NIHRDataInsights/HRCSData huggingface dataset:
Title: Functional characterization of Sox2-p27 interactions in normal and cancerous stem cells
Funder: Worldwide Cancer Research

Abstract: Cancers display remarkable phenotypical and functional intratumoral heterogeneity. The discovery of a subpopulation of cancer cells with stem cells properties (cancer stem cells, CSCs) in several malignancies has profound implications for cancer therapy as these cells are postulated to be responsible for the origin, progression and recurrence of the cancers. It has been observed that some CSCs derive from tissue stem cells (SCs). It is therefore very important to understand differences and similarities between SCs and CSCs to be able to use the former in regenerative medicine, and target the latter to fight cancer. The Stem Cell Factor SOX2 and the Cell Cycle Regulator p27 are essential transcription factors in processes during embryonic development and in the regulation of stem cells in multiple tissues including pituitary and brain. We have recently shown that there is genetic interaction between them where Sox2 haplo-insufficiency rescues some aspects of the p27 null phenotype. In particular, the incidence of pituitary tumors in Sox2+/-; p27-/- animals is greatly reduced compared to p27-/- ones. We hypothesize that the SOX2-P27 interaction may regulate the balance between quiescence and proliferation in normal SCs and is involved, if altered, in the transformation into CSCs. The goals of this translational research project are characterize the role of SOX2-p27 pathway in the regulation of neural and glioma stem cells, determine their function in pituitary adenomas and investigate the clinical relevance of SOX2-p27 in glioblastoma pathobiology. To achieve our aims, we will generate a unique set of cellular and animal models to study in vitro and in vivo the biology of pituitary, neural and glioma stem cells.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Pre-clinical drug validation in acute lymphoid and myeloid leukaemia
Funder: Children with Cancer UK

Abstract: Despite the great advances in therapy of childhood leukaemia, resistant leukaemia subtypes, late effects of intensive chemotherapy and late relapses remain significant problems Novel therapies that target signalling pathways critical for leukaemia progression are urgently needed. We and others have recently found that many paediatric acute lymphoblastic leukaemias (ALL) and acute myeloid leukaemias (AML) are dependent upon STAT3 (signal transducer and activator of transcription 3) signalling. Targeting STAT3 activity therefore represents a novel therapeutic opportunity for poor-prognosis, refractory and relapsed childhood leukaemia. We plan screening newly-diagnosed and relapsed ALL and AML patients samples, obtained from the Haematology department at GOSH, for in vitro sensitivity to small molecule STAT3 inhibitors, and to transplant the leukaemia cells into immunodeficient mice. Leukaemia cells isolated from engrafted primary recipients will then be transduced with luciferase-expressing lentiviral vectors and re-transplanted into secondary recipients to generate in vivo pre-clinical models of the different leukaemia subtypes. These models will then be used to examine the efficacy of pharmacological STAT3 inhibition for leukaemia eradication in vivo. STAT3 induced ALL and AML gene expression signatures will also be used to identify clinically approved drugs that have STAT3 inhibitory activities, through connectivity map analysis. The in vivo anti-leukaemia activities of these drugs will then be examined and compared to those of defined small molecule inhibitors. This will lead to the identification of drugs that can be fast tracked into the clinic for use in the therapy of STAT3-dependent paediatric leukaemias.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Development of an allosteric inhibitor of Aurora A that induces proteasomal degradation of MYCN in childhood neuroblastoma
Funder: Children with Cancer UK

Abstract: Neuroblastoma is a common solid tumour that accounts for 15% of cancer deaths in children. Amplification of the MYCN oncogene is the most common genomic alteration in aggressive tumours and associated with poor clinical outcome. Although MYCN is expressed as a tumour-specific oncoprotein in poor-outcome neuroblastoma [1], making it a therapeutic target of great importance, no drugs with significant activity against MYCN or MYC are available for clinical use in cancer. We have identified a set of druggable MYCN-binding proteins that interfere with proteasomal destruction of MYCN through specific protein:protein binding interactions, among these Aurora-A. Recently we demonstrated that a structurally unique clinical inhibitor of Aurora-A kinase (MLN8237) dissociates MYCN:Aurora-A complexes and efficiently targets MYCN but retains potent kinase inhibition, which is associated with significant clinical toxicity [2]. Our recent data, backed by structural chemistry and mutational mapping of MYCN:Aurora-A interacting domains indicate that complex formation and kinase activity are structurally distinct functions of Aurora-A [2, 3], that can be independently targeted. In this project we will use our significant preliminary data on MYCN binding proteins, and specifically on structural determinants that regulate Aurora-A:MYCN binding, to: 1) characterise a set of novel MYCN binding proteins we identified that stimulate MYCN degradation and could be targeted therapeutically in similar fashion to Aurora-A, and 2) use our significant preliminary data to drive the development of second-generation Aurora-A inhibitors that are more potent and specific destabilisers of MYCN but lack Aurora-A kinase inhibitory activity.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Extension to 12/134 Williamson - Functional genomic profiling of hSNF5/INI1 inactivation in malignant rhabdoid tumours
Funder: Children with Cancer UK

Abstract: MRT (malignant rhabdoid tumour) are cancers of childhood and infancy with a dismal prognosis and high metastatic potential. MRT may occur at any part of the body, this phenotypic heterogeneity contrasts with an extreme genetic homogeneity; >80% of MRT show biallelic inactivation of hSNF5/INI1 and no other consistent mutations. hSNF5/INI1 is a core subunit of the SWI/SNF chromatin remodelling complex and regulates the expression of hundreds of downstream genes and pathways. The proposed project aims to elucidate the way in which loss of hSNF5/INI1 achieves MRT tumourigenesis. Given that hSNF5/INI1 cannot be targeted directly, characterising the downstream mechanisms of tumourigenesis will allow us to identify target genes and pathways which may ultimately be exploited as novel therapies. We will generate a set of integrated functional genomic data regarding the role of hSNF5/INI1 in MRT cell line models. Using lentiviral methods we will re-express hSNF5/INI1 in a panel of 5 MRT cell lines and profile concomitant changes in expression, methylation and DNA binding of SWI/SNF complexes using RNA-seq, 450k methylation array and CHIP-seq respectively. We will further cross-reference this data with primary MRT profiling data in order to contextualise our findings. Given the lack of published genomics data for MRT we anticipate that this start-up project will substantially add to knowledge in the field and provide a necessary first step to a wider project to ultimately develop targeted therapies for MRTs.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Actomyosin regulatory MRCK as metastatic cancer drug targets
Funder: Worldwide Cancer Research

Abstract: The metastatic spread of tumours has been directly linked with 90% of cancer deaths, suggesting that treatments which combat this process could improve outcomes for a significant number of cancer patients. The ability of the actomyosin cytoskeleton to generate force, which is promoted by the MRCK kinases, provides the mechanical power that drives tumour cell invasion and cancer metastasis. Therefore, our central hypothesis is that MRCK represents an important cancer drug target due to a role in promoting tumour cell invasion and metastasis. To further improve our basic understanding of these influential cytoskeleton regulators and establish the cancer types in which MRCK inhibition would be most likely to have clinical benefit, we will use the unique research tools we have developed (MRCK selective small molecule inhibitors, activation state sensitive antibodies) to determine which cancer types are associated with increased MRCK activity. We will also identify how MRCK kinase activity responds to factors in the tumour microenvironment and thereby contributes to processes that promote cancer cell invasion and metastasis. Finally, over 1000 cancer cell lines will be treated with MRCK inhibitors to identify tumour types and/or genetic alterations associated with sensitivity to MRCK inhibitors as single agent chemotherapeutic agents. These experiments will identify the cancers and contexts in which MRCK inhibitors would have the best chance to improve patient outcomes.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Metabolic permissiveness and chemoprevention in Hereditary Leiomyomatosis and Renal Cell Cancer
Funder: Worldwide Cancer Research

Abstract: During transformation cancer cells rewire their metabolism to sustain the increased energy demand of unrestrained proliferation. This metabolic transformation is granted by the action of oncogenes and tumour suppressors and is shaped by environmental cues. Interestingly, perturbation of cellular metabolism can, in some circumstances, predispose to tumour formation. For instance, mutations in the key mitochondrial enzymes Fumarate Hydratase have been associated to Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC), a hereditary cancer syndrome characterised by benign tumours of the smooth muscle of skin and uterus and an aggressive form of renal cancer. The accumulation of fumarate in FH-deficient cells has been correlated to the activation of oncogenic pathways such as the hypoxia inducible factors HIFs and Nuclear factor (erythroid-derived 2)-like 2. While the mechanisms of tumorigenesis in HLRCC have been extensively investigated, how FH-deficient cells can survive and sustain the high energy demand of fast proliferation without functional mitochondria is still poorly understood. We have recently demonstrated that FH-deficient cells undergo profound metabolic changes in order to compensate for the loss of FH. Importantly, the inhibition of pathways involved in these metabolic adaptations leads to the selective death of FH-deficient cells. Given the role of metabolic adaptations in supporting the loss of FH, we hypothesise the presence of tissue-specific metabolic adaptations that are required to survive an otherwise lethal mitochondrial dysfunction and that these adaptations would allow fumarate to accumulate and trigger oncogenic pathways. In this proposal we will use a combination of metabolomics, proteomics and systems biology to analyse the tissue-specific effects of the loss of fumarate in an inducible FH knock out model. Our ultimate goal is to identify which metabolic pathways are required to compensate the loss of FH in in vivo order to inhibit these pathways during the early phases of tumorigenesis to prevent tumour formation.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Rescuing Thermally Unstable p53 Mutants with Small Molecules; New Targeted Cancer Therapies.
Funder: Worldwide Cancer Research

Abstract: Structural mutations of p53 are rife in cancer and the thermal instability of such mutants is a major cause of loss of p53 function. Temperature sensitive (ts) mutants rapidly denature at physiological temperatures but can be reactivated and gain wild type p53 function by the binding of small molecules, slowing down protein denaturation, triggering apoptosis. The p53-Y220C (tyrosine to cysteine) mutation is a ts mutant that has been investigated in detail and found in ca. 80,000 new cancer cases p.a.. Small molecule hits with KD s of ca.150 micromolar, based on a carbazole (PhiKan083) or pyrazole (PK7088) template, have been investigated in our groups and co-crystal structures of each series have been obtained in p53-Y220C. PhiKan083 raised the melting point (mpt) of p53-Y220C by approx. 2K yet failed to show any significant cellular effects. In contrast, PK7088 raised the mpt of p53-Y220C by approx. 1K, induced apoptosis, activating caspases 3/7 and inducing p21 and G2/M cell cycle arrest, and increased the amount of correctly folded p53 (using a Pab1620 antibody), in HUH-7 (p53-Y220C) cells. The aim of this proposal is to build on these initial studies, using parallel synthesis and directed by molecular docking and Xray studies: to investigate structure activity relationships in each series (SAR) with the aim of obtaining KD values vs. p53-Y220C to show cell-based activity for the PhiKan083 series. to improve the cell-based activity of PK7088 vs. p53-Y220C. to select a lead on the basis of in vitro cellular activity and using a gamut of in vitro ADME investigations (hERG, P450 inhibition, microsomal turnover, AMES…..). Three separate synthetic approaches to the compounds are presented in the objectives. This will mitigate the risk of any one objective not reaching the milestones of activity and cellular activity.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: The role of XRCC5 and SAFB1 in the transforming activity of HOXA9 in acute myeloid leukaemia
Funder: Worldwide Cancer Research

Abstract: Acute Myeloid Leukaemia (AML) is an aggressive and often incurable haematological malignancy. It consists of a number of heterogeneous subtypes often driven by specific and unrelated mutations. Despite this, common downstream mediators do exist. One such mediator is the HOXA9 transcription factor which is downstream of many AML mutations and is over-expressed in over half of cases, co-segregating with the aggressive subtypes. We have identified two novel proteins, XRCC5 and SAFB1, that interact with HOXA9. This proposal will assess the role of XRCC5 and SAFB1 in HOXA9-mediated transformation in AML. Our application has three complementary aims The first is to determine the nature and composition of the HOXA9 containing complexes in AML, and specifically the role of XRCC5 and SAFB1 in these complexes. We will perform multiple protein studies in this aim, including Co-IP studies to determine interaction with other known HOXA9 complex members, as well as size-exclusion chromatography to determine specific complex composition. Having characterised the HOXA9-XRCC5-SAFB1 complex, or second aim will determine the role of specific HOXA9 complexes in the transcriptional dysregulation that characterises AML. This aim will utlise gene expression by RNA-seq, ChIP-Seq analysis for multiple complex members (including HOXA9, XRCC5,SAFB1, MEIS1 and CREB), luciferase assays and perturbation of complex members via RNAi. The third aim of the proposal is to further determine the cellular consequences for leukaemogenesis following perturbation of complex members via RNAi, using in vitro and in vivo leukaemia models. This last aim would validate the putative HOXA9-XRCC5-SAFB1 complex as a therapeutic target in AML, and along with aim 1 will provide a basis for the development of rational structurally designed therapeutics.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Characterisation of C1ORF106 a novel mediator of TGFbeta driven tumour promotion
Funder: Worldwide Cancer Research

Abstract: TGF&beta can act as both a potent tumour promoter and tumour suppressor in a context dependent fashion. During cancer progression tumour cells can modify their response to TGF&beta from anti-proliferative to pro-tumourigenic whereby they can utilise TGF&beta to promote tumour cell proliferation, survival, motility, invasion, intravasation and extravasation at distant metastatic sites, promotion of angiogenesis, inhibition of the anti-tumour immune response and promotion of cancer stem cell straits. Cancer stem cells (CSCs) represent defined subsets of cells within tumours that are capable of sustaining tumour growth, allowing spread and reinitiation at distant metastatic sites and therefore represent a key target for effective cancer therapy. We have previously shown that loss of DAB2 expression switches TGF&beta from a tumour suppressor to a tumour promoter in squamous cell carcinomas and enables TGF&beta to promote anchorage independent growth in both spheroid and soft agar conditions in-vitro, key attributes of CSCs. Our preliminary gene regulation and siRNA knockdown data indicate that a previously uncharacterised gene is a novel TGF&beta target gene which is required for TGF&beta mediated promotion of anchorage independent growth in SCC cells and proliferation and migration of breast cancer cells. Bioinformatics analyses indicate that this gene may be an important promoter of cancer progression in several malignancies including SCC, breast cancer, ovarian cancer, myeloma, liver cancer and lung cancer and may therefore be an important new cancer gene. We will employ a combinatorial approach both in vitro and in vivo employing bioinformatics, biochemical, cell biology, microscopy, protein-protein interaction, gene expression profiling and xenograft techniques coupled with clinical investigation of human tumour tissue to determine the function and regulation of the novel gene in cancer. These studies should provide novel mechanistic insight into the regulation of cancer and CSCs and could ultimately lead to exploitation of these findings in future cancer therapies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Integrin driven invasion in ovarian cancer
Funder: Worldwide Cancer Research

Abstract: Ovarian cancer is the 6th most prevalent cancer among women worldwide. 80-90% of ovarian cancers are epithelial in origin, and 50-60% are serous adencarcinomas that present at high grade and carry poor prognosis. We aim to identify new targets for therapeutic intervention, and to develop new strategies involving blockade of integrin function to generate more effective treatment for late stage disease. Epithelial ovarian cancer (EOC) origin and classification is still under debate, however genetic alterations are commonly found. p53 mutation is seen in the vast majority, and Rab25 is overexpressed in aggressive EOCs. Integrins play an important role in metastasis of EOC; the fibronectin (FN) receptor α5β1 is emerging as a potential driver, whilst αvβ3 acts as a metastasis suppressor. However, the mechanisms through which integrins change cell phenotype and influence EOC progression are poorly understood. The endocytic trafficking of α5β1 contributes to invasive migration of EOC cells into FN-rich extracellular matrix by generating a local signal to regulate the cytoskeleton through a RacGAP1-IQGAP1 complex, and we observed increased RacGAP1 and IQGAP1 expression in metastatic human EOC. Coupled with the observation that p53 mutation, expression of Rab25 and inhibition of αvβ3 can each act as triggers to promote endocytic recycling of α5β1, we hypothesise that α5β1 trafficking and downstream signalling contribute to metastatic progression in EOC. We will combine cell biological discoveries, revealing the pathways that mediate actin reorganisation downstream of α5β1, with in-depth analysis of human EOC samples to validate the contribution of α5β1 trafficking to EOC progression. We will also explore combination of α5β1 antagonists with other therapies to specifically prevent the movement of metastatic EOC cells, and inhibit their growth at metastatic sites. In doing, so we hope to build new strategies that can be used to improve the prognosis of patients presenting with high grade EOCs.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Assessment of the genotoxicity of dietary acrylamide: 4 years
Funder: World Cancer Research Fund

Abstract: In 2002 it was discovered that cooking some foods rich in carbohydrate at high temperatures produces small amounts of a chemical called acrylamide, exposure to which is known to produce cancer in animals. Subsequent studies showed that many highly consumed food products such as potato chips and crisps, and coffee, contain low levels of acrylamide. The significance to human health of this exposure is unknown at present, and is of extensive interest worldwide. The way in which acrylamide causes cancer is by damaging DNA, and we plan to determine the extent of this damage in human populations and see how it is associated with diet. This will be done both by using high sensitivity analytical equipment (mass spectrometry) and by using antibodies. DNA from both blood and urine will be examined for evidence of the damage products induced by acrylamide. The project will lead to a clear understanding of the extent of cancer risk associated with acrylamide ingestion and will also indicate ways by which to minimise this risk.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Folic acid, epigenetic regulation of BRCA genes and DNA repair in healthy and cancer cells
Funder: World Cancer Research Fund

Abstract: TITLE: How folic acid changes the ability of damaged cells to repair themselves. BACKGROUND: The genes BRCA 1 and 2 are important for repairing damaged DNA in all cells and so prevent the formation of cancers. Impaired function of these genes is important in cancers of the breast and ovary. However, most of these cancers do not involve mutations in BRCA genes. Instead, the processes which control how these genes work are altered in a way that reduces their ability to repair damaged DNA. The vitamin folic acid is involved in controlling the function of BRCA genes. Our findings show that more folic acid may increase the activity of the BRCA genes in some cells, but decrease it on others. In order to make safe dietary recommendations for consumption of folic acid, including dietary changes to prevent or help treat cancers, we need to understand why different tissues respond differently to folic acid. AIMS and GOALS: We will test in the laboratory how different types of cells, normal and cancer, respond to folic acid treatment. We will then investigate how this affects the control of the BRCA genes and their ability to repair damaged DNA. POTENTIAL IMPACT: We hope this project will tell us how folic acid alters risk of different cancers. In so doing we aim to clarify some of the uncertainty about the effects of folic acid on cancers shown in previous studies. This will help nutritionists devise dietary recommendations for folic acid intake to the general population and to those at risk of cancers involving BRCA genes. Understanding how folic acid alters the control of the BRCA1 and 2 genes may lead to treatments that use nutrients to reduce cancer risk. The findings of this study will also contribute to the wider understanding about how nutrients modify cancer risk.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Does bariatric surgery increase the risk of colorectal cancer?
Funder: World Cancer Research Fund

Abstract: Background: Excess body weight is associated with increased risk of colorectal cancer (CRC). However, it is currently not clear how weight loss strategies alter future CRC risk. Bariatric (or obesity) surgery (BS) is increasingly performed in individuals


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: CANCER AND NEOPLASMS