NIHRDataInsights/HRCSData huggingface dataset:
Title: Identification of novel tumor suppressors in CEBPA mutant AML
Funder: Worldwide Cancer Research

Abstract: "Cancer stem cells are emerging as fundamental to the maintenance, dissemination and relapse of malignant tumors. Importantly, by virtue of their position at the top of the cellular hieracy of the tumor, isolation and characterization of CSCs can yield important information about the deregulation of gene expression required for malignant transformation. We have previously generated highly accurate models of human acute myeloid leukemia (AML) with mutations in the CEBPA gene, and used these to identify genes that are commonly down-regulated in myeloid leukemia initiating cells (LICs), the term commonly used for CSCs in this disease. These genes were identified through comparison of the gene proflies of Cebpa mutant and MLL-AF9 expressing myeloid-committed LICs. In the present project we will use systematic shRNA-mediated knockdown of these down-regulated genes to identify those whose suppression accelerates disease development. In this manner we hope to identify novel tumor suppressors in AML, the knowledge of which will improve our understanding of how ectopic self-renewal is instilled in malignant cancer cells, as well as our ability to develop rational therapeutic strategies against myeloid leukemias."


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Development of the next generation cancer models using high fidelity ZFN technology
Funder: Worldwide Cancer Research

Abstract: "Development of faithful disease models is a critical step towards understanding the biology and underlying mechanisms of the diseases. While a significant amount of effort has been made in the past decades to develop models for studying cancer, the resultant models suffer from various pitfalls that significantly impede the progress in understanding the transformation mechanisms and the development of effective therapeutic strategies for the diseases. The most common and major problems associated with the current models, including non-physiological level of expression of the candidate genes in large number of cells and/or inappropriate cell types, lead to deceitiful and even sometimes wrong models that do not recapitulate the corresponding human diseases. Using MLL (mixed lineage leukaemia) leukaemia as a proof of principle study, the primary aim of this project is to develop much-improved next-generation MLL leukaemia models. This will be achieved by a highly innovative approach which combines high fidelity zinc finger nuclease genome editing technology with a non-integrating lentiviral transduction/transplantation approach, which will allow expression of MLL fusions under the endogenous MLL promoter in a small number of functionally and phenotypically defined population of primary haematopoietic stem/progenitor cells derived from either murine or human tissues. The next-generation MLL leukaemia models will not only represent a cheaper and quicker alternative to the conditional knockin approaches but will also bypass the current technical shortfalls associated with the knockin and the most commonly used viral transduction/transplantation approaches. Thus we reason that the novel models will act as a paradigm for next-generation cancer modeling, which will improve our understanding of the biology of the diseases and facilitate the future development of more effective therapeutics."


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Crosstalk between oncogenic BRAF and TGF-ß signalling during tumourigenesis
Funder: Worldwide Cancer Research

Abstract: "TGF-β acts as a tumour suppressor in normal epithelial cells and during early stage tumourigenesis. During malignant progression some tumours switch their response to TGF-β and paradoxically utilise this factor as a potent promoter of disease but the mechanistic basis for this is poorly understood. Consequently defining how, when and where TGF-β acts in a pro-tumourigenic fashion is pivotal to both the design and implementation of TGF-β targeted therapy. Our studies have revealed that V600E mutation of BRAF, a frequent driving mutation in human cancer, diverts TGF-β from inhibiting to promoting cell proliferation. Mechanistically, autocrine TGF-β signals through activin like kinase 5 (ALK5) to suppress p21 accumulation and enable anchorage-independent growth in vitro and xenograft tumour growth in vivo. Using small molecule inhibitors of ALK5 we find that BRAF mutant human tumour cell lines are dependent on ALK5 regardless of the tissue of origin. It is the aim of this application to build on these initial observations in vitro and to investigate the consequence of ALK5 inhibition in vivo using recently established mouse models of BRAFV600E driven tumourigenesis. We will take both pharmacological and genetic approaches using an ALK5 specific kinase inhibitor and targeted conditional deletion of ALK5 in “state of the art” mouse models of Braf driven melanomagenesis and serrated colorectal cancer. These studies will provide important mechanistic insight into the crosstalk of TGF- β and BRAF during tumourigenesis, test the potential of targeting TGF-β signalling as a therapy for BRAF driven disease and aid in the development of biomarkers for essential stratification criterion for the use of anti- TGF-β therapeutics for cancer treatment."


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Targeting the oncogene ALK is efficacious in the treatment of high-risk neuroblastoma
Funder: SPARKS

Abstract: Neuroblastoma is the most common solid tumour of childhood. 50% of high-risk cases of neuroblastoma remain refractory to conventional treatment. Several genes are altered in neuroblastoma, including the anaplastic lymphoma kinase (ALK) gene. Our laboratory has created the first genetically engineered cancer model of high-risk neuroblastoma in which ALK is over-activated. These models are an important resource to understand how ALK functions to stimulate growth of neuroblastoma. Most importantly they provide a reliable model in which to carry out pre-clinical drug trials of specific inhibitors of ALK to identify new agents to be taken forward into clinical trials.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Preclinical evaluation of novel MDM2/p53 inhibitors in neuroblastoma
Funder: SPARKS

Abstract: Background: New treatments are needed to improve outcome for patients with high-risk neuroblastoma. DNA damaging chemotherapy acts via the p53 pathway inducing apoptosis in tumours with wild-type p53. p53 is a tumour suppressor gene and transcription factor inducing many genes, including its own regulator, MDM2 which then binds to p53 and degrades it forming a negative feedback loop. The p53 pathway can be activated using inhibitors of the MDM2/p53 interaction. These are most effective if p53 is wild-type as it is in most neuroblastomas at diagnosis and relapse. Aims: 1) To test novel MDM2/p53 antagonists in wild-type p53 neuroblastoma cell lines and control paired cell lines with mutant p53 2) To determine whether novel MDM2/p53 antagonists synergise with conventional chemotherapy 3) To study selected MDM2/p53 inhibitors in animal models of neuroblastoma before entry into clinical trials Plan of investigation: Year 1 Evaluate growth inhibition and p53 pathway status of wild-type p53 neuroblastoma cell lines treated with MDM2/p53 inhibitors +/- conventional chemotherapy Year 2 Evaluate the effectiveness of MDM2/p53 inhibitors in reversing multi-drug resistance in p53 mutant cell lines Year 3 Test selected inhibitors in animal models and take a clinical trial candidate forward into Phase I study


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Enhancing anti-GD2 immunotherapy for neuroblastoma by manipulating Fc gamma receptors
Funder: SPARKS

Abstract: Neuroblastoma is one of the commonest childhood tumours and accounts for 15% of childhood cancer deaths. In the majority of children the tumour has spread by the time of diagnosis, resulting in poor treatment success despite intensive, highly toxic, conventional therapies. Anti-GD2 antibody therapy offers a more tumour-specific treatment and has been shown to improve survival. However, it does not cure all children, and many children still die from their disease. This project aims to identify new ways of improving anti-GD2 therapy, such that the antibody more effectively engages the immune system to kill neuroblastoma cells.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Targeting ErbB4 to treat metastatic Ewing's sarcoma
Funder: SPARKS

Abstract: We have identified that ErbB4, a known growth-promoting protein, drives survival of metastases (tumours that have spread) in the high-risk childhood cancer Ewing sarcoma. ErbB4 is upregulated in metastatic and chemoresistant tumours, and is also mandatory for cell survival, growth, and tumour cell invasion. We have demonstrated that blocking ErbB4 dramatically reduces the metastatic potential of Ewing sarcoma cells, and sensitizes metastatic/chemoresistant Ewing sarcoma cell lines to standard forms of chemotherapy. We now propose to test the effect of two novel drugs to target ErbB4, namely i) specific antibodies that block ErbB4, and ii) an irreversible chemical inhibitor of ErbB4.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Could signalling between placenta and fetus provide a first hit for childhood leukaemia?
Funder: Children with Cancer UK

Abstract: Childhood leukaemia is thought to occur in two stages. The first may occur within the womb. We have discovered a new mechanism for how a baby might be damaged during pregnancy, and now wish to test whether this could explain the first stage of childhood leukaemia. In human pregnancy, there is barrier in the placenta separating the baby’s and mother’s blood. We have found that chemicals, toxic particles or altered oxygen cause laboratory models of this barrier to secrete substances that damage the DNA of human cells on the other side (i.e. potentially on the baby’s side). Similar effects were seen in experimental mice models and using human placenta. We now wish to test whether these signals from human placenta can cause DNA damage and chromosome aberrations in human fetal blood cells and whether this damage is similar to that observed in childhood leukaemia. We wish to test at which stage of development the blood cells might be damaged and whether damage leads to altered cellular function of the kind that is associated with leukaemia. We will test whether altering a naturally protective mechanism in cells (autophagy) could influence this process, thereby allowing a new concept towards therapy.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Development of novel chemical therapies against the paediatric form of human craniopharyngioma
Funder: Children with Cancer UK

Abstract: The main goal of the proposed research is to develop novel therapies for treatment of childhood craniopharyngioma (adamantinomatous craniopharyngioma, ACP), a devastating rare childhood brain tumour. Recent research from my lab has led to the generation of a mouse model that develops very similar tumours to those seen in children with ACP. This mouse model is a unique resource to identify and test novel therapies for these aggressive tumours.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Optimisation of the use of L-Asparaginase and Dexamethasone in childhood Acute Lymphoblastic Leukaemia
Funder: Children with Cancer UK

Abstract: Current therapies for childhood acute lymphoblastic leukaemia are intensive. Dosing of drugs is standardised to a uniform mg/m2. This does not account for the wide variability with which each child metabolises drugs. Thus therapy can be suboptimal in some, resulting in disease recurrence. In others, reduced drug clearance may result in excessive toxicities. Our research proposes to identify such individuals so that we may tailor therapy. In Newcastle we have over 10 years experiences in carrying out therapeutic drug monitoring approaches, working with nurses and clinicians in clinical centres to individualise the treatment of children with cancer. In this project we seek to obtain a better understanding of the individual variability and potential synergy of three key antileukaemic drugs: dexamethasone, L-Asparaginase and methotraxate.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Assessment of [131I]MIBG in combination with cytotoxic drugs for neuroblastoma therapy
Funder: Children with Cancer UK

Abstract: [131I]MIBG is highly specific for its tumour target. It is at least as effective as other treatments for neuroblastoma but is not associated with gut toxicity or hair loss. Although [131I]MIBG has generated long-term remissions its applciation has not resulted in cure of advanced disease nor has any other treatment. We hypothesise that optimal benefit will be gained by combining [131I]MIBG with drugs which overcome the resistance of tumours to radiation. In this project we aim to make the most effective use of a potent new version of [131I]MIBG by combination with drugs which prevent cancer cells' ability to repair radiation damage.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Preclinical testing of FGFR inhibitors for the treatment of Rhabdomyosarcoma
Funder: Children with Cancer UK

Abstract: Our aim is to improve the outcome of patients with rhabdomyosarcoma (RMS). Little progress has been made using standard cytotoxic agents in the last 20-30 years, particularly for recurrent and metastatic disease. Molecular evidence supports Fibroblast Growth Factor Receptors (FGFRs) as a therapeutic target in RMS and testing of agents, alone or in rational combinations, that have been used in the adult setting represents the best way to rapidly introduce novel treatments for children. It has been agreed at an International consensus meeting that targeting FGFR is an important goal to cure more children with Rms The aim of this project is to provide preclinical evidence to support a novel therapeutic approach for patients with RMS using specific FGFR inhibitors. The study will also identify biomarkers to support their clinical testing.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Combinatorial targeting of ALK for neuroblastoma immunotherapy
Funder: Children with Cancer UK

Abstract: This research aims to improve on current immunotherapy for neuroblastoma in terms of improving efficacy and reducing toxicity. We will generate reagents for targeting an alternative neuroblastoma surface molecule called ALK. ALK is present on the surface of neuroblastoma cells from most patients with the disease but absent from normal cells so we do not expect that effective targeting of ALK will result in toxicity as is seen with current antibody-based treatment. Moreover, we have available new small molecule drugs to target ALK and will test whether the comination of these drugs with immunotherapy will be effective.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Combination treatments to drive neuroblastoma tumour differentiation and senescence
Funder: Children with Cancer UK

Abstract: Many neuroblastoma tumours are intractable and cure rates remain too low. Our goal is to provide a better understanding of how phosphatases control neuroblastoma cell biochemistry and to harness this knowledge for therapeutic gain. Having recently demonstrated cytotoxicity by inhibitors of phosphatases in neuroblastoma cells, we now aim i) to prove that these inhibitors are effective under physiological conditions, and ii) to identify their key biochemical targets. Specifically, by understanding the biochemical detail of how phosphatase inhibitors suppress neuroblastoma cell growth, we will provide a unique opportunity to exploit the potential of these novel biochemical pathways and generate new therapeutic paradigms


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: The clinical importance and prognostic relevance of cellular heterogeneity in precursor B cell acute lymphoblastic leukaemia
Funder: Children with Cancer UK

Abstract: The treatment for childhood acute lymphoblastic leukaemia (ALL) is arduous with many complications; overall 20% of patients die. In survivors, the toxicities of treatment can leave serious problems Minimal residual disease (MRD) cells are responsible for deaths - we believe their unique biological properties make them resistant to conventional chemotherapy. Our work offers a totally new way of looking at these cells and may help us develop new drugs to efficiently kill them. We will evaluate a series of children and teenagers with B-ALL to see if we can better define the features of MRD cells. We will compare the different types of cell present at diagnosis with those remaining after chemotherapy (MRD) and those present when patients relapse. Because we will study sequential samples from individual patients, we can directly compare the effects of standard treatment on MRD cells.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: The role of Nrf2 in protecting AML cells from chemotherapy-induced apoptosis
Funder: Worldwide Cancer Research

Abstract: "Acute myeloid leukemia (AML) is one the most common malignant haematopoietic disorders in adults with 75% of patients diagnosed after the age of 60 and current intensive chemotherapeutic strategies generally limited to a minority of younger, fitter patients there is a significant need for better tolerated anti-AML chemotherapy. We have recently highlighted the transcription factor NF-E2 related factor 2 (Nrf2) as one of the cancer cell survival pathways highlighted by inducing cytoprotective and detoxification genes which protect cancer cells from apoptosis. We hypothesise that in AML, high basal Nrf2 activity induces high cytoprotective and detoxification gene expression that protects cancer cells from undergoing apoptosis in response to current and new chemotherapeutic drugs. Therefore we shall: (1) Determine the function of Nrf2 in resistance of AML cells to current and new chemotherapeutic drugs; (2) Elucidate the mechanism that control elevated Nrf2 expression and activation in AML patient samples, and (3) Understand the role of reactive oxygen species in regulating Nrf2 in AML. The role of Nrf2 in AML samples will be examined by nuclear expression of Nrf2 in AML patient samples comparing to non-cancerous control samples. We will fully dissect the mechanisms by which constitutive Nrf2 is present in AML cells, by examining for mutations present in either KEAP1 or Nrf2 and also investigate the promoter of Nrf2 to determine if there is a problem with its de novo expression. We will also determine the role of cellular reactive oxygen species in regulating both constitutive and drug-induced Nrf2 activition in human AML. These studies will identify the role of Nrf2 in resistance of AML cells from current and new chemotherapeutic drugs. These data may pave the way for the development of Nrf2 screening and more targeted drug therapies to combat AML"


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Regulation of cancer cell pH by stromal fibroblasts: studies of novel cancer-stroma interactions
Funder: Worldwide Cancer Research

Abstract: "Regulation of intracellular pH (pHi) is a fundamental homeostatic mechanism. Cells must defend their acid/base balance from disturbances, such as the respiratory production of CO2 and lactic acid, in order to maintain a pHi that is conducive for growth and function. Removal of excess acid (or base) typically involves transport-proteins that transfer H+ ions (or their equivalents, e.g. HCO3− ions) across cell-membranes, followed by diffusion of the acid/base disturbance towards blood-capillaries for venting. Tumours need sophisticated regulatory mechanisms to overcome inherent challenges to pHi control, arising from elevated respiration and inadequate blood-perfusion. Most of the research on tumour pHi-regulation has focused on cancer cell mechanisms Little is known about the role of stromal fibroblasts. These have been shown to support cancer cells through metabolic coupling, growth factor-mediated crosstalk and matrix remodelling. We propose to study the role of fibroblasts in regulating cancer cell pH using fluorescence imaging for pH in 2-D monolayer and 3-D spheroid co-culture. Our pilot data suggest that the pHi-regulatory phenotype in fibroblasts is considerably different to that of cancer cells. This complementarity may give rise to unique fibroblast-cancer cell interactions that benefit cancer cells. We propose that membrane-bound acid-loaders in combination with gap junctions produce a highly-buffered fibroblast-syncitium for absorbing cancer cell acidity. This arrangement also protects the extracellular milieu from excessive acidification. We propose that low intracellular carbonic anhydrase activity in fibroblasts improves extracellular CO2 venting away from cancer cells. Slow cytoplasmic CO2 hydration kinetics reduce the degree of CO2 ‘trapping’ inside cells, in the form of poorly membrane-permeant ions (HCO3− and H+). We aim to identify fibroblast-cancer cell interactions that may be critical for improving pH control in cancer cells. Their unique setting in tumours may provide novel targets for drugs, complementing current efforts aimed primarily at cancer cells."


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