NIHRDataInsights/HRCSData huggingface dataset:
Title: The Cambridge Molecular Therapeutics Programme (MRC Programme 2)
Funder: Medical Research Council

Abstract: The MRC Cancer Unit s overarching strategic aim in its next quinquennium will be to translate improved understanding of early steps in epithelial carcinogenesis to interventions that improve the outcome of patients with epithelial cancer. A new programme in the Unit - the Cambridge Molecular Therapeutics Programme - brings together a unique interdisciplinary group of internationally recognized Cambridge science and scientists towards this end. It will provide a powerful new resource that is expected to have a far-reaching impact on the work of the Unit, and the Cambridge Cancer Centre. The CMTP s primary aim in the next quinquennium will be to establish the scientific and technical know-how to target macromolecular interactions using small molecules. We will aim to determine: Which macromolecular interactions in biological pathways are most appropriate as drug targets (ie, Where to drug?); Through what methods can chemical tools against these targets be developed (ie, How to drug?). A complementary but secondary aim will be to develop the appropriate preclinical models and clinical outlets for translation to the clinic. These studies will ask in what clinical settings agents targeting DNA repair or mitosis are most likely to be effective (ie, Who to drug?).


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: The role of p63 isoforms in head and neck cancers
Funder: Medical Research Council

Abstract: Head and neck cancers, in particular oro-pharyngeal cancers, are on the increase in a population of patients who do not have the usual demographics of, elderly male with a history of smoking and heavy alcohol consummation. The increase is thought to be due, in part, to increased infection with human papillomavirus (HPV) type 16 which is found in 20 to 40% of cases. The HPV positive cancers have a better prognosis than HPV negative ones, although the reasons behind this outcome are unknown. Epithelial to mesenchymal transition (EMT) is a normal process in development, but also occurs in cancers during invasion and metastasis. p63, a member of the p53 family of transcription factors, has multiple isoforms We have found that some of these isoforms inhibit EMT, while others potentiate EMT. The TGF-beta pathway is important in EMT and also carcinogenesis and we have found that the TGF-beta gene is regulated by certain p63 isoforms The isoforms deltaNp63alpha and deltaNp63beta inhibit EMT, while deltaNp63gamma stimulates EMT through its regulation of the TGF-beta gene and perhaps other genes in the TGF-beta pathway. HPV proteins up-regulate p63 isoforms at the transcriptional and post transcriptional level and our hypothesis is that this up-regulation protects HPV positive cancers from the growth potentiating effects of TGF-beta , resulting in a better prognosis. To widen these studies and determine at a global level the genes regulated by p63 isoforms, we have carried out ChIP-seq experiments to determine potential p63 binding sites. We have validated a number of genes that are involved in EMT during normal tissue development and we want to determine if they have a role in oro-pharyngeal cancers. We will initially determine what p63 isoforms are expressed in HPV positive and negative oro-pharyngeal cancers, then investigate the differential functions of p63 isoforms and the consequences of their disruption and finally elucidate the role of the genes involved in tissue EMT during development.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Role of ARID1A in endometrial proliferation, endometriosis and endometriosis-associated ovarian cancer pathogenesis
Funder: Medical Research Council

Abstract: Ovarian cancer is the leading cause of death from gynaecologic malignancies in the western world. Together, endometrioid and clear-cell ovarian adenocarcinomas account for approximately 20% of ovarian cancer and are epidemiologically related to endometriosis. Very recent work has identified mutations in ARID1A, a component of the SWI/SNF chromatin remodelling complex, in 57% of ovarian clear-cell adenocarcinomas (OCCA). Importantly, in 2 examined cases of OCCA, adjacent foci of atypical endometriosis carried the same ARID1A mutation, implying that ARID1A mutations are an early driver event in carcinogenesis. Previous work has shown that ARID1A plays a role in the maintenance of an embryonic stem-cell phenotype, cell differentiation, cell cycle arrest and steroid-hormone mediated gene transactivation. The first aim of this project is to study the role of ARID1A in the control of oestrogen and progesterone regulation of normal endometrium and endometriotic lesions. This will involve in vitro assays of proliferation in disaggregated and explanted endometrial tissue from ARID1Aflox mice as well as in vivo experimentation following site-specific inactivation of ARID1A in the same mouse model. To identify the transcriptional targets of ARID1A, microarray and ChIP-Seq experiments are planned. The second aim of the project is to create a mouse model of OCCA that will reflect the association between endometriosis and OCCA observed in humans. For this, ARID1A will be knocked down or out on a background of endometriosis mouse models. Current medical treatments for OCCA are unsatisfactory. In particular, and in stark contrast to the more common high grade serous ovarian cancers, these tumours are resistant to standard platinum-based chemotherapy. An improved understanding of the molecular and cellular events that result from ARID1A mutation has the potential to identify novel treatment targets for this difficult to treat malignancy. The parallel development of a mouse model of OCCA will provide the opportunity and possibility for preclinical testing of therapeutics.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Investigating The Genetic Basis Of Inherited Renal Cell Carcinoma
Funder: Medical Research Council

Abstract: Aims: To gain a novel insight into the pathogenesis of renal cell carcinoma (RCC) by identifying new tumour associated genes in familial kidney cancer. Objectives: 1. Investigate candidate genes for mutations in a cohort of non-syndromic familial renal cell carcinoma (NSFRCC) patients. 2. Perform whole exome sequencing on germline DNA from NSFRCC patients to identify novel inherited renal cancer gene(s) 3. Investigate the role of novel NSFRCC genes in sporadic RCC. 4. Initiate functional/therapeutic investigations Methodology: Initially, I will use conventional and second generation DNA sequencing methodologies to identify mutations in candidate genes in a panel of 50 NSFRCC germline DNA samples. I have already investigated two candidate genes, and have compiled a list of other candidate genes from published data, and unpublished epigenetic studies. Whole exome sequencing will be performed on a subgroup of patients with NSFRCC who do not harbour mutations in known or candidate inherited RCC genes to identify novel inherited RCC gene(s). Having prioritised candidate mutations, I will perform analyses to validate the candidate as a novel inherited RCC gene. Furthermore, I will investigate its contribution to the pathogenesis of NSFRCC and to sporadic RCC (by sequencing and CpG island methylation analysis as appropriate). Further investigations of a novel inherited RCC gene will be dependent on knowledge of the gene of interest. If the gene is well characterised and part of a well defined pathway, I will investigate the effect of potential therapeutic agents on the proliferation of RCC cell lines defective for the novel RCC gene to determine if genetic status might be used to guide targeted therapy (I have experience of using siRNA treatments to identify new targets in VHL +/- isogenic cell lines). Scientific and Medical Opportunities Insights from familial RCC have led to significant developments in the treatment of RCC. Segregation analysis studies indicate NSFRCC is inherited in an autosomal dominant manner. Most NSFRCC kindreds are not accounted for by known inherited RCC genes. A combined strategy of candidate gene and exome sequencing is likely to identify novel genes, and to provide better insight into the pathology of kidney cancer.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: The effect of tumour microenvironment on arginine deprivation in malignant pleural mesothelioma.
Funder: Medical Research Council

Abstract: Aims: (a) To determine whether the macrophage component of the tumour microenvironment is a critical modulator of the response of malignant mesothelioma to arginine-depleting agents; and b) to develop strategies that overcome MPM stromal resistance to arginine deprivation. Background: Tumours deficient in argininosuccinate synthetase (ASS1), a key enzyme involved in arginine synthesis, are auxtrophic for arginine and sensitive to amino acid deprivation. However, arginine derived from the tumour microenvironment, particularly tumour-associated macrophages (TAMs), may limit the clinical effectiveness of arginine-catabolising enzymes, such as pegylated arginine deiminase (ADI-PEG20) in the treatment of ASS1-negative tumours. Previously, we have shown that malignant mesothelioma (MPM) cells undergo caspase-dependent apoptosis with ADI-PEG20 treatment. Since MPM is an ASS1-methylated and macrophage-rich tumour, it provides an excellent model to study whether the tumour microenvironment regulates the response in ASS1-negative cancers to arginine deprivation. Objectives: First, I will validate the host lab‘s preliminary Affymetrix gene expression data, which reveals widespread regulation of immune and inflammatory pathways in ADI-PEG20-treated MPM cell lines, including TGF- 2, FGFB1, IL-1 , IL-6, IL-8, IL-11, IL-24, CXCL2, CXCL3, and VEGF-A. Second, I will analyse the effect of arginine deprivation on the MPM-TAM interaction in vitro and in vivo. Third, I will determine the effect of arginine deprivation on the tumour microenvironment using samples from a multicentre clinical trial of ADI-PEG20 in patients with MPM (ADAM Trial). Design and methodology: The project explores basic mechanisms of TAM-tumour cell interactions and is fully integrated into the ADAM clinical trial. I will employ a range of cell and molecular biology techniques all of which are established in the host or in collaborating labs: the micro fluidic card platform to validate the Affymetrix data with subsequent gene pathway interrogation using in situ hybridisation of MPM tumour sections; co-culture experiments of TAMs and MPM cells using small molecule inhibitors and/or blocking antibodies to determine whether TAM-mediated ADI-PEG20 resistance is reversible; and animal studies aimed at either depleting or re-educating TAMs, using liposome-encapsulated clodronate or small molecules/antibodies respectively, to validate that TAMs are a critical modulator of the response of ASS1-negative MPM to arginine deprivation in vivo. Scientific and Medical Opportunities: Rigorous training will be provided in the scientific method at the Barts Cancer Research UK Centres for Molecular Oncology and Imaging, Cancer and Inflammation and Tumour Biology. In addition, my studentship will link into a weekly thoracic oncology clinic, providing an understanding of clinical trial design and translational clinical research.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Brf1 - a novel contributor to prostate cancer?
Funder: Medical Research Council

Abstract: Aims: Prostate cancer (PC) is the most common cause of cancer and second most common cause of cancer death in men in UK. Brf1 is a transcription factor that can transform cells when overexpressed. Its activity is counteracted by the tumour suppressor RB. Preliminary studies show that Brf1 levels increase at the earliest stages of human PC and that patients with the highest Brf1 levels have significantly worse survival prospects. Our aim is to determine whether Brf1 levels correlate with clinical parameters and have reliable prognostic significance. By using transgenic mouse models we aim to identify the role of Brf1 in the transformation of prostate cells. Hypothesis: Overexpression of Brf1 is an important step in prostate carcinogenesis. Objectives 1.) To show whether Brf1 levels are raised in PC specimens and to correlate its expression levels with clinical parameters including Gleason scores and survival outcome of PC patients. 2.) To explore the consequences of over-expression and heterozygous deletion of Brf1 in prostates of adult mice in transgenic mouse models. Methodology 1.) Expand on TMAs pilot data showing expression of Brf1 in prostate cancer biopsy specimens via immunohistoechemical (IHC) techniques. TMA available through the prostate collaborative network PROMPT (including Cambridge, Glasgow and Newcastle) will be studied by IHC and data corroborated to clinical parameters including survival outcome to test for prognostic significance. 2.) To test whether Brf1 mRNA assay by PCR is a reliable and useful diagnostic test: Urine samples from men with locally advanced tumour or benign prostates following digital rectal examination will be collected and processed to isolate prostate enriched cell pellet. RT-PCR will be applied to test if robust data can be obtained. 3.) Transgenic mouse models with Brf1 deletion or overexpression to determine effect on prostate tumour development. Cohorts will be monitored to determine whether Brf1 overexpression in this tissue is sufficient to drive any of the changes associated with prostate carcinogenesis. Characterisation of mouse models will be rigorous and involve histological and IHC assessment as well as in vitro cell culture and functional assays. Scientific and Medical opportunities: Preliminary data suggest Brf1 may be a reliable biomarker for the early changes of prostate carcinogenesis. Brf1 manipulation has the potential to be a translational target for novel small molecule inhibitors and aid our understanding of the mechanisms that underlie early disease progression in prostate cancer.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: The role of Eps8 in regulating pancreatic cancer invasion
Funder: Medical Research Council

Abstract: Background: Pancreatic adenocarcinoma has one of the worst prognoses of any cancer, with a 5-yr survival rate of 3% and a median survival of <6 months. Less than 20% of patients present with localised disease treatable by surgery, and even then, 5-year survival remains low (20%)1. It is clear that new molecular-based treatments are required Eps8 is a multifunctional protein, central to actin cytoskeletal reorganisation. Although the biochemistry of Eps8 has been investigated, its regulation and functional role in cells is less well understood, particularly in tumours. Recently we identified a functional link between tumour motility, Rac1 activation and Eps8. This was the first study showing that Eps8 can regulate collective tumour invasion in a physiologically relevant 3-D assay. Preliminary data: Our preliminary unpublished data show that Eps8 promotes PAC cell motility, and this is modulated through the integrin v 6, which is upregulated in numerous carcinomas, particularly PAC, where over 60% of tumours express the integrin strongly. We were the first to show that ?v?6 promotes tumour invasion, and further discovered that this process is modulated through activation of the small GTP-ase, Rac1, and requires integrin internalisation. Since Eps8 regulates GTP-ase activation, actin reorganisation and receptor endocytosis, ii may be of central importance in modulating v 6-dependent cell functions Aims: The aim of this project is to determine the mechanism(s) by which Eps8 links integrin signalling, regulation of the actin cytoskeleton and cell function. Objectives and methodology: We will examine the expression and distribution of Eps8, and ?v?6 in human PAC, and relate these findings to disease development and progression. We will identify the Eps8 binding partners in PAC cells, before dissecting the mechanism(s) by which Eps8 modulates ?v?6-dependent invasion: specifically examining its role in GTP-ase activation, integrin endocytosis and integrin-dependent TGF- 1 activation. The effect of Eps8-dependent actin bundling and capping on PAC invasion will also be examined. Finally we will use PAC models to examine the functional role of the Eps8/ ?v?6 axis in vivo. Scientific and medial opportunities: This study may uncover novel targets for the treatment and/or prevention of PAC, and will also give crucial insight into the general biology of tumour cell invasion.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS
Title: Improving the Diagnosis and Treatment of Localised Prostate Cancer
Funder: Medical Research Council

Abstract: To improve the diagnosis and treatment pathways in prostate cancer so that fewer and better biopsies are taken with fewer and better treatments conducted. Objectives A. To evaluate the ability of novel tissue and imaging biomarkers to detect and rule-out clinically significant prostate cancer (fewer and better biopsies, fewer treatments) B. To evaluate the genito-urinary, bowel, quality of life and cancer control outcomes after a issue-preserving strategy that targets only the area of prostate cancer (better treatments) Design and Methodology The two objectives will be evaluated in the following way: A. Fewer and better biopsies, fewer treatments 1. Collect and store tissue samples and imaging data-files from men prior to biopsy 2. Validate known diagnostic tests in detecting and ruling-out clinically significant prostate cancer, a) tissue biomarkers: urinary MSMB, serum kallikreins and PTEN-associated glycoproteins b) imaging datafiles: diffusion-weighted and dynamic contrast enhanced Mr.I quantitative parameters and ultrasound tissue characterisation algorithms 3. Conduct a discrete choice experiment to evaluate men‘s preferences for, and trade-offs between, the attributes of different diagnostic strategies and tests B. Better treatment 1. Conduct a phase II multicentre trial to evaluate the, a) precision and reproducibility of genitourinary, rectal and health-related quality of life outcomes b) medium-term histological outcomes of treated and untreated prostate tissue c) clinical validity of tissue and imaging biomarkers in detection of local failure after focal therapy 2. Develop a predictive model, using tissue and imaging biomarkers to predict outcomes after focal therapy 3. Conduct a formal consensus panel meeting of international experts to discuss and develop a pragmatic randomised controlled trial protocol comparing focal therapy to standard of care Scientific and Medical Opportunities A. Fewer and better biopsies, fewer treatments 1. A risk calculator that may identify men who require a biopsy so that detection of clinically significant disease is improved and men with insignificant disease can avoid an unnecessary biopsy and treatment 2. A unique collection of blood and urine samples and imaging datafiles, linked to template mapping biopsy findings, that can be used to test future promising biomarkers of prostate cancer Better treatment 1. The development of a pragmatic phase III randomised controlled trial protocol to evaluate the long term outcomes of focal therapy compared to standard of care 2. A unique collection of pre- and post-treatment pathological samples from men in whom the dominant or index lesion has been ablated and all other cancer foci remain in-situ.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Dissecting roles of High Mobility Group A1 (HMGA1) pathway in pancreatic adenocarcinoma progression through in vivo monitoring of cancer dynamics...
Funder: Medical Research Council

Abstract: Introduction: Pancreatic ductal adenocarcinoma (PDA) is the 5th leading cause of cancer-related death in the UK. To improve our understanding of this deadly cancer, we have engineered the KPC mouse harbouring conditional mutant alleles in K-ras and p53 genes targeted exclusively to pancreas, which recapitulates PDA (100% penetrance). The HMGA1 gene encodes for chromatin-associated proteins which regulate a constellation of pro-oncogenic genes. Our data suggests that HMGA1 is overexpressed in >90% of PDAs. Previously, we showed that HMGA1 promotes malignant phenotype in PDA cells. We now propose to dissect the roles of HMGA1 in PDA progression. Project aims: We have formulated 3 independent study aims Aim-1: To examine the process of PDA progression in real-time by in vivo introduction of pro-oncogenic HMGA1 coexpressed with a fluorescent reporter We hypothesize that in vivo introduction of HMGA1 gene will accelerate the process of cancer progression in KPC murine pancreas. We will introduce the HMGA1 gene coexpressed with a reporter gene (i.e. eGFP) into the pancreas of KPC mouse. At the site of HMGA1-eGFP introduction, the developing PDA will be labeled with eGFP which allows imaging studies (intravital multiphoton microscopy, bioluminescence) to track tumour progression, at an unprecedented single-cell level in vivo. Aim-2: To evaluate if HMGA1 promotes initiation and maintenance of PDA using a conditional transgenic mouse model We will perform a genetic dissection of HMGA1 functions using 3 novel targeted mouse models: conditional knock-in (CKI-1 &-2) and conditional knockout (CKO) HMGA1 mice. We will assess the dependence of PDA initiation and maintenance on HMGA1 expression. Co-operative roles of HMGA1 with K-ras and p53 will be elucidated by crossing the HMGA1 transgenic mice (CKI-1, CKI-2, CKO) with KPC mice. Aim-3: To perform a genome-wide analysis of HMGA1 transcriptional and signaling networks in PDA to identify novel biomarkers and therapeutic targets Using chromatin immunoprecipitation sequencing (ChIP-Seq), microarray expression profiling and constructed PanIN-PDA tissue microarrays, we will systematically examine integrated HMGA1-related pathways to identify ‘direct‘ and ‘indirect‘ targets of HMGA1. Harnessing bioinformatic strategies, we will focus on clinically-relevant candidate pathways of functional importance to identify novel biomarkers and therapeutic targets. Medical Opportunities: Our research strategy of characterising the mechanisms driving PDA progression will yield rational therapies and new biomarkers for early detection of this deadly cancer.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS