NIHRDataInsights/HRCSData huggingface dataset:
Title: The regulatory role of the non coding genome in cancer
Funder: Cancer Research UK

Abstract: A substantial amount of transcript expression occurs between protein coding genes. In previous work, we have been able to show that some of these novel RNAs encode previously unknown proteins (Bitton et al. 2011; Bitton et al. 2010). However, it is clear that the majority of these transcripts are not protein coding, and that non coding RNAs form the basis of a diverse and extensive set of regulatory mechanisms that control gene and protein expression. The aim of this programme of work os to identify novel non coding RNA regulators of gene expression that play a critical role in human tumours. Of particular interest are the regulatory interactions that occur via the 3' UTR. The RNAi processing machinery in the fission yeast Schizosaccharomyces pombe is highly conserved with human cells, making it a particularly useful model organism with which to rapidly investigate RNA regulatory mechanisms We will therefore use fission yeast as a model organism with which to investigate basic mechanism, whilst seeking their analogues in in vitro cell-line models and human tumour datasets. Studies will make extensive use of deep sequencing and quantitative proteomics, and a substantial aspect of the research programme will be to develop novel software tools in R/Bioconductor to integrate these genome-wide datasets.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Investigating and exploiting 5T4 oncofoetal glycoprotein function in cancer spread
Funder: Cancer Research UK

Abstract: 5T4 oncofoetal glycoprotein was discovered while searching for molecules with invasive properties likely to be shared by trophoblast and cancer cells. 5T4 expression has been shown to influence adhesion, cytoskeletal organization and motility, properties which contribute to its association with poorer clinical outcome in several solid cancers. We have also recently shown that 5T4 expression is associated with high risk of relapse childhood pre-B acute lymphoblastic leukemias (B-ALL). There are currently three commercially driven approaches to targeting 5T4: TroVax, a recombinant viral vaccine based on MVA delivering 5T4, in late phase clinical trial (Oxford BioMedica, UK); Anyara, an antibody targeted super-antigen which acts to target T cells to tumours, in late phase clinical trial (Active Biotech, Sweden); and 5T4 antibody targeting of a toxin in clinical development (Pfizer, USA). This project aims to provide a platform for the further exploitation of 5T4 expression by human tumours, derivative from its functional influence on key signaling pathways that contribute to the spread and growth of tumours. The project will investigate the 5T4 marked “switch” of CXCL12 stimulation via CXCR4 or CXCR7 or canonical Wnt/ß catenin versus non-canonical pathway signaling in cancer cells to explore their roles in potentiating tumour spread or survival. The coregulation and/or synergy of the chemokine and Wnt pathways will be investigated in functional in vitro assays and where possible and appropriate in vivo. Interestingly 5T4 expression in B-ALL cells correlates with increased invasion, adhesion and CXCR4/CXCL12 chemotaxis in vitro and differential infiltration of extramedullary sites in xenograft challenge. Several therapeutic agents utilize 5T4 specific antibody to target therapies while TroVax induces patient antibodies which are strongly associated with improved clinical outcome. We will test existing and new h5T4 antibodies for modulation of 5T4 associated signaling in vitro and for therapeutic activity in vivo. Our studies will analyse B-ALL, ovarian, prostate and lung cancers where there is an unmet need for treatment.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Advanced Technology and Radiation Biology
Funder: Cancer Research UK

Abstract: This application deals with the development of technologies and instrumentation systems used in ionising radiation delivery systems and with the development of optical imaging systems, with application in the diagnostic arena. Development of such state-of-the-art instrumentation requires a multidisciplinary approach, including physics, mathematics, computer science and electronics expertise, all of which are available in our group. The treatment of cancer with radiotherapy in the clinic has evolved over the last decade to become significantly more sophisticated and increasingly reliant on imaging to locate the tumour. In the near future such treatments will include modifiers of tissue response to radiation. In order to properly evaluate such treatments, it becomes increasingly important to not only deliver the best technical radiation treatment but also to be able to replicate such methods in a pre-clinical research setting. This requires significant technological advances to existing pre-clinical radiation delivery systems, to include highly conformal irradiations of tumours and/or normal tissues, as well as reliable image guidance. The proposed work includes development of enabling technologies for this purpose. It includes the use of phase contrast X-ray tomographic imaging and optical molecular imaging which exploits fluorescence to identify critical volumes. These approaches will allow the consequences of treatment to be followed in time and with specificity afforded by use of fluorescent proteins and other markers, particularly in the near-infra-red region of the optical spectrum. Such optical methods have been used in microscopy imaging for many years; indeed we have developed technologies to identify specific protein-protein interactions within live cells and in patient biopsies. This exploits a mechanism which becomes prominent when fluorescently labeled proteins are interacting, allowing us to determine interaction distances on the nanometer distance scale. This mechanism relies on short-range energy transfer between fluorescent molecules which affects the time (typically a few nanoseconds) during which such molecules emit light, once excited by a short light pulse. We will continue to exploit this process to allow identification of critical interactions in patient samples with a view to optimizing treatment. In addition we seek to develop microscopy super-resolution methods, which bridge the resolution gap between fluorescence lifetime and conventional microscopy methods. This technology will also be used to determine protein recruitment and repair processes following ionizing radiation DNA damage. The proposed work will thus add to the understanding of treatment consequences, encompassing work at the molecular level through to in vivo measurements.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES;4.4 POPULATION SCREENING
Health categories: CANCER AND NEOPLASMS
Title: Pharmacology and Drug Development Laboratory
Funder: Cancer Research UK

Abstract: The success of the development of new therapeutics for treating patients with cancer is dependent on their effective pre-clinical evaluation and science-led clinical investigation. Effective drug treatments for advanced pancreatic ductal adenocarcinoma (PDAC) are needed urgently, as over 80% of patients present with inoperable disease. The dense stroma associated with PDAC reduces the effectiveness of existing therapeutics. We plan to develop new pre-clinical models, in particular co-culture and spheroid models, to allow us to study agents which target, or whose activity is mediated by, stroma/cancer cell interaction. It is apparent that combinations of therapeutics will be used increasingly in the future. Current approaches to evaluate therapeutic drug interactions, to identify and translate synergistic combinations are inadequate. We have developed computer software (SynergySurface) to address this issue. We plan to use the results of analyses in cell culture to guide the later phases of pre-clinical drug development and ultimately clinical trial design, initially with an aurora kinase/taxane combination. Gemcitabine is used commonly in the treatment of patients with PDAC and studying its pharmacology in detail will guide future combination strategies. Using novel biopsy techniques and analytical methods, we aim to understand the pharmacokinetics and pharmacodynamics of gemcitabine and study a new metabolite of gemcitabine, which we have discovered. We will utilise systems pharmacology (mathematical modelling of therapeutic effects on complex biological processes) to guide combination design and potentially identify new drug targets. Systems pharmacology will play an integral role in our development of the ADAM17 antibody (D1(A12)). We are also collaborating on the design and synthesis of a specific HSET inhibitor (the first of its kind) and further studies will identify whether this "hit" leads to a clinical candidate. PDAC has been labelled as being non-immunogenic, but studies in the CRI have demonstrated that stromal components generate local immunosuppression. Together, we will develop clinical strategies to overcome this. Cachexia is a significant clinical feature in PDAC and may be linked to the stromal reaction, which has enabled us to discover biomarkers of cachexia. We aim to validate these in the clinic, to monitor treatment and possibly identify new therapeutic strategies. We are developing new approaches to clinical trials, using Bayesian techniques to guide clinical design. This, linked to intensive pharmacodynamic studies, including novel non-invasive imaging approaches, in our Early Phase trials will improve the translation of scientific discoveries to routine clinical practice.


Research activity codes: 5.1 PHARMACEUTICALS;5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Stem cells and cancer
Funder: Cancer Research UK

Abstract: Every organ harbours adult stem cells which have the potential for long-term replication, together with the capacities of self-renewal and multi-lineage differentiation. These stem cells function in tissue homeostasis and contribute to regeneration in response to injury. In addition, many cancers are caused by transforming mutations occurring in tissue-specific stem cells. The JNK family of mitogen activated protein kinases and the DNA damage kinase ATM (Ataxia Telangiectasia Mutated) are essential mediators of transcriptional control and maintenance of genomic integrity in eukaryotic cells. Our major focus is the elucidation of the molecular mechanism of JNK and ATM kinase signalling and to understand their function in stem cells and cancer.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Novel approaches to targeting RAS oncogene signaling in cancer
Funder: Cancer Research UK

Abstract: Our focus is on characterisation of molecular mechanisms involved in tumorigenesis by RAS oncogenes with a view to identifying novel therapeutic strategies for RAS mutant cancers. Principal achievements have been: - We completed a series of large-scale functional genomic screens for unique dependencies of RAS mutant cancer cells. These have highlighted a number of vulnerabilities of RAS mutant cells, in particularly dependence on the function of the transcription factor GATA2, the origin of DNA replication complex protein CDC6 and, in the case of cells that have undergone epithelial mesenchymal transition, the transcriptional regulator SNAIL2. - One of these hits, GATA2, has been investigated in detail, both in vitro and in vivo. RAS mutant cells show non-oncogene addiction to pathways in the GATA2 regulated transcriptional network, in particular the proteasome, NF-κB and RHO signaling. Genetic removal of GATA2 blocks RAS induced tumour formation in a mouse lung cancer model and also causes marked regression of established tumours. Similarly strong inhibition of tumour maintenance can be achieved through inhibition of GATA2 pathways using clinical inhibitors of the proteasome and RHO kinase. - We also investigated dependencies of RAS mutant lung cancer cells using a drug library screen. This revealed dependencies of RAS mutant cells on both MEK and insulin-like growth factor receptor (IGF1-R) signaling input. We have established that direct RAS activation of the catalytic p110α subunit of PI 3-kinase relies on coordinate input from IGF1-R via IRS1/2 and p85, suggesting the potential of combination therapy with MEK and IGF1-R inhibitors. - We have created an inducible mouse model in which we can assess the need for the RAS binding domain (RBD) of p110α in the maintenance of RAS driven lung tumours. In an established lung tumour, removal of the ability of p110α to interact with RAS causes long-term tumour stasis, but only partial regression, which is somewhat improved by combined MEK inhibition. - We have investigated the function of the RBD of p110ß, the other ubiquitously expressed type I PI 3-kinase isoform. This does not interact with RAS, but rather with the RHO subfamily protein RAC. We map out a pathway from G protein coupled receptors (e.g. for LPA, S1P) via Gßγ to DOCK/ELMO, RAC and p110 ß. Through the creation of p110ß RBD mutant mice, this interaction is shown to be important in fibroblast motility in vivo and PTEN loss induced tumourigenesis. _x000D_


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: TGF-beta superfamily signalling in early vertebrate development and cancer
Funder: Cancer Research UK

Abstract: The TGF-ß superfamily of growth and differentiation factors comprises the TGF-ßs, Nodal, Activin, BMPs and GDFs. These ligands play pivotal roles in early vertebrate embryos in the specification and patterning of the germ layers and in organogenesis, and misregulation of TGF-ß, BMP and Nodal signalling drives both tumour development and metastasis of many human cancers. The goal of our work is to understand the molecular machinery that transduces signals from TGF-ß superfamily receptors to the nucleus to regulate transcription, to determine how these pathways are regulated in both normal physiological contexts and are deregulated in pathological contexts, and to define their functional roles in vertebrate development and cancer. The work in this proposal represents an integrated project that addresses TGF-ß superfamily signalling at each of these levels. Our experimental approach combines the use of in vitro tissue culture models and in vivo systems with bioinformatics, computational modelling and biochemical analysis._x000D_ We propose to dissect the intracellular pathways downstream of the TGF-ß superfamily receptors, focusing on elucidating the mechanism of action of components we have previously identified, in particular, the E3 ubiquitin ligases, Arkadia and TIF1gamma and to use siRNA screens and proteomic approaches to find novel players. Downstream we will exploit our Xenopus and zebrafish developmental systems, cell culture and tumour models to determine the importance of novel components/regulators in vivo, and potentially identify new therapeutic targets. To determine how TGF-ß superfamily ligands regulate transcription through the remodelling of the chromatin template we will use a combination of ChIP-seq, RNA-seq and innovative mass spectrometry. Understanding the dynamics of TGF-ß superfamily signalling is crucial for predicting how cells will respond to ligands in complex physiological and pathological contexts. TGF-ß superfamily ligands function in early development as morphogens, although how activity gradients are established and interpreted is controversial. Excessive ligand production is a feature of late stage tumours, but how cells respond in such conditions is not known. We will use transgenic zebrafish lines we have generated that contain Nodal and BMP reporters to determine how gradients of these ligands are established across fields of cells over time, and how these pathways interact with other signalling pathways to specify cell fate decisions, in particular, neural crest. We will use cell culture systems and early embryos, combined with mathematical modelling, to investigate the dynamics of signalling, and to determine how different strengths and duration of signal elicit distinct biological responses.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: The transformation-associated actions, the signalling network lessons and the intervention opportunities for the PKC superfamily.
Funder: Cancer Research UK

Abstract: We are working on developing a molecular understanding of how and when nodes within signal transduction networks that define transformed phenotypes, behave aberrantly in cancer. In understanding how particular nodes operate and the context of their operation e.g. their addictiveness in transformed cells, we can determine the value of intervention, and applying our detailed understanding of these signaling nodes facilitate development of interventions and biomarkers. Our laboratory’s contributions to this endeavour are principally at the discovery end of this spectrum seeking to understand signaling nodes and the opportunities for intervention (cancer biology), the liabilities (the physiological reliance that defines therapeutic index), the contextual network (informing on pharmacodynamic and predictive biomarkers – the personalised medicine agenda) and in the development of interventions. Our expertise in biochemistry and cancer molecular cell biology complements those of our collaborators contributing to these objectives. Within this research landscape our focus is on a family of protein kinases (the PKC superfamily), which individually are directly or indirectly implicated in cancer. Our work on these proteins concerns whether particular family members impinge on cancer pathophysiology and where they do, how they exert their actions, what the opportunities and realities of intervention are, and what specific and general signaling principles we can derive from our dissection of their operation.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Mechanisms and biology of the SRF network and Rho-actin signalling
Funder: Cancer Research UK

Abstract: The SRF transcription factor controls growth factor-inducible genes, and also functions as a global regulator of cytoskeletal gene expression. SRF controls transcription through two families of coactivators, the actin-binding MRTFs (MRTF-A/MAL and MRTF-B/Mkl2), which couple its activity to cytoskeletal dynamics, and the ERK-regulated TCFs (Elk-1, SAP-1, Net). Our recent work has implicated TCF-SRF signalling in sensitivity to mitogenic stimulation. We have also shown that MRTF-SRF signalling supports the motile and invasive behaviour of breast carcinoma and melanoma cancer cells in vivo and in vitro. We have shown that the G-actin binding RPEL motif controls activity of both the MRTFs and the Phactr proteins, a novel family of PP1 cofactors, and functions as a sensor of G-actin concentration. We propose that RPEL proteins provide a general mechanism coordinating cellular behaviour with the dynamics of the actin cytoskeleton. We will pursue two areas of research in this project. • Molecular mechanisms of SRF network regulation • Biology of the SRF network and Rho-actin signalling We will continue work on the mechanisms by which SRF dependent gene expression is controlled, aiming to use the transiently activate immediate-early gene response as a model for molecular analysis of transcriptional activation and shutoff. We will map MRTF and TCF cofactor recruitment to SRF targets genome-wide, identify the steps in transcription controlled by actin-MRTF interaction, and study how target genes differ in different cell contexts. In parallel we will investigate the role of the SRF network, particularly the TCF proteins, in cell proliferation and transformation, both in vitro and in transgenic cancer models. Our other programme focusses on the Rho-actin signal pathway, which controls the MRTF coactivators. There is revitalised interest in the role of actin in nuclear processes, but little is known about the molecular mechanisms involved. We will characterise the actin-based control of the MRTFs and Phactrs, and study their roles in cell motility and invasion. We will search for other actin-regulated proteins, and establish their relevance to motility and invasiveness. We will elucidate the role of Rho-actin signalling in cancer development and spread using appropriate in vivo models. Our aim will be to establish whether interference with SRF network activity or Rho-actin signalling represents a potential route by which to attack cancer invasion and metastasis. Work in the laboratory is supported by Cancer Research UK, the European Research Council, and fellowship funding from the EU, EMBO, and other research organisations.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Immunobiology Laboratory
Funder: Cancer Research UK

Abstract: In the recent past, the Immunobiology Laboratory has expanded on its finding that RIG-I detects 5’ triphosphate-bearing single stranded RNA to show that replicated virus genomes are the main component that is recognised by RIG-I in cells infected with RNA viruses. In addition, the lab built-up on its earlier discovery of the anti-fungal Dectin-1/Syk signalling pathway to show that another C-type lectin receptor specific for fungal cell walls, Dectin-2, similarly signals via Syk and contributes to DC activation by fungi. Both the Dectin-1 and -2/Syk signalling pathway instruct DC to induce the development of effector CD4+ Th17 cells that are important for immunity to fungi and extracellular bacteria. As an extension of this work, the lab has been studying additional C-type lectin receptors that signal via Syk. One of these, DNGR-1, is highly restricted in expression to CD8a+ DC and can be exploited for delivering antigens to this specialised subset of DC in mice in order to induce antigen-specific immunity or tolerance. DNGR-1 was further used by the lab as a marker to identify the hitherto elusive human equivalents of mouse CD8a+ DC, thus paving the way for potentially translating mouse experiments into human vaccines and immunotherapies. Finally, DNGR-1 was shown by the group to function as a receptor for dead cells that is able to bridge innate recognition of necrotic cells by DC to the induction of an adaptive immune response. The future plans of the Immunobiology Laboratory involve continuing to work on molecular pathways involved in DC activation, mapping DC heterogeneity and its functional implications across species, and trying to understand how signal integration by DC can regulate both immunity and tolerance to foreign or self antigens. It is anticipated that such studies will lead to the development of new strategies to target and activate or deactivate DC, thereby improving their use as tools for vaccination and immunotherapy in multiple clinical conditions.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: CANCER AND NEOPLASMS