NIHRDataInsights/HRCSData huggingface dataset:
Title: Transcriptional programmes of myeloproliferative neoplasms
Funder: Cancer Research UK

Abstract: Background._x000D_ Somatic mutations affecting JAK/STAT occur in multiple tumour types and are especially common in human myeloproliferative neoplasms (MPNs). The discovery of the JAK2 V617F mutation in 2005 has catalysed an explosion of activity in the MPN field with Cambridge at the forefront. This programme grant application builds on the long-standing collaborative studies and plays to respective expertise in MPN biology and transcriptional regulation. _x000D_ _x000D_ Aims_x000D_ We propose to define the transcriptional programmes whereby JAK/STAT signalling regulates normal myelopoiesis and to ascertain how these programmes are subverted as a consequence of mutant JAK2 signalling. STAT transcriptional programmes downstream of wild-type JAK2 will be characterised in three normal cell types: haematopoietic stem and progenitor cells (HSPCs), erythroblasts and megakaryocytes (Aim 1). This will provide a comprehensive picture of how the STAT programmes amalgamate inputs from multiple cell surface receptors that signal through JAK2. Results will be integrated with analyses of mutant JAK2 signalling, using patient samples and mouse models, to characterise transcriptional mechanisms that contribute to MPN pathogenesis (Aim 2)._x000D_ _x000D_ Method._x000D_ We will integrate results from cellular and murine model systems with studies of primary samples from well-characterised patients. A wide variety of molecular and cellular approaches will be used including transgenic and knockin mouse models together with genome scale analysis of normal haematopoietic cells and those from patients with myeloproliferative neoplasms_x000D_ _x000D_ Use of results._x000D_ This programme will define the STAT transcriptional programme downstream of JAK2 at genome scale. Together with studies of other signalling pathways our results will begin to provide a systems biology view of normal haematopoiesis. Moreover the knowledge thus gained will inform our analyses of how STAT transcriptional programmes are perturbed in the MPNs, both at presentation and in late-phase disease. Our results will clarify MPN pathogenesis, will have implications for classification, diagnosis and risk stratification and are likely to identify novel therapeutic targets. Lastly, although we have focused on the MPNs, the involvement of JAK-STAT pathways in a wide range of malignant and non-malignant disease suggests that our results will have considerable general relevance.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Molecular function of BRCA1 in the maintenance of genome stability and breast cancer
Funder: Cancer Research UK

Abstract: BACKGROUND:<br/>To maintain the genetic and physical integrity of the genome in the face of a broad range of endogenous and exogenous insults cells have developed a network of pathways collectively known as the DNA damage response (DDR). These include mechanisms for detecting and signalling DNA damage, regulating gene expression and cell cycle progression and for repairing a wide variety of DNA lesions. The coordination of this multi-faceted response involves a group of proteins known as mediators, one of which is the tumour suppressor BRCA1. Defects in BRCA1 are associated with predisposition to early onset breast and ovarian cancer. The molecular mechanism(s) through which BRCA1 functions to coordinate different aspects of the DNA damage response are unknown.<br/><br/>RELEVANCE TO CANCER:<br/>Cancer cells commonly exhibit a profound increase in genomic instability manifested through increased chromosome aberrations including mutations, DNA breaks and chromosome translocations. Consequently, corruption of the genome is frequently associated with sporadic defects in factors involved in the DDR. Moreover, inherited defects in the DDR are linked with a broad range of cancer-predisposing diseases including, Fanconi's anaemia (FA proteins), Ataxia telangeictasia (ATM) and early onset breast and ovarian cancer (BRCA1, BRCA2). As well as a driving force towards cancer, defects in DNA repair can be exploited for therapy by virtue of the sensitivity of cancer cells to DNA damaging agents. In recent years it has become clear that the genetic relationships between different DNA repair pathways, and specifically those involving BRCA1, are also exploitable for cancer therapy through synthetic lethality.<br/><br/>SPECIFIC AIMS OF THE RESEARCH:<br/>The aim of the proposed programme is to use biochemical and genetic approaches to investigate the role of BRCA1 and its interacting partners in the maintenance of genome stability, to determine at a molecular level the mechanism of BRCA1 function, to identify new components in the DNA damage response and to explore how different BRCA1-dependent pathways might be exploited for cancer therapy.<br/><br/>OUTLINE OF RESEARCH:<br/>-To determine the role of the BRCA1-interacting protein BARD1 in the DNA damage response.<br/>-To determine the contribution of the BRCA1-interacting protein FANCJ in the maintenance of G-quadruplex DNA (G4-DNA) and investigate use of G4-DNA ligands in cancer therapy.<br/>- To identify the molecular mechanism of the ubiquitin mediated DNA damage signaling pathway involving BRCA1 and its interacting partner Abraxas.<br/>- To determine the contribution of BRCA1 and its interacting partners to BRCA1-dependent cell cycle arrest in late S/G2 phase


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Structural and mechanistic insights into the pathways of mitotic regulation
Funder: Cancer Research UK

Abstract: BACKGROUND:_x000D_ Cells undergo many changes during mitosis, such as bipolar spindle assembly, the regulation of which is poorly understood at the level of molecular structure. A subset of mitotic proteins function in multiple pathways and the elucidation of structural mechanisms will enable the dissection of their individual functions. This programme builds on my discoveries on the mechanisms of regulation in mitotic kinases and their targeted inhibition._x000D_ _x000D_ RELEVANCE TO CANCER: _x000D_ The proper execution of mitosis is essential for maintaining genomic fidelity and the disruption of any of a number of proteins that regulate mitosis results in chromosomal abnormalities. Many of the key regulatory proteins that we will investigate are frequently altered in cancers. Compounds that target mitotic spindle assembly are widely used in the clinic (e.g. taxanes), and others are in clinical trials (e.g. Aurora-A inhibitors). There is a need for further research to improve the effectiveness of existing compounds, to circumvent drug resistance and to extend the range of cancer types treated. Our programme of research will improve our understanding of the pathways targeted by anti-mitotic drugs and the pathways that affect sensitivity to drugs. We will reveal mechanistic insights into potential targets in the pathways of mitotic regulation._x000D_ _x000D_ SPECIFIC AIMS:_x000D_ The aim of this research programme is to decipher the structural mechanisms by which the physical events of mitosis are regulated, focussing on:_x000D_ - The activity of protein kinases in bipolar spindle assembly. We will investigate the mechanisms by which Aurora-A is localized, activated and inhibited; decipher the mutual regulation of NEKs 6,7 and 9, and study the regulation of microtubule-binding proteins by these kinases._x000D_ - The antephase checkpoint, which is the cellular response to stress in early mitosis such as drugs that interfere with spindle assembly. We will study the structure and function of molecular interactions of CHFR, an E3 ubiquitin ligase that is crucial for checkpoint function. CHFR is inactivated in many tumours by mutation or promoter hypermethylation_x000D_ - The segregation of chromosomes triggered by the protease separase. We will determine the structural basis of separase inhibition by binding partners, and its activation mechanism._x000D_ _x000D_ OUTLINE PLAN: _x000D_ We will (i) reproduce the regulatory pathways in vitro using recombinant proteins (ii) determine structures of regulatory proteins and protein complexes using primarily X-ray crystallography, (iii) decipher the mechanisms of regulation in vitro (iv) interrogate the mechanisms in cells using genetics and chemical tools._x000D_


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS
Title: High Resolution MR imaging as a predictive biomarker for determining resectability in oesophageal and oesophagogastric cancer
Funder: Cancer Research UK

Abstract: Background: The incidence of Oesophageal and Oesophagogastric cancer has increased significantly in the_x000D_ past three decades. There is a need for research targeted towards staging and treatments to optimise outcome._x000D_ For patients with localised disease, surgery is the treatment of choice. In addition to T & N stage, completeness_x000D_ of the surgical resection is an important factor for post operative survival, with patients who undergo resection_x000D_ leaving either microscopic (R1 resection) or macroscopic (R2 resection) residual disease having a significantly_x000D_ poorer prognosis than those patients with a negative resection margin (R0 resection). Intraoperative frozen_x000D_ sections reduce the risk of tumour at longitudinal resection margins. The radial or circumferential resection_x000D_margin (CRM) remains at risk and currently R1/R2 resection rates due to a positive CRM are 39%. High_x000D_ resolution T2 weighted MRI can demonstrate oesophageal wall layers; identify tumour within wall layers and_x000D_ perioesophageal tissues; and the surgical anatomy of the posterior mediastinum, vital to assessing resectability._x000D_ Aims & Objectives: The aim is to use T2 weighted MRI as a predictive biomarker for resectability in patients_x000D_ with oesophageal and oesophagogastric cancer. Our hypothesis being that MRI improves patient selection for_x000D_ surgery by more accurately predicting patients at risk of an R1/R2 resection than conventional staging._x000D_ Methods: Patients recruited into the ST03 clinical trial at designated centres will be eligible for the MR_x000D_ imaging substudy. Patients will undergo an MRI before and after neoadjuvant chemotherapy. The MRI studies_x000D_ will be observational. Specific MRI criteria will be used to predict resectability based on achieving a negative_x000D_ resection margin and the tumour T & N stage. MRI prediction will be compared with histopathology as the gold_x000D_ standard, to enable calculation of sensitivity, specificity and accuracy of MRI as a predictive biomarker and for T_x000D_ & N staging. All studies performed outside the lead centre will be sent for review at the lead centre. The lead_x000D_ centre report will be the primary outcome measure, with corresponding reports from the other centres providing_x000D_ data to test reproducibility in the form of interobserver variability._x000D_ How results of research will be used: Assuming the hypothesis is validated, MRI would become part of the_x000D_ established staging algorithm for all patients with localised disease. The association with current NRCI trials_x000D_ would enable the technique to be easily incorporated into future National clinical trials. Of particular interest in_x000D_ the future would be its role in planning targeted radiotherapy.


Research activity codes: 4.4 POPULATION SCREENING
Health categories: CANCER AND NEOPLASMS
Title: Liverpool Cancer Research UK Centre (Clinical Training Account)
Funder: Cancer Research UK

Abstract: Clinical training associated with a centre: The Liverpool Cancer Research UK Centre - the second centre to launch in our Centres programme - will set the pace for national and international progress in pancreatic, head and neck, and blood cancers. It will also concentrate on pioneering the latest techniques in surgery, radiotherapy and the treatment of children's cancers. Collaboration is the key to the success of this virtual Centre, a partnership between the Royal Liverpool University Hospital, Clatterbridge Centre of Oncology NHS Trust, the University of Liverpool, the Liverpool City Council, the Merseyside and Cheshire Cancer Task Force, and Cancer Research UK. It aims to be a world leader in developing treatments tailored to individual cancer patients based on understanding the biology of the disease and how that varies among patients. Researchers will also be focusing on a better understanding of how cancers start and behave, developing more effective treatments with fewer side effects, and tackling cancer in low-income communities where survival is lowest.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: CANCER AND NEOPLASMS
Title: Diagnostic accuracy of MRI, diffusion-weighted MRI, FDG-PET/CT and Fluoro-ethyl-choline PET/CT in the detection of lymph node metastases in surgically staged endometrial and cervical carcinoma
Funder: Cancer Research UK

Abstract: Background and relevance to cancer_x000D_ Accurate staging is required for optimal cancer treatment. In endometrial and cervical cancer, the presence of nodal metastases indicates a worse prognosis and significantly alters treatment. Current imaging techniques, using node size criteria, are not sufficiently accurate to obviate the need for surgical node staging, a highly specialised invasive procedure. New imaging technologies may be sufficiently accurate for non-invasive nodal staging, potentially saving patients from additional surgery and morbidity._x000D_ _x000D_ Aims and objectives_x000D_ The primary aim is to compare the diagnostic accuracy of diffusion weighted (DW)-MRI, FDG-PET/CT and Fluoro-ethyl-choline (FEC) PET/CT with standard size criteria in the preoperative diagnosis of nodal metastases, using histology as the gold standard. The secondary aims are to compare DW-MRI, FDG-PET/CT and FEC-PET/CT with each other and to examine whether one modality performs better than another in different sub-groups._x000D_ _x000D_ Methods_x000D_ 150 patients with endometrial or cervical carcinoma will be invited to undergo standard staging MRI followed by DW-MRI, FDG-PET/CT and FEC-PET/CT. Imaging detection of nodal metastases will be reported using size criteria, DW-MRI, FDG-PET/CT and FEC-PET/CT. Patients will undergo surgical lymphadenectomy. The diagnostic accuracy of each imaging test will be calculated using histology as the gold standard and within-persons comparisons performed._x000D_ _x000D_ How the results will be used_x000D_ The results will determine whether any of these imaging modalities is sufficiently accurate to obviate the need for surgical lymphadenectomy in order for appropriate decisions to be made concerning patient treatment._x000D_


Research activity codes: 4.4 POPULATION SCREENING
Health categories: CANCER AND NEOPLASMS
Title: Understanding and Exploiting Stemness in Childhood Acute Lymphoblastic Leukaemia
Funder: Cancer Research UK

Abstract: BACKGROUND & RELEVANCE TO CANCER:_x000D_ Acute lymphoblastic leukaemia (ALL) is the most common malignancy in children and adolescents. Its treatment is associated with significant morbidity and, despite a high cure rate, ALL remains one of the leading causes for cancer-related and overall deaths in this population. Novel therapeutic approaches are required that can be applied both to primary and relapsed disease to both reduce toxicity and increase efficacy. We propose to address this problem by investigating and exploiting "stemness" in ALL, i.e. the ability of the leukaemic blasts to maintain and re-grow the disease. _x000D_ Our group has challenged the hierarchical model for B cell precursor ALL and we have shown that self-renewal is not restricted to the immunophenotypically most immature cells. However, it remains controversial whether the lack of a stem cell hierarchy is universal or limited to advanced and high risk leukaemias. Furthermore, it needs to be shown whether all populations have the same fitness for competitive repopulation._x000D_ _x000D_ SPECIFIC AIMS OF THE RESEARCH:_x000D_ The aims of the proposed programme are to:_x000D_ -define the cells that maintain B lineage ALL;_x000D_ -identify the key mechanisms by which leukaemic blasts maintain stemness; _x000D_ -therapeutically exploit the way in which leukaemic blasts access and regulate the stem cell programme._x000D_ _x000D_ OUTLINE PLAN OF RESEARCH:_x000D_ We plan to mark different ALL blast populations with lentiviral vectors expressing different luciferases. These can then be monitored in vivo by bioluminescence in a competitive repopulation assay. This approach will also allow tracking individual ALL clones by analysing lentiviral integration sites using ligation-mediated PCR. Heterogeneity of the self-renewal potential will be studied by identifying clones that only contribute to the leukaemia in primary recipients compared with other clones that show sustained activity over several transplantations._x000D_ Based on our experience with modulating leukaemic fusion genes, our goal is to take both a candidate (e.g. angiopoietin) and an unbiased approach to identify and characterise key components of the leukaemic stem cell programme. We will functionally screen leukaemic cell lines with a lentiviral pGIPZ-based library (Open Biosystems) followed by an in vivo screen. Hits from the RNAi screens will be selected for functional validation in primary cells based on relevance for stem cell biology, selectivity for the leukaemia and "druggability". The main focus of the proposed programme is to identify novel mechanisms of how ALL blasts regulate stemness and to explore these as potential therapeutic targets.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Characterisation of leukaemic stem cell biology in childhood AML
Funder: Cancer Research UK

Abstract: Background: _x000D_ Acute Myeloid Leukaemia (AML) is a common cause of cancer death in children. Despite an initial therapeutic response, treatment fails to eradicate chemoresistant AML clone(s). Furthermore, over the last three decades not a single novel class of effective therapy has been developed._x000D_ Studies in adult AML have led to hypotheses that AML is organised in cellular hierarchies, at the apex of which are are multi-potent, largely quiescent, long-lived leukaemic stem cells (LSC) with marked self-renewal capacity that sustain disease and differentiate into "bulk leukaemic cells". Recently, we have characterised primary adult human AML LSC and in detail. We have shown that two expanded LSC populations with haemopoietic progenitor immunophenotype coexist in most patients. The LSC populations are hierarchically ordered, with one LSC population giving rise to the other. Furthermore, for the first time, we have also recently shown that adult malignant myeloid LSC are more chemoresistant, suggesting that LSCs have to be eradicated to cure adult AML. In contrast to adult AML and childhood Acute Lymphoblastic Leukaemia where we, and others, have identified LSC, LSCs have not yet been defined in childhood AML. _x000D_ Here we plan to characterise childhood AML LSC and contrast the gene regulatory pathways of childhood and adult AML LSCs. _x000D_ _x000D_ Relevance to Cancer: _x000D_ In addition to providing fundamental scientific insight into myeloid leukaemogenesis, this work has translational potential of developing LSC-based biomarker of clinically relevant minimal residual disease and rational AML LSC-targeted therapy. More broadly, the work could provide insight into abnormal self renewal pathways in cancer stem cells and use of cancer stem cells as disease biomarkers and therapeutic targets. _x000D_ _x000D_ Outline research: _x000D_ 1) Identification of childhood AML LSC. We will obtain diagnostic bone marrow samples from children newly diagnosed with AML spanning a wide range of karyotypes and test LSC activity in xenograft assays._x000D_ 2) Gene regulatory pathways in childhood and adult AML LSCs compared with normal stem/progenitor cells. _x000D_ i) Gene expression signatures obtained by RNA-sequencing from highly purified functional childhood and adult LSCs that share common karyotypes. We will select specific genotypes most commonly associated with a poorer prognosis in childhood AML. Extended genomic characterisation will be performed by SNP arrays. _x000D_ ii) Childhood and adult LSC expression signatures with those from paediatric and adult normal stem and progenitor cells._x000D_ 3) Single cell molecular heterogeneity of LSCs. To test whether heterogeneity exists, we will compare gene expression in individual LCSs using single cell RNA-sequencing protocols.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Glasgow Cancer Research UK Centre (Non-Clinical Training Account)
Funder: Cancer Research UK

Abstract: Non-clinical training associated with: Researchers at the Cancer Research UK West of Scotland Cancer Centre are particularly focusing on bowel cancer and leukaemia, although their work will touch on many other cancer types. Scientists at the Centre also have considerable expertise in studying how cancer cells break away from a tumour and spread through the body - their work is paving the way for new treatments to halt this process. The Centre builds on Glasgow's excellent track record in developing new drugs for cancer. Scientists, doctors and nurses are working together to understand the molecular faults that lie at the heart of cancer, and find new drugs to target them. Researchers at the Centre also have the expertise to take exciting new treatments out of the lab and into the clinic, testing them in early-stage clinical trials with patients. To ensure that Glasgow continues to be a focus for cancer research for years to come, the Centre will play an important role in recruiting and training the next generation of cancer researchers. The staff at the Centre will reach out to the local community, highlighting the importance of a healthy lifestyle in cutting the chances of cancer, and how to spot the early signs of the disease (http://aboutus.cancerresearchuk.org/what-we-do/research/research-near-you/glasgow/science-research/)*** Grants support a variety of training projects - where available coding is done on the basis of these individual pieces of research.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: CANCER AND NEOPLASMS