NIHRDataInsights/HRCSData huggingface dataset:
Title: The role of microglia during the formation of neural network-like connections in glioma
Funder: Cancer Research UK

Abstract: Background High grade gliomas represent a complex and devastating disease and are posing an unmet clinical need. Recent studies show that glioma cells make neural network-like connections with one another and with healthy neurons. This results in the formation of a functional network providing the tumour with a growth advantage and resistance to therapy. Interestingly, these functional tumour networks resemble features of neural networks that are formed during development. I hypothesise that glioma cells repurpose developmental functions of microglia to promote outgrowth, connectivity and maturation of functional glioma networks. Objectives 1) How do microglia influence the initial steps of glioma network formation? 2) How do microglia influence network dynamics and topology? 3) What are the underlying mechanisms of microglia induced network formation? 4) How can network formation in glioma be inhibited? Methods Objective 1 We will utilise our larval zebrafish model which allows us to study network formation from glioma initiating cells and from solid human glioma cells. We will image the highly dynamic cellular interactions between microglia and the forming network in real time in vivo. Genetic and pharmacological depletion of microglia will allow us to study their role in network formation in detail. Objective 2 To understand the role of microglia in regulating the dynamics and topology of glioma networks, activity within the network will be assessed by live imaging Ca2+ transients. Network dynamics and topology will be analysed in collaboration with Prof Per Uhlén (Karolinska Institute, Stockholm). Objective 3 To study the underlying mechanisms of microglia induced network formation, we will utilise a candidate gene approach as well single cell RNA sequencing to identify the transcriptomic identity of network forming tumour cells and interacting microglia. Objective 4 Candidate genes involved in glioma network formation will be functionally analysed (CRISPR/Cas9) to understand their role in network formation and proliferation of tumour cells. Upon confirmation in the zebrafish model we will test the role of these genes in rodent glioma models (collaboration with Prof Steven Pollard). In collaboration with Prof Neil Carragher we aim to test clinical approved and investigational new drugs (IND’s) which offer the possibility of rapid repurposing for glioma treatment At the conclusion of this programme we will have a detailed understanding of the mechanisms underlying network formation in glioma and the role of microglia in this process. We will have identified drugs to interfere with these pathways, which will offer new opportunities for future therapies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Manchester ECMC
Funder: Cancer Research UK

Abstract: OUR STRATEGIC GOALS Improving cancer patient outcomes in Manchester will only be realised when the right treatment for the right patient is routinely prescribed with regular patient monitoring, allowing treatment modification as the patient’s tumour evolves, i.e. the delivery of precision medicine. Within the Manchester ECMC, we have already established the four critical elements needed to deliver routine precision medicine: #1 A large, well-characterised disease population across the 3.2m population of Greater Manchester (essential as molecular stratification can render prevalent diseases ‘niche populations’). #2 Molecular profiling (of both tumour and cfDNA) to the quality standard and timeliness required for clinical decision-making. #3 A growing clinical trial portfolio of targeted therapies to match patients based on information from molecular profiling. #4 Strengthened networking with other ECMCs (above) to ensure both a broadening of the portfolio of molecularly targeted agents available to patients and to augment enrolment of patients to protocols in molecular subtypes. The strategic goal for the Manchester ECMC is to become one of the top three Experimental Cancer Medicine Centres for the delivery of precision medicine in Europe by 2020 and one of the top five in the world by 2025. To achieve this will require a step change in the latter three of our four existing capabilities: • Our scientific (translational) capabilities: for routine molecular profiling and drug sensitivity testing. • Our clinical capabilities: to double the number of patients (from ~250 to 500/annum) treated on ECMC trials. • Our outreach/networking capabilities: to provide a larger portfolio of ECMC drug trials to match patients to.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: CANCER AND NEOPLASMS
Title: Heterocellular APC Signalling in Colorectal Cancer
Funder: Cancer Research UK

Abstract: 1) Background Colorectal cancer (CRC) is a heterocellular disease comprised of mutated cancer cells, stromal fibroblasts, and multiple immune cells. Each of these cell types contribute to CRC, but the signalling mechanisms underpinning their malignant behaviour are poorly-understood. 80% of CRC tumours are driven by loss of APC in epithelial cells. Although APC-loss deregulates cell-autonomous signalling in cancer cells, how APC communicates with stromal and immune cells to drive CRC tumours is unknown. I hypothesise that APC-loss drives CRC tumours via heterocellular signalling. Moreover, I propose that heterocellular APC signalling nodes in stromal and immune cells represent an unexplored opportunity for therapeutic intervention. 2) Aims This project aims to discover how APC-loss in cancer cells deregulates stromal and immune cells to drive CRC. Foundational work will quantify how APC-loss regulates signalling across colon organoid, fibroblast, and macrophage co-cultures. This will be followed by single-cell analysis of APC-loss heterocellular signalling of cancer cells, fibroblasts, myeloid cells, and lymphocytes in CRC tumours in vivo. Finally, heterocellular APC-regulated signalling nodes will be tested as novel therapeutic targets in CRC models in vivo. 3) Methods I previously established a heterocellular multivariate phosphoproteomics approach to study cell signalling in multiple cell types (Tape et al., Cell, 2016). This technique will be used to study APC-loss in CRISPR-engineered colon organoid co-cultures. This will be followed by single-cell mass-cytometry analysis of organoid co-cultures to identify subpopulation-signalling responses. These studies will comprehensively define how cancer cells, fibroblasts, and macrophages process APC signalling in vitro. Detailed models of heterocellular APC signalling will then be tested in vivo using an inducible APC-loss genetically-engineered mouse model of CRC. Single-cell mass-cytometry will provide high-dimensional insight into how cancer cell, fibroblast, myeloid, and lymphocyte signalling is deregulated by epithelial APC-loss. Finally, heterocellular signalling models will be used to generate rational perturbations of CRC. These models will be tested using high-throughput organoid drug screening in vitro and genetically-engineered mouse models in vivo. 4) How The Results Of This Research Will Be Used By studying CRC as an emergent system of heterotypic cell types, this research will uncover fundamental signalling events downstream of APC-loss in CRC tumours. These heterocellular signalling events will represent novel drug targets that could never have been discovered by homocellular analysis. This work will reveal new therapeutic opportunities for CRC treatment and demonstrate how one of the most important genetic events in cancer deregulates heterocellular signalling throughout an entire tumour.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Investigating the role of protein hydroxylation in cancer
Funder: Cancer Research UK

Abstract: Background Protein hydroxylases of the 2-oxoglutarate- (2OG) oxygenase family are emerging as important players in cancer through their regulation of epigenetics, gene expression, oxygen sensing and extracellular matrix deposition. Overall, this enzyme family remains relatively poorly characterised however, partly due to incomplete substrate assignment. A more comprehensive understanding is required in order to more fully appreciate the roles of hydroxylation in tumour biology, to accurately assign the targets of hypoxia and oncometabolites, and to promote the effective translation of 2OG-oxygenases. Aims Here we begin to help alleviate these constraints through detailed characterisation of three cancer-associated hydroxylases that, through substrate discovery, we have implicated in fundamental hallmarks of (tumour) cell biology. Methods We have developed a reliable approach for discovering substrates of protein hydroxylases. This work, together with others, has demonstrated that hydroxylation is far more common than previously appreciated. We recently applied our proteomic approach to three cancer-associated hydroxylases and identified substrates involved in important hallmarks of cancer. We will use a common workflow for studying novel hydroxylations in cancer. First, we characterise their regulation by hypoxia, oncometabolites, and hydroxylase cancer mutations. Then we investigate their roles in tumourigenesis through a combination of cell biology, proteomics and genomics approaches in a variety of models, including hydroxylase-mutant tumour cell lines and patient-derived organoids. Finally, we extend our findings into tumour samples through a combination of targeted resequencing and pathology analyses. How the results of this research will be used Importantly, although we predominantly use gastrointestinal and oncometabolite-driven cancers as models, the work will describe novel mechanisms of tumourigenesis that will likely be applicable across cancers, including those of unmet need. As such, the findings have the potential to highlight novel therapeutic opportunities and will have important implications for the successful translation of 2OG-oxygenases in cancer.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Multi-parametric ultrasound imaging for assessment of tumour response to radiotherapy
Funder: Cancer Research UK

Abstract: Around 50% of cancer patients receive radiation as their primary treatment for cancer, either alone or combined with other treatments, such as surgery or chemotherapy. Unfortunately, not all tumours respond to radiotherapy in the same way. For example, some tumours may be radiation resistant, resulting in treatment failure. Currently, we are unable to identify all tumours that do not respond before treatment, meaning that patients may undergo treatments and experience side effects unnecessarily. Tumour characteristics, such as the tumour blood supply, can be used to assess the “health” of the tumour, and these characteristics can be measured by imaging modalities such as magnetic resonance imaging (MRI), positron emission tomography (PET), computed tomography (CT) and ultrasound (US). Evidence suggests they may be used to identify tumours that will respond to RT, and those that will not. PET and MRI are the most established methods for assessment, but they are not integrated into radiation treatment rooms. They require separate imaging examinations, which increases cost and makes them less tolerable for patients. Functional and molecular US imaging techniques are affordable, quick to perform, well-tolerated by patients and may be implemented concurrently with radiotherapy. We have already devised new methods to integrate US imaging into the treatment room to improve the accuracy of radiotherapy by localising tissues before radiotherapy is delivered. This study proposes to develop a novel US system which combines three types of US imaging that measure different tumour characteristics in three dimensions (3D). These are dynamic contrast enhanced US, which measures tumour blood supply; shear wave elastography, which measures tumour stiffness; and US backscatter spectroscopy, which measures tumour structure. We will also measure how these characteristics vary between sub-regions of the tumour. Using this novel US system and technology that enables accurate registration of US images with data that describe the radiotherapy dose that is delivered to the tumour we will investigate US assessment of tumour response to radiotherapy. We will perform experiments to (1) help us understand how US-measured tumour characteristics (US metrics) are related to the biology of the tumour and (2) measure the changes in US metrics in response to treatment. This study identifies US metrics or combinations of US metrics (mpUS metrics) that can identify tumours that do not respond to radiotherapy. Early assessment of response will allow clinicians to change treatments according to the individual, potentially sparing patients ineffective therapy and associated side-effects. (Cancer sites: Cervical, Nasal Cavity, Oral Cavity, Pharyngeal)


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: CRUK/16/019 FITNEsS (Myeloma XIV): Frailty-adjusted therapy In Transplant Non-Eligible patients with newly diagnosed Symptomatic myeloma
Funder: Cancer Research UK

Abstract: Background: Multiple myeloma predominantly affects those aged over 70 (median age of onset 66 years) and its incidence is increasing as the population ages. New therapies have advanced treatment outcomes over the last decade but their impact has been less marked in older/less fit patients. This group has a high un-met need for novel effective treatments that are deliverable without excess toxicity and are usually excluded from trials. Recent trials have demonstrated the efficacy of the immunomodulatory drug (IMiD) lenalidomide in older/less fit patients but studies in younger patients suggest combination treatments with proteasome inhibitors (PI) improve outcomes further. The development of a novel, oral, well-tolerated PI Ixazomib, provides an opportunity to investigate such a combination in older/less fit patients, both as induction and maintenance treatment. There is considerable heterogeneity, in terms of fitness, amongst older patients. The International Myeloma Working Group has defined a scoring system for patient frailty that predicts survival, adverse events and treatment tolerability and recommends prospective studies to investigate whether using this score to guide up-front dosing can improve tolerability and outcomes for patients. Aims: This trial, of newly diagnosed, older/less fit myeloma patients, aims to address whether: 1) The use of frailty index to adapt up-front dosing can improve tolerability and outcomes compared to standard of care. 2) The combination of ixazomib, lenalidomide and dexamethasone attenuated (IRDa) is superior to cyclophosphamide, lenalidomide and dexamethasone attenuated (CRDa). 3) The addition of ixazomib to single agent lenalidomide is a more efficacious maintenance strategy. Methods: In order to answer these questions we have designed a multi-centre, open label, randomised controlled trial with a 2x2 factorial design at randomisation 1 to answer both induction questions (Aims 1+2) followed by a maintenance randomisation once patients have reached maximum response to induction (Aim 3). Outcomes: This study will establish whether the use of prospective dose adjustments in newly diagnosed older/less fit myeloma patients improves outcome and quality of life. It will also establish whether the combination of new generation IMiD and PI agents at induction and maintenance is tolerable and improves efficacy. The outcomes from this trial will inform national and international guidelines, routine clinical practice in the UK and will define the new standard of care around which trials of agents with novel mechanism of action, currently in early stages of clinical development, can then be designed.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Exploiting a new cell cycle control pathway for cancer therapy
Funder: Cancer Research UK

Abstract: Background Cell cycle control remains one of the prime targets for successful cancer therapy. This is reflected by the recent success of new targeted therapies involving key cell cycle regulators, including Cdk4/6 and Wee1. Thus, a crucial aim for cancer research is to improve our understanding of how cell cycle control works, how it is altered in cancer, and how these changes can be exploited in new therapeutic approaches. Based on both published work and on preliminary results, I propose that Greatwall kinase, a key regulator of the interphase to mitosis transition, has been deregulated in different tumour types. This renders some tumours highly dependent on Greatwall kinase activity. Our hypothesis is that this increased dependency presents a therapeutic window to target Greatwall kinase using small molecule inhibitors. This could provide a promising new avenue in cancer therapy. Aims This program will tackle two related and important questions:: What distinguishes cancer cells that show increased dependency on Greatwall, and how can we recognise these types of tumour cells. The first question addresses a novel mechanism of cell cycle control deregulation in cancer. The second question aims to build on our improved mechanistic understanding to design biomarkers that predict sensitivity to Greatwall inhibition. Methods We will use a highly interdisciplinary approach involving a novel small molecule inhibitor, chemical genetics, large scale genomic and proteomic studies and bioinformatic analysis to explore the deregulation of the G2/M network and to support biomarker discovery. We will initially focus our analysis on triple-negative breast cancer and perform an in-depth mechanistic validation of Greatwall kinase as a target in cancer therapy. In parallel, we will expand our study on a wider range of tumours to identify additional cancer types that could be susceptible to Greatwall kinase inhibition. Outcomes This project will clarify, how cell cycle control mechanisms that ensure the separation of interphase and M-phase have been altered in cancer cells and provide new ideas, how to exploit this knowledge in therapy. Our work will contribute to the development of Greatwall kinase as a therapeutic cancer target and support the rational design of clinical trials for Greatwall inhibitors.


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: Evolutionary dynamics of the cancer epigenome in myeloproliferative neoplasms.
Funder: Cancer Research UK

Abstract: Background: Cancer clones emerge and evolve through somatic mutation acquisition and Darwinian selection, but the dynamics of clonal evolution remain poorly understood and predicting disease progression remains a real challenge. Genes that regulate the epigenome are clearly important targets of mutations in cancer, but the mechanisms by which they drive tumour evolution remain unknown. The myeloproliferative neoplasms (MPN) are haematopoietic disorders that represent an excellent model to study genomic and epigenomic evolution in human cancers: (i) They are genetically well-defined with disease driving mutations in JAK2, CALR (which I described in 2013) or MPL, present alongside mutations in epigenetic regulators, such as, DNMT3A. (ii) Disease can be either stable, or progress to leukaemia or myelofibrosis, providing the opportunity to study the basis for these evolutionary differences, and (iii) Primary cells can be serially sampled at the clonal level enabling inter- and intra-clonal studies. Aims: My key goal is to understand the genetic and epigenetic basis of clonal evolution in MPNs. Specifically, 1. I will determine the mutational patterns, mutational processes and clonal dynamics underlying disease stability versus progression. 2. I will study the aberrations in DNA methylation resulting from mutations in DNMT3A (and later TET2), at the clonal level in MPNs to understand how DNA methylation drives clonal evolution. Methods: 1. Whole-genome sequencing of 2-3 disease time-points in 32 MPN patients with either stable or progressed disease has completed. Genome-wide somatic mutations will be analysed and the absolute timing of genetic events in relation to disease phenotype will be determined using targeted sequencing of further disease timepoints. Mutational processes and clonal dynamics underlying disease evolution will be determined by studying subclonal architectures, mutational signatures and rates of mutation acquisition. 2. Whole-genome bisulphite sequencing of individual single-cell derived haematopoietic colonies will be performed in 15 DNMT3A- or TET2-mutated MPNs. Perturbations in DNA methylation across patients, between genetic subclones, between colonies of the same genotype, and within individual colonies, will address the mechanisms by which DNA methylation dysregulation contributes to clonal evolution. How the results of this research will be used: This study will provide information on why MPNs remains stable in some but unfortunately progress in others, and which patients may be at risk of future disease progression. Deciphering DNA methylation perturbations at a clonal level will provide unprecedented insight into the epigenetic mechanisms that drive clonal haematopoiesis and evolution. The evolutionary insights gained will be relevant to other cancers.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: CANCER AND NEOPLASMS