NIHRDataInsights/HRCSData huggingface dataset:
Title: Molecular mechanisms in a C. elegans model of tumourigenesis
Funder: Worldwide Cancer Research

Abstract: "There are over 200 different types of cancer, but all manifestations of this disease feature inappropriate cell proliferation. During development, cells must stop proliferating and differentiate in order to assume appropriate specialized functions, and this balance between cell proliferation and differentiation is thought (along with the regulation of cell death) to lie at the heart of carcinogenesis. Model organisms offer great inroads to understanding the basic biology of cancer mechanisms because they are experimentally tractable, yet the majority of their genes are conserved in humans, thus knowledge gained will be immediately applicable to cancer research. In my laboratory we use the nematode worm C. elegans. We study the stem cell-like seam cells that go through a simple re-iterative pattern of asymmetric divisions during development, providing an excellent model system for studying genes that regulate the balance between cell proliferation and differentiation. Our recent work has firmly established the worm as a promising model system for studying the Runx/CBFβ cancer-associated genes, homologues of which in C. elegans (rnt-1 and bro-1) were identified as rate-limiting regulators of seam cell proliferation. My current AICR funded project set out to identify novel regulators of RNT-1/BRO-1 induced hyperplasia in our seam tumourigenesis model. The most significant outcome of this work is our identification of unc-62 and ceh-20 as novel “tumour suppressor” genes in our system. Given the human homologues of these genes (the interacting Meis and Pbx genes) and their links (like Runx/CBFβ) to stem cell cancers such as leukaemias, coupled with the fact that they operate in the RNT-1/BRO-1 pathway, makes them important candidates for further analysis. The specific topics this proposal seeks to address include detailed mechanistic analysis of CEH-20/UNC-62 induced tumour formation, expression of human CEH-20 /UNC-62 homologues in C. elegans and genome-wide tissue-specific ChIP-seq approaches to finding direct CEH-20/UNC-62 transcriptional targets."


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Regulation of Rac function by ubiquitylation
Funder: Worldwide Cancer Research

Abstract: "Cancer results from deregulated cell proliferation and cell migration (among other aberrations). The formation of distant metastases is the main cause of morbidity and mortality in patients with cancer. Understanding the mechanisms underlying migration of tumour cells is critical to developing new, more effective anti-cancer therapies. Rho-like GTPases are key regulators of cytoskeletal reorganization, cell motility, cell-cell and cellextracellular matrix adhesion, as well as cell cycle progression, gene expression and apoptosis. As such, they play a pivotal role in the regulation of cellular functions associated with malignant progression and metastasis. The activities of Rho proteins are regulated at multiple levels, including 1) Guanine nucleotide binding and hydrolysis, 2) subcellular localization, 3) modulation of expression levels, and 4) other regulatory events such as post-translational modifications that can affect the previous mechanisms We have detected a novel interaction between the Rho-like GTPase Rac1 and an E3-ubiquitin ligase which is stimulated by Hepatocyte Growth Factor (HGF)-signalling, a cytokine that is associated with epithelialmesenchymal transition and tumour cell migration. Further, our initial data suggest that this E3-ubiquitin ligase ubiquitylates Rac1 promoting its degradation. Moreover, our preliminary results show that overexpression of this particular E3-ligase increases epithelial cell migration. The aims of this proposal are: 1. To understand the role of Rac1 ubiquitylation by this particular ubiquitin ligase in the induction of cell migration using well established cell culture models (namely HGF and vSrc induced scattering of MDCKII cells). 2. To analyze the significance of this modification for tumour progression by examining expression of this particular ubiquitin ligase in human tumour cell lines and primary tumour specimens and by modulating its expression in human tumour cells and determining the effects on Rac levels/activity, and in turn on tumour cell motility and invasion."


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Mechanisms of NF1 Tumourigenesis
Funder: Worldwide Cancer Research

Abstract: "Neurofibromatosis Type-1 (NF1) is a common (1:3500) genetic disorder characterised by the development of benign Schwann cell tumours, which can progress to malignancy. Schwann cells are the glial cells of the peripheral nervous system and have remarkable regenerative capabilities. In the adult, they are quiescent, highly specialised myelinating or non-myelinating cells associated with axons, however, following nerve injury, Schwann cells downstream of the wound dedifferentiate to progenitor-like cells, which aid in the clearance and repair process. The injured state is associated with a robust inflammatory response, which resolves upon axonal regrowth and the Schwann cells then redifferentiate to restore the function of the nerve. In many ways, neurofibromas resemble injured nerves in that the Schwann cells are found in a proliferating progenitor-like state accompanied by large numbers of inflammatory cells and because of this are commonly referred to as unrepaired wounds. Previous mouse models for NF1 have shown that neurofibromas only form, if the NF1 gene is removed from Schwann cells at a precise developmental stage and it is unclear how relevant these models are to human tumour formation. We have developed a mouse-model in which we can selectively remove the NF1 gene from Schwann cells in the adult following tamoxifen injections. We find that this alone has no effect but when coupled to a nerve injury, the majority of the mice develop tumours. Remarkably, all tumours develop at the wound site, despite the Schwann cells dedifferentiating, with an associated inflammatory response, along the length of the nerve. Using this new mouse model together with complementary primary coculture systems, which mimic the organisation of peripheral nerves, we will determine how these signals cooperate to induce tumour formation. Moreover, we will use these parallel systems to identify new targets and test for new therapeutics for the treatment of these tumours."


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Contribution of tumour-associated lymphatic vessels towards tumour-stroma development and function
Funder: Worldwide Cancer Research

Abstract: There is a renewed interest in research that exploits and enhances the immune system to fight cancer instead of conventional cytotoxic drugs. While studies have proved successful in vitro, transition to the clinic has not lived up to expectation. One thought is that these failures arise as a consequence of a tumour’s formidable ability to create a protective microenvironment, to which our immune system in ineffective. Accumulation of non-cancerous cells in the tumour leads to the formation of tumour stroma network. We do not fully understand how the stroma promotes tumour development, but fibroblasts within the tumour assist invasion via MMP secretion and deposit collagen to provide structural support. Lymphatic vessels within the stroma at the tumour site drain fluid and proteins from leaky blood vessels, and act as escape routes for disseminating tumour cells, but also connect the tumour to our immune system. Therefore, the questions arise as to how, although there is a functional connection to our defences, can the tumour manage to avoid immune destruction? What is so special about the tumour site? Recent evidence suggests melanomas develop a stroma with features common to the specialized stroma of the lymph node (where immune system decisions are made) and may help to switch off the anti-tumour immune response. Remarkably, this "lymph node-like" tumour stroma also shares typical lymphatic markers. Such specific functional and phenotypic similarities between the tumour lymphatics, stroma and the lymph node point to a unique, co-operative relationship between lymphatic vessels and stromal cells in defining the tumour-immune repertoire and ultimate tumour fate. Using in vivo and complementary tissue-engineered in vitro models, this proposal aims to determine how the tumour microenvironment, with particular reference to the effects of lymphatic drainage on the stromal compartment, functions to promote a non-effective immune response and tumour progression.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Characterisation of JMJD2B and JMJD1A in estrogen receptor regulation and breast cancer.
Funder: Worldwide Cancer Research

Abstract: "The importance of the estrogen receptor (ER) in breast cancer development make it a prominent target for therapy. Current treatments, however, have limited effectiveness hence the definition of new therapeutic targets is vital. The ER is a member of the nuclear hormone receptor super-family of transcription factors that requires co-regulator proteins for complete regulation. Aberrant activity of co-regulators has been postulated to result in failure of ER-targeted therapies. Histone methyltransferase (HMT) and demethylase (HDM) enzymes play an important role in transcriptional regulation. Although emerging evidence has implicated a small number of these proteins within the ER signalling cascade, our understanding of the function of the 50 HMT and 27 HDM enzymes in receptor regulation remains limited. By examining the role of each member of the HMT and HDM families in ER signalling we hypothesised that we would identify novel regulators of the receptor that may constitute new therapeutic targets. To this end, we applied an unbiased and comprehensive HMT/HDM siRNA library screen in MCF-7 breast cancer cells to identify additional HMT and HDM enzymes that were important for ER control. We identified the demethylase enzymes JMJD1A and JMJD2B as regulators of ER-mediated transcription. In this study we plan to extrapolate these preliminary findings and perform the following experiments: i. Characterise the role of JMJD1A and JMJD2B in regulating ER expression and activity using RNAi-rescue experiments combined with chromatin immunoprecipitation (ChIP) and gene expression profiling. ii. Assess interplay between JMJD1A and JMJD2B in controlling ER activity using reporter, immunoprecipitation and ChIP-Seq experiments. iii. Examine the role of JMJD1A and JMJD2B in additional cell line-models of breast cancer to provide more robust translational validation of these enzymes in breast cancer development. Ultimately, these studies have the potential to validate JMJD2B and JMJD1A as novel targets for breast cancer therapy."


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Identifying Combination Therapies to Overcome Resistance in Melanoma Skin Cancer
Funder: Worldwide Cancer Research

Abstract: "The MAP-kinase pathway consisting of RAF, MEK and ERK is deregulated in over 90% of melanoma skin cancers. Last year a novel inhibitor targeting the oncogenic RAF kinase V600E-BRAF in melanoma patients demonstrated an unprecedented 80% anti-tumour response. However, acquired resistance occurs rapidly through various and partially unknown mechanisms Hence, there is need for a better understanding of resistance mechanisms in order to identify alternative ‘druggable’ targets. Improved approaches can then be based on the combined inhibition of such targets and the MAP-kinase pathway. We have discovered a novel mechanism of resistance to MAP-kinase pathway inhibition that involves the transcription factor PAX3 and its target MIcrophthalmia-Transcription-Factor (MITF). Most importantly, targeting the MAP-kinase-kinase MEK in combination with PAX3 or MITF induces synergistic cytotoxicity, suggesting that this combination is a good rationale for killing melanoma cells. But, although effective MEK inhibitors are currently tested in the clinic, targeting transcription factors is difficult. We therefore propose to identify regulators of PAX3 -and hence MITF- expression that can be readily targeted by small-molecule inhibitors. We will perform an expression screen for regulator kinases (using a kinome-siRNA library) and for approved drug targets (using an FDA approved drug library). PAX3 and MITF expression can be assessed simultaneously as the readout is immunofluorescence based. To reduce the number of false positives, only hits regulating both, PAX3 and MITF will be further analysed for combinatorial cytotoxicity with MEK inhibition. For this a functional screen will be performed in a ‘combinatorial-effect’ sensitive melanoma cell line and a resistant clone (stably over-expressing MITF), allowing highly stringent selection. Identified hits will be further characterised for their synergistic function in vitro. Furthermore, the combinatorial action of identified candidates on MEK inhibition will be tested in vivo in a potent zebrafish model for melanoma, which will allow assessing novel combination therapies."


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: How does the microbiome of the hypochlorhydric stomach promote gastric tumourigenesis?
Funder: Worldwide Cancer Research

Abstract: <p>Gastric cancer is a common and life threatening malignancy and most cases develop as a consequence of chronic <em>Helicobacter pylori</em> infection. Cancers of the stomach arise via a series of premalignant stages, including gastric atrophy. This latter condition is characterised by a loss of acid-secreting parietal cells, which results in&nbsp;elevated gastric pH (hypochlorhydria). Recent murine studies have suggested that additional microorganisms colonise the stomach when acid secretion is impaired and that these bacteria act as cofactors to promote the development of gastric cancer. However, other conditions which are associated with reduced gastric acid secretion, such as longterm acid suppressing drug use are not associated with gastric cancer development in the same way. We therefore hypothesise that specific changes occur in the gastric microbiome in association with <em>H. pylori</em> associated gastric atrophy and that these act as cofactors to promote gastric cancer development in susceptible individuals. We therefore propose to investigate the gastric microbiome using 16S rDNA sequencing in a well established and validated transgenic mouse model in which gastric cancer develops as a result of chronic <em>Helicobacter </em>infection. In addition we will analyse the microbiome present in gastric biopsy samples that have already been collected from well characterised cohorts of human patients who have reduced gastric acid production due to a variety of causes (<em>H. pylori</em> infection, medication or autoimmune). We anticipate that these studies will lead to the development of specific microbial biomarkers that are associated with gastric cancer development. These may have future clinical utility for relatively non-invasive screening of individuals who are susceptible to developing gastric cancer. In addition, we will test the efficacy of one antibiotic and one probiotic strategy (the details of which will be determined by the results of our sequencing studies) for reducing susceptibility to <em>Helicobacter-</em>induced gastric cancer in mice.</p>


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Personalised Targeted Nanocapsules for Combinatory RNAi and Cancer Radiotherapy
Funder: Worldwide Cancer Research

Abstract: <p>Typical current radiotherapy approaches use external beam strategies that require a given beam to pass through surrounding healthy tissue before reaching the tumour, thus resulting in an unwanted irradiation of healthy cells. Current licensed therapies use beta emitters. It has been estimated that if properly delivered an alpha or Auger-electron emitter is up to 20 times more effective than beta emitters. Early clinical trials are exploring the use of antibodies for targeting purposes but are essentially limited by the number of radionuclides that may be attached to the antibody. This research programme focuses on the preparation and radio toxicity studies in cancer cells <em>in vitro </em>&amp;<em>&nbsp;</em> in tumour-bearing mice <em>in vivo</em>. The nanocapsules seal in their interior a therapeutic radio isotope. After sealing the chosen radionuclides, the external walls of the nanocapsules (closed-ended filled nanocapsules) will be decorated with biomolecules to render them biocompatible &amp; for targeting purposes. Concurrent delivery of therapeutic siRNA will be achieved via nanocapsule-mediated delivery by complexation of siRNA to the cationic surface of the nanocapsule. RNAi is expected to render cancer cells more susceptible to radiotherapy by silencing genes responsible for either resistance to radiotherapy or for cancer cell replication.These nanocapsules allow the delivery of unprecedented radio-dosage (through the carbon wall) &amp; remain stable for extended periods thus guaranteeing essentially zero leakage of the radionuclides. Surface functionalisation of these nanocapsules offers versatility towards modulation of tissue biodistribution of the radioemitting crystals in a manner determined by the nanocapsule that delivers them. Furthermore, combinatory RNAi approach will work in synergy with radiotherapy. Nanocapsule stability, selective tumour targeting and combinatory RNAi therapy could minimise radio-toxicity in healthy tissues &amp; its associated side effects. The present research objectives go beyond the-state-of-the art in the field &amp; innovative solutions are expected.</p>


Research activity codes: 5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Development of a novel pro-angiogenic approach for cancer therapy
Funder: Worldwide Cancer Research

Abstract: <p>&nbsp;&nbsp; &nbsp; &nbsp;&nbsp;Angiogenesis, the formation of blood vessels from pre-existing ones, is essential for cancer growth. Our laboratory focuses on the molecular basis of tumour angiogenesis (<strong>eg., L. Reynolds <em>et al.,</em> <em>Nature Medicine</em>, 2002; L. Reynolds et al., <em>Nature</em>, 2010) </strong>and we have come to realize that the current paradigms which drive anti-angiogenic therapy may be flawed. Unfortunately, current anti-angiogenic approaches, although very promising, require a great deal of refinement before they can become a reliable strategy for cancer treatment. Important limitations of anti-angiogenic strategies include: (1) reduced chemotherapeutic delivery to tumour cells, (2) evasive resistance to therapy and (3) serious adverse side effects. Thus we hypothesise that a pro-angiogenic approach, that increases tumour blood vessel density, in combination with chemotherapy, could be an effective anti-cancer regime.</p> <p>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; We have published previously that low doses of beta3-integrin inhibitors can enhance tumour angiogenesis (<strong>A. Reynolds et al., <em>Nature Medicine</em>, 2009)</strong><strong>.</strong> <strong>Here </strong><strong>we provide compelling preliminary evidence that enhancing tumour angiogenesis, in combination with chemotherapy, actually results in inhibiting tumour growth significantly.</strong>&nbsp; In addition, this approach is sufficient to significantly extended survival with no apparent side effects to date. Our data provide proof-of&ndash;principle that, paradoxically, using a pro-angiogenic approach may have anti-cancer value.</p> <p><strong>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; We propose to:</strong></p> <p><strong>1. Validate the efficacy of combined pro-angiogenic therapy in mouse models cancer. </strong></p> <p><strong>2. Determine the effects of combined therapy on tumour angiogenesis, immune responses, drug delivery, hypoxia and any possible side effects.</strong></p> <p><strong>3. Elucidate the combined effects of these drugs on endothelial cells and tumour cells <em>in vitro</em>. </strong></p> <p>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; The ultimate goal of our work is to test the efficacy and safety of using pro-angiogenic approaches, in combination with chemotherapy, in cancer models, with the long-term hope of taking this type of therapy into clinical trials for the treatment of human cancer.</p>


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Identification of genetic modifiers of age-at-onset and cancer risk in Lynch Syndrome
Funder: Worldwide Cancer Research

Abstract: <p>We will capitalize on our unique resource, comprised of international sample sets of mutation carriers, in order to identify novel genes interacting with DNA mismatch repair (MMR) genes. Lynch Syndrome (LS) is the most common autosomal dominant genetic disorder resulting in cancer (population carrier frequency &gt;1:3000) and is due to loss of function mutations in MMR genes. We estimate the annual cancer burden attributable to germline MMR gene mutations is 1,800 in the UK and 26,000 in Europe. Intensive GI, gynaecological and urinary tract surveillance is recommended for carriers. Although penetrance is high, there is wide variation in age at onset of cancer (AAO). The ability to predict AAO would provide invaluable clinical information to guide surveillance protocols and even potentially prophylactic surgery. We aim to identify common genetic variants influencing AAO and cancer risk in LS patients who are MMR mutation carriers. We have collected a large high quality UK-based sample and data resource. This, combined with samples from our international collaborations, means we have assembled an internationally unparalleled resource of LS samples (with MMR mutations) and affiliated data (n~8,100). Capitalising on our GWAS analyses of sporadic colorectal cancer, we will construct a custom genotyping array (enriched for SNPs influencing cancer AAO) and genotype 2,500 affected carriers in the discovery phase to test for associations with AAO, followed by replication/validation phases. We will conduct bioinformatic interrogation of regions that we discover to influence AAO to gain new biological insight into genes interacting with DNA mismatch repair genes. We would also test such modifier loci for association with colorectal cancer risk in the general population using very large sample sets at our disposal. The proposed research would have direct translational value since we will develop, and validate, age-specific risk prediction algorithms, for use in clinical management of Lynch Syndrome.</p>


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS