NIHRDataInsights/HRCSData huggingface dataset:
Title: Development of an effective therapeutic regimen for treatment of advanced pancreatic cancer using a novel immunotherapeutic agent
Funder: Medical Research Council

Abstract: Pancreatic ductal adenocarcinoma (PDAC) is an almost uniformly lethal disease with less than 5% survival at five years. This is largely due to locally advanced and metastatic disease, and new treatment strategies are clearly imperative. Tumour-targeted oncolytic viruses (TOVs) are attractive therapeutics for cancer. TOVs not only kill the tumour cells by direct lysis but also act through multiple other mechanisms of action by targeting molecular pathways involved in carcinogenesis, as well as breaking down the immuno-suppressive tumour microenvironment and inducing a long-lasting tumour-specific immunity. Furthermore, TOVs can specifically deliver therapeutic proteins into tumours at increasing levels following viral replication within the malignant cells. Although clinical trials with various TOVs have produced evidence of response, many have ultimately disappointed, especially for PDAC. Vaccinia virus (VV) has several features that make it a promising therapeutic agent, especially since one such virus (JX594) has recently been shown to target tumours effectively after intravenous infusion, making VV an ideal TOV for treatment of inaccessible tumours such as pancreatic cancer. We have recently developed a new generation of VV (VVTKN1L, a patent filed by QMUL Innovation Ltd), which is more tumour-specific and results in an improved antitumour efficacy. Based on this new platform, we have created a set of VVTKN1L vectors expressing immunomodulatory genes including VV-IL10, VV-GMCSF, VV-IL12, VV-IL15/IL15R and VV-IL-21. VVTKN1L-IL21 has demonstrated the highest therapeutic index for treatment of peritoneally disseminated pancreatic cancer. In addition, we also found that a PI3K delta inhibitor can dramatically enhance infection of PDAC tumours after intravenous delivery of VV. In this project we are among to develop an optimised therapeutic regimen by combining our novel virus with the PI3K inhibitor and conventional chemotherapy (gemcitabine).


Research activity codes: 3.4 VACCINES
Health categories: CANCER AND NEOPLASMS
Title: Permeabilisation of brain metastases for early detection and treatment
Funder: Medical Research Council

Abstract: Secondary spread, or metastasis, to the brain is a major challenge in cancer therapy and prognosis is extremely poor. A significant barrier to both early detection and effective treatment is the blood-brain barrier (BBB), which is intact during the early stages of tumour development and only heterogeneously permeable at later stages. The presence of an intact BBB excludes both therapeutic and diagnostic imaging agents from metastases. However, we have shown in mouse models that intravenous injection of the cytokine tumour necrosis factor (TNF) selectively induces BBB permeabilisation at sites of micrometastasis in the brain, leaving the rest of the BBB intact. Using this approach we could both detect metastatic colonies using contrast-enhanced MRI and deliver a common cancer therapeutic, trastuzumab, to micrometastatic colonies. Our work indicates that the permeabilisation is mediated primarily though activation of the TNF type 1 receptor (TNFR1); this receptor was found selectively on vessels closely associated with brain metastases both in mouse models and in human brain metastasis tissue. The toxicity of high-dose TNF limits its use as a tumoricidal therapy. However, we have demonstrated that its permeabilising activity occurs at concentrations below the maximum tolerated dose. Moreover, given the TNFR1 specificity of the permeabilising effect, we now propose to develop a highly selective TNFR1 agonist, which will further reduce the dose required and eliminate toxicity associated with TNFR2 activation. We will assess binding specificity and permeabilising action in vitro and in vivo and undertake preliminary toxicology studies. At the end of this project, we will be in a position to undertake cGMP manufacture, full toxicology studies and a Phase I/IIa clinical trial. Our solution, to the problem of an intact BBB in early brain metastasis, will open a window of opportunity for both diagnosis and treatment that currently does not exist.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: A Joint Centre for Cancer Biology & Therapeutics
Funder: Medical Research Council

Abstract: There is little scientific understanding of the mechanisms that normally maintain cellular and molecular homeostasis in epithelial tissues, or how derangements in these mechanisms foster carcinogenesis. However, there is remarkable potential that better understanding of these mechanisms will engender novel methods for early diagnosis, risk stratification and cancer therapy. Therefore, translational research in this important area is an urgent strategic priority in India, at a time when epithelial cancers are already a major cause of morbidity and mortality, and their importance is increasing sharply with changing disease demographics. However, few institutional efforts in India currently address this need. The proposed Joint Centre will exploit a timely opportunity for a synergistic strategic partnership in this important area between the MRC Cancer Unit (CU) in Cambridge, and NCBS / inStem in Bangalore. The CU seeks to advance understanding of the earliest steps in epithelial carcinogenesis, and to exploit this knowledge in new approaches for clinical intervention, through innovative enabling technologies. The CU's internationally recognized programmes led by clinicians and scientists closely complement those of multiple NCBS and inStem faculty leading outstanding basic science programmes investigating epithelial tissue homeostasis, receptor signalling, inflammation, stem cells and regeneration, and mathematical biology. An extensive collaboration between the institutions has been led since 2011 by Ashok Venkitaraman, the Director of the MRC CU, and Satyajit Mayor, Director of NCBS and inStem. They attracted significant DBT funding to establish in 2013 a new Centre for Chemical Biology & Therapeutics (CCBT) in Bangalore that complements MRC-funded research at the CU, with the support of Cambridge University and the MRC. The proposed Joint Centre will build on this strong foundation to (a) further develop joint research on the maintenance of homeostasis in epithelial tissues, on mechanisms underlying the pre- neoplastic to neoplastic transition, and on knowledge-directed clinical interventions for early diagnosis, risk stratification and cancer therapy, (b) enrich in Bangalore a framework for translational cancer research leading to clinical intervention, and (c) provide a unique trans- national training environment to build capacity in India for researchers and clinicians in translational cancer research.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: the roleDefining of IL-1B in breast cancer bone metastasis
Funder: Medical Research Council

Abstract: This project aims to determine the specific roles played by IL-1B in the development and progression of breast cancer bone metastasis. Genetically manipulated breast cancer cell lines and in vitro modelling will be used to elucidate effects of IL-1B on parameters associated with early metastasis. Mouse models of human breast cancer metastasis to human bone as well as syngeneic IL-1B/IL1-R1 knockout models of bone metastasis will be employed to assess the specific effects of IL-1B from tumour cells and from the host environment on different stages of metastasis. Dr Ottewell is experienced in all proposed techniques: Genetic manipulation of cell lines: IL-1B/IL1-R1 knockout and control bone metastatic mammary cancer cell lines will generated using CRISPR. Overexpressing/control cells will be generated by stable transfection with IL-1B, IL-1R1 or scramble sequence. Cells will be transfected with GFP and luciferase to allow in vivo imaging and detection of tumour cells in blood. In vitro analysis of metastasis: Knockout, overexpressing and control cells will be assessed for: Proliferation - Z2 Coulter counter; migration - scratch assay; invasion towards media or bone cells -transwell assay. Mouse models of human breast cancer metastasis to human bone: Human sub-chondral bone will be implanted subcutaneously into female NODSCID mice. 4 weeks later wild-type or genetically manipulated MDA-MB-231 or T47D breast cancer cells will be injected into each hind mammary fat pad and mice monitored for bone metastasis. Identification of bone metastasis in syngeneic models will be assessed following intra cardiac or intravenous injection of IL-1B/IL-1R1 knockout, overexpressing or control cells. Analysis: Primary tumour growth and bone metastases- callipers/luciferase imaging; dissemination of tumour cells in the blood - flow cytomentry; dissemination of tumour cells in bone - two photon microscopy; bone lesions- uCT; apoptosis - caspase; proliferation - Ki67; angiogenesis.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Investigation of control of pRB and cell transformation by a long non-coding RNA
Funder: Medical Research Council

Abstract: The earliest apparent human melanocytic neoplasms are normal benign nevi (moles), which result from proliferative expansion of oncogene-expressing melanocytes. Like melanoma, virtually all nevi harbor mutations in N-RAS or its downstream effector, BRAF. But, typically, benign nevi do not progress to melanoma. At least in part, this is because cellular senescence blocks further proliferation of the melanocytes. Cellular senescence is an irreversible proliferation arrest that is activated by various molecular triggers, including activation of oncogenes (oncogene-induced senescence (OIS)), such as BRAF and N-RAS, in primary human cells. Activation of the pRB tumor suppressor pathway is critical for onset of senescence, and inactivation of the pRB pathway promotes melanomagenesis. Inactivation of pRB or its known regulators is a frequent event in human melanoma and most other cancers. Hence, a better understanding of cellular senescence and its control by the pRB pathway in melanocytes can contribute to a better understanding of the origins of melanoma and other cancers. Recently, long non-coding RNAs have emerged as important regulators of genome function in mammals. Long non-coding RNAs (lncRNAs) are non-protein-coding transcripts that do not fit into defined classes of known small RNAs (e.g. microRNAs) and structural RNAs (e.g. ribosomal RNAs). In a recent screen, we identified many lncRNAs that are robustly upregulated during BRAFV600E-induced senescence of primary human melanocytes. One of these lncRNAs, ENST00000430998 (LNC98), is necessary for robust expression of pRB in senescent cells. We will investigate the role of LNC98 in control of pRB, cell senescence and suppression of melanocyte transformation through two Objectives : Objective 1. Investigate how LNC98 is upregulated in senescent melanocytes. Objective 2. Investigate how LNC98 controls expression of pRB and contributes to cellular senescence and suppression of melanocyte transformation.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: RE-ENGINEERING RADIOIODINE THERAPY FOR THE 21ST CENTURY
Funder: Medical Research Council

Abstract: We will utilise a combination of straightforward technical approaches, new in vivo models, and challenging experimental systems. We will refine our existing pathway of increased radioiodine uptake via targeted inhibition of Src phosphorylation of PBF to determine whether we can we improve upon the 70-100% enhanced radioiodine uptake efficacy we have achieved via combination treatment. Thus, we will screen additional TKIs and N-myristoyltransferase inhibitors (NMTis) at increased resolution via real time and time lapse microscopy studies, and via cell surface biotinylation assays. In parallel, we will explore in high throughput screening via our commercial partner Evotec whether any of 6,000 annotated compounds modulating central cellular signalling pathways alter NIS function, and, via HTS PE OPERA screening, PM localisation. Subsequently, we will perform in vivo screening in double transgenic zebrafish embryos. Screening of the corresponding stable transgenic zebrafish lines will elucidate whether drug treatments identified in vitro alter NIS function in vivo. We will then progress to mESC differentiated into thyroid follicular cells organised into follicles via doxycycline treatment to induce expression of NKX2.1 and PAX8. Functional in vitro follicles will be subject to the optimal drug treatments identified thus far. ESC-derived thyroid follicles will be grafted into hypothyroid mice and drug treatments altering follicular uptake of radioiodine will be appraised in grafted ectopic thyroid glands. Finally, we will perform real-time orthotopic tumour modelling in mice utilising transformed thyroid cell lines transduced with GFP-LUC for in vivo imaging. This will progress to 'high-risk, high payoff' experiments with human primary thyroid cultures from patients with thyroid cancer injected orthotopically into mice treated with the identified drug combinations and subject to ablative radioiodine treatment.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Understanding how an MLH1 promoter polymorphism predisposes to colorectal cancer
Funder: Medical Research Council

Abstract: Microsatellite-unstable (MSI+) tumours are commonly found in the colon where they comprise ~15% of all cancers. The underlying cause is mismatch repair (MMR) deficiency which in the majority of cases is caused by MutL homologue 1 (MLH1) promoter methylation. Why MLH1 is inactivated rather than other MMR genes and why methylation occurs rather than gene mutations are unknown, although there may be a causal link to the putative CpG Island Methylator Phenotype (CIMP). Intriguingly, a polymorphism, rs1800734, lies within the MLH1 promoter upstream of the translational start site of MLH1, and this SNP shows a strong association with the risk of MSI+ colorectal cancer (CRC), but not with MSI-negative cancers. We shall 1)expand the analysis of the association between rs1800734 and CRC risk, and mine existing data for rare germline genetic variants near rs1800734 2)determine associations between rs1800734 genotype, MLH1 methylation, MLH1 expression and CIMP in human normal, benign and malignant colorectal samples and find the statistically most likely causal links 3)construct isogenic CRC cell lines with all three rs1800734 genotypes 4)investigate chromatin structure and transcription factor binding to identify molecules and processes differentially associated with rs1800734 alleles 5)modulate DNA methylation and follow subsequent methylation (re-)acquisition and consequences according to rs1800734 genotype. 6)repress MLH1 mRNA transcription and determine whether promoter methylation occurs as a consequence 7)set up a mouse model of rs1800734 and determine effects of each SNP genotype on MLH1 methylation and intestinal tumours in a Braf-mutant model of MSI+ carcinogenesis 8)if time permits, develop a mouse with a general tendency to MLH1 methylation and determine the influence of rs1800734 therein These experiments will identify many of the mechanisms underlying the association of rs1800734 with MSI+ CRC and provide broader insights into MMR-deficient canc


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Identifying emerging subclones in individual colorectal cancer patients by mapping the spatio-temporal evolution of the tumour phenotype
Funder: Medical Research Council

Abstract: Aim 1: We will isolate 300 glands as previously described (Sottoriva et al., 2015; 2013) from 4 regions of 10 stage IV, 10 stage II/III carcinomas and 10 adenomas, and perform whole-genome sequencing at 30x in each gland and matched normal. We will use Platypus (Rimmer et al., 2014) to call somatic nucleotide variants (SNVs) and reconstruct copy number profiles using VarScan2 (Anderson et al., 2012). We will perform ATAC-seq in each sample and call chromatin states with MACS (Zhang et al., 2008). We will reconstruct the phylogenies using maximum likelihood (Guindon et al., 2010). We will check for mutations in mismatch repair genes and analyse the mutational signatures in each branch (Alexandrov et al., 2013). Aim 2: We will develop phylogenomic and population genetics methods to perform rigorous measurements in the phylogeny and identify distinct subclones with Poisson changepoint analysis (Killick et al., 2012), tree balancing algorithms (Heard, 1992) and dN/dS ratio analysis. We will use SNVs as molecular clock to time CNAs (Durinck et al., 2011). We will also develop a statistical model to time chromatin changes based on the observation that mutations accumulate differently in areas of open versus close chromatin (Polak et al., 2015). We will reveal recent clonal expansions in the tree by TMRCA analysis in each subclone (P Donnelly and Tavaré, 2003). Aim 3: We will apply the methods from Aim 2 to the ITH data in Aim 1. We will detect subclones and time their alterations to identify subclonal drivers. We will validate them at the transcriptomic level using qPCR or IHC when possible. Using the results from Aim 2, we will characterise the dynamic properties of each subclone: - How fast is a subclone growing? - How long has the emerging subclone been there? - Has the subclone evolution punctuated or gradual? - How fast is the clone mutating? - How big is the clone in the tumour? My preliminary data show the feasibility of these methods in my hands


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Development and Assessment of a Genetic and Environmental Risk Model for Colorectal Cancer
Funder: Medical Research Council

Abstract: Colorectal cancer (CRC) is the second leading cause of cancer deaths in developed nations. Whilst CRC is highly preventable using colonoscopic screening, this is expensive. Intermediate tests such as faecal occult blood tests (FOBT) are therefore used to identify individuals for further investigation. Modulating screening modality, interval, test interpretation and follow-up by prior risk could enable better targetting of NHS funding, and improve outcome measures such as cancer incidence and quality of life. Genetic risk is a major contributing factor, including around 40 common polymorphisms with moderate effects and 14 rare high risk genes. Non-genetic factors such as age, family and personal medical history, and diet also affect CRC risk. I will initially use a genome wide association study meta-analysis of state-of-the-art data to identify more common CRC single nucleotide polymorphisms (SNPs), followed by additional genotyping to identify further new CRC SNPs. I will then profile the known genetic and non-genetic factors in a nested case-control study within UK Biobank to construct and quantitate a CRC risk model, initially using classical logistical regression based approaches. This will then be validated in other cohorts. An appropriate genetic testing methodolgy for bowel cancer screening programmes (based on saliva samples) will be identified and optimised using an amplicon based gene and SNP panel and next generation sequencing platform. I will develop a bioinformatics pipeline for analysis of this data. Finally, I will summarise the resources required to use this new technology and associated costs, to provide information on the budget impact for the NHS.The project will give new insight into cancer risk, and provide a genetic and environmental risk model and associated technology. These have the potential to be applied nationally and internationally to bowel cancer screening programmes, thereby improving patient outcomes and resource management.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: The role of the immune micro-environment in the evolution of colitis-associated cancer
Funder: Medical Research Council

Abstract: Background: Patients with ulcerative colitis (UC) have a significantly increased risk of developing colorectal cancer (CRC), and so are entered into endoscopic surveillance programmes with the aim of detecting pre-cancerous dysplastic lesions. The detection and clinical management of these lesions remain challenging, leading to over-diagnosis and over-treatment of CRC risk. Hypothesis: We have demonstrated that epithelial clonal evolution underpins UC-mediated carcinogenesis; however, this evolution must be critically dependent on the micro-environmental context. We hypothesise that the stromal microenvironment in UC patients co-evolves alongside epithelial mutation accumulation in the colitis-dysplasia-carcinoma sequence, and that these micro-environmental changes represent a powerful biomarker of cancer risk. Key Goals: The particular scientific novelty of this proposed project is my ability to study the co-evolution of epithelial clonal populations and stromal microenvironment composition in the UC colon. By combining the unparalleled clinical resources of the world's oldest (and the UK's largest) IBD surveillance programme at St. Mark's Hospital with the scientific expertise of Barts Cancer Institute, I aim to: 1- analyse the micro-environmental composition in archival samples from 100 patients who progress to cancer (progressors) and 300 matched non-progressors. 2- correlate the micro-environmental composition in these samples with the pattern of epithelial somatic mutations. 3- use RNA-seq on fresh samples derived from a subset of progressors and non-progressors to characterise genome-wide the paired micro-environmental and epithelial cell biology, and assess the impact on stem cell biology during progression. Ultimately, I aim use my micro-environmental characterisation to develop a biomarker of CRC risk that spares low risk patients from unnecessary colonoscopy and surgery, and validate its utility in a future prospective clinical study.


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