Scotland take up smoking, through campaigning for legislation on plain packaging for tobacco products and promoting new Government targets to reduce smoking rates amongst young people; 3) To oppose attempts by the tobacco industry to speak through more respectable proxy voices, particularly amongst local retailers and hospitality industries and their national organizations; 4) To maintain and enhance an appropriate support and enforcement regime, ensuring smoke-free and point of retail legislation continue to deliver on their potential; 5) To build a wider public and political discussion on, and then deliver targets to reduce, the impact of second hand smoke (SHS) exposure in homes and vehicles across all Scottish communities; 6) To achieve a multi-agency plan, with specific targets, to tackle illicit tobacco in Scotland Approach: We will: - continuously update and share the evidence base relevant to topical political issues - analyse and provide commentary on progress towards national targets and in delivering strategy commitments - have regular engagement with msPs, Scottish Government Ministers and civil servants, working with Members of the Westminster and European Parliaments when issues within their remit (such as plain packaging) impact upon Scotland - conduct rapid rebuttal of tobacco industry tactics, alongside improved engagement with sectors (such as retail) susceptible to industry engagement - engage politicians and media at local level, to maximize support for national policy progress - emphasise building the wider tobacco control movement through engaging the broad range of our contacts and in particular supporting the SCOT coalition


Research activity codes: 3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION)
Health categories: CANCER AND NEOPLASMS
Title: The Cancer Research UK Centre at The Institute of Cancer Research and The Royal Marsden (Core)
Funder: Cancer Research UK

Abstract: Funding to the Cancer Research UK Centre supports innovative translational research activities at the ICR and The Royal Marsden aimed at delivering precision cancer treatment. Research infrastructure funding to our joint Drug Development Unit forms a large part of the centre funding and will help expand the number of investigator-initiated trials we undertake and the sequencing analysis of patient samples from these trials. Radiotherapy physics research within the centre is focused on the development of integrated treatment and imaging technologies, preclinical studies of radiation-induced biological effects on tumours and healthy tissues, and the translation of technologies into clinical practice. The aim of this research is to develop the most efficient and accurate radiation treatments. An Informatics Facility has been established to capture, analyse, model and integrate data from across the centre. This is comprised of interdisciplinary staff and includes statisticians, bioinformaticians, computer scientists, data modellers and web developers. Training of the next generation of cancer researchers is also a vital component of the Cancer Research UK Centre with funding provided for clinical and non-clinical PhD training programmes. The centre recognises the importance of engagement activities to encourage the talent of the future and help make young people aware of opportunities for careers in cancer research. We are developing activities designed to engage with school-age students and support their national curriculum learning activities.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: The Institute of Cancer Research Centre (Non-Clinical Training Account)
Funder: Cancer Research UK

Abstract: Non-clinical training at a CRUK centre: At the Institute of Cancer Research researchers are refining radiotherapy for many types of cancer. They are focusing on cancers including sarcomas (cancer of bone, fat, muscle or cartilage), head and neck cancers and children’s cancers. The Cancer Research UK Centre at The Institute of Cancer Research and The Royal Marsden is part of a national network of centres funded by Cancer Research UK with the aim of delivering world-leading translational research and improved patient care. Funding to the Cancer Research UK Centre was renewed in April 2014 and supports innovative translational research activities at the ICR and The Royal Marsden aimed at delivering precision cancer treatment. Research infrastructure funding to our joint Drug Development Unit forms a large part of the centre funding and will help expand the number of investigator-initiated trials we undertake and the sequencing analysis of patient samples from these trials. Radiotherapy physics research within the centre is focused on the development of integrated treatment and imaging technologies, preclinical studies of radiation-induced biological effects on tumours and healthy tissues, and the translation of technologies into clinical practice. The aim of this research is to develop the most efficient and accurate radiation treatments. An Informatics Facility has been established to capture, analyse, model and integrate data from across the centre. This is comprised of interdisciplinary staff and includes statisticians, bioinformaticians, computer scientists, data modellers and web developers. Training of the next generation of cancer researchers is also a vital component of the Cancer Research UK Centre with funding provided for clinical and non-clinical PhD training programmes. The centre recognises the importance of engagement activities to encourage the talent of the future and help make young people aware of opportunities for careers in cancer research. We are developing activities designed to engage with school-age students and support their national curriculum learning activities. http://www.icr.ac.uk/our-research/our-research-centres/cancer-research-uk-centre


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: CANCER AND NEOPLASMS