NIHRDataInsights/HRCSData huggingface dataset:
Title: Investigating the potential for synergistic radiosensitisation of bladder cancer by gemcitabine and the PARP inhibitor olaparib
Funder: Cancer Research UK

Abstract: Background Radiation (RT) kills cells by damaging DNA, and inhibition of the DNA damage response (Ddr) increases radiation sensitivity. The nucleoside analogue gemcitabine is a promising and well-tolerated radiosensitiser in patients with muscle-invasive bladder cancer and the PARP inhibitor olaparib also acts as a radiosensitiser, but only in S-phase, due to conversion of excess unrepaired single-strand breaks to double-strand breaks (DSB) during DNA replication. This, and the DSB repair defects seen in muscle-invasive bladder tumours, should result in relatively greater tumour than normal tissue radiosensitisation. We can deliver focussed irradiation to bladder/surrounding bowel using our small animal radiation research platform (SARRP) to investigate potential acute and late normal tissue effects of the triple combination. Acceptable normal tissue effects and additive or synergistic tumour responses would support progression of this novel combination into clinical trials. Aims To produce in vitro and in vivo data on the efficacy and normal tissue effects of olaparib in combination with gemcitabine and radiotherapy to support a phase I clinical trial of this novel combination in bladder cancer patients. Methods We shall perform clonogenic assays in eight bladder cancer cell lines to determine whether olaparib increases radiosensitivity and then whether gemcitabine enhances this effect. We shall study potential biomarkers, including cell cycle parameters by FACS analysis and DNA repair components by western blotting. If we observe additive or supra-additive sensitisation in vitro in at least three of the eight cell lines, then the radiosensitising effects of olaparib+/-gemcitabine will be studied in vivo, initially in subcutaneous xenografts derived from two cell lines with promising in vitro data. The SARRP will then be used to irradiate normal bladder and surrounding bowel, to compare double/triple combination toxicities. Xenografts and bladder/surrounding bowel will be examined post-mortem for radiation-related pathological features and treatment effects on the tumour microenvironment. Relevant biomarkers will also be studied. How the results of this research will be used If data indicate that pre-clinical models of bladder cancer are radiosensitised by olaparib, and that the combination with gemcitabine is either additive or synergistic, without an unexpectedly severe exacerbation of toxicity, we shall apply to the CRUK Novel Agents Committee to undertake a phase I dose-escalation clinical trial of this combination in muscle-invasive bladder cancer. The study would incorporate high quality translational work to validate predictive biomarkers identified pre-clinically. This trial would be followed by a randomized phase II trial comparing RT/gemcitabine with RT/gemcitabine/olaparib.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: October 2013 Postdoctoral Career Development Day Poster Prize
Funder: Cancer Research UK

Abstract: mTORC1 mediated translational elongation is limiting for intestinal tumour initiation and growth. Mutation and inactivation of the Apc gene is a key event in the development of colorectal cancer. Deletion of the Apc gene in vivo initiates a Wnt-driven Myc-dependent crypt progenitor cell-like phenotype, characterised by hyperproliferation and altered differentiation. We have shown that Myc-dependent activation of mTORC1 is essential for Apc-loss induced proliferation. Genetic ablation of Raptor or treatment with rapamycin completely blocks proliferation of Apc-deficient cells and triggers differentiation to the paneth cell lineage. Recent studies have suggested that mTORC1 functions mainly through 4EBP1 to inhibit translation initiation and thus acts as a rate limiting step for proliferation in cancer. However, through examining the effectors downstream of mTORC1, we have shown that the S6K-eEF2K-EF2 axis is critical for Wnt-dependent proliferation and regeneration in the mouse and fly. Mechanistically, Apc deficient cells show a significant increase of translational elongation compared to wild type cells, which could be blocked by inhibition of mTORC1 activity. Critically, loss of the negatively regulator of eEF2, eEF2K, allowed Wnt-driven proliferation and regeneration in vivo in the presence of rapamycin. Taken together these results suggest that in order to coordinate the burst of transcriptional activity that occurs following Apc loss (due to the activation of ß-catenin/Myc), translational elongation is increased in an mTORC1 dependent manner. If this is blocked, cells engage a long-term growth arrest and differentiation response. This data would suggest that inhibition mTORC1 could be of benefit to suppress colorectal cancer initiation and growth of early adenomas in high risk patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Acinar cells - The missing link in tumour-stroma signaling during PDAC development?
Funder: Cancer Research UK

Abstract: Pancreatic ductal adenocarcinoma (PDAC) is the fifth leading cause of cancer death in Europe and America and has a very poor prognosis with a median survival of 6 months and an estimated 5-year overall survival of only 5%. The poor prognosis results from the aggressive nature of the disease and late diagnosis as there is currently a complete lack of biomarkers to identify the disease at early stages. PDAC evolves through a series of premalignant histo-pathological changes called pancreatic intraepithelial neoplasms (PanINs), which are accompanied by a recurrent pattern of genetic lesions. The Kras gene is mutated in almost all human PDAC cases (90%) and is considered the earliest genetic event to drive the development of PDAC in combination with the inactivation of the tumour suppressors INK4, SMAD4 and TP53. One of the hallmarks of PDAC is an extensive stromal remodelling, with some of the earliest histopathological changes being ductal transformations, increased amount of activated fibroblasts, and the abundance of extracellular matrix. It is speculated that the rigidity of this extracellular matrix and the activated fibroblasts contribute to the unusual chemotherapy resistance of PDAC patients. Pancreatic cancer is a multicellular disease and therefor understanding the mechanisms of tumour-stroma signalling will help our understanding of the tumour microenvironment and may lead to the identification of new therapeutic targets. The main objective of our lab is to study tumour-stroma signalling in pancreatic cancer. By understanding the signalling better between the different cells in the tumour microenvironment we are hoping to acquire better understanding of PDAC, to find new biomarkers and anti-cancer drug targets. Currently we are using tumour and stellate cells for all our signalling studies, grown as mono- or co-cultures, but being able to include the acinar cells into these studies would have a great impact for the labs future investigations. The more factors we can include in our assays to resemble the actual in vivo microenvironment in an in vitro setting, the more precise and valid results we can obtain.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: The role of Mre11 nuclease activity in replication fork progression after treatment with the nucleoside analogue Gemcitabine
Funder: Cancer Research UK

Abstract: Nucleoside analogues are widely used in cancer treatment. They exert their cytotoxicity by inhibiting nucleotide synthesis and/or through incorporation into nascent replicating DNA causing chain termination. While previous investigations have addressed import and metabolism of various nucleoside analogues, not much is known about the DNA repair mechanisms which underlie cellular resistance. Recent data from our lab indicate that the nuclease activity of Schizosaccharomyces pombe Mre11, a subunit of the evolutionarily conserved Mre11-Rad50-Nbs1 (MRN) complex, is directly involved in the nucleolytic removal of the nucleoside analogue Gemcitabine incorporated into DNA and thus contributes to replication fork progression in Gemcitabine-treated cells. We have previously demonstrated that the nuclease activity of S. pombe Mre11 is required to remove topoisomerases I and II which are covalently attached to DNA-ends in cells treated with clinically important topoisomerase inhibitors, and that this nuclease function is not required for homologous recombination-mediated repair downstream of lesion removal. Using mre11 nuclease-deficient mutants, this separation of function allows us to investigate Mre11 nuclease-dependent functions without interfering with its role in recombination. Previous studies have shown that MRN localizes to replication forks during unperturbed replication and in response to DNA damaging agents including Gemcitabine. Together with our data, this suggests that Mre11-dependent nucleoside removal happens in the context of a replication fork. Collapsed replication forks can be restarted by homologous recombination. I now want to visit the lab of dr. Sarah Lambert (Curie Institute, Paris) to learn two-dimensional agarose gel electrophoresis, in order to study if the Mre11 nuclease function supports replication fork progression without initiating recombination, or if it promotes recombination-mediated fork restart and the formation of abnormal replication intermediates in Gemcitabine-treated cells. Using a genetic assay which measures mutation frequency due to replication slippage during fork restart, I aim to further investigate a potential role of Mre11 in this process. The excision of nucleoside analogues from nascent DNA during replication, thus avoiding mutagenic fork restart, would constitute a novel function of the MRN complex. The techniques I will learn in Paris will be important to pursue my interests in DNA replication and repair in the future, and will be of benefit to several projects currently running in our lab. In the long term, the analysis of MRN-dependent repair pathways and their mechanisms acting on nucleoside analogues and other clinically important cancer drugs might help inform therapeutic decisions (personalised medicine) and lead to the design of novel drugs.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS
Title: BACR Special Meeting Development of Cancer Medicines From Target to Disease: Modelling Stratified Approaches in Oncology
Funder: Cancer Research UK

Abstract: The British Association for Cancer Research (BACR) has held a successful series of one-day conferences focused upon the preclinical modelling of cancer disease and therapeutic response. We believe this to be an important area of translational research, which brings together a spectrum of researchers working in academia, industry and the clinical sciences.??The fifth meeting in the biennial series is scheduled for Thursday 27th November 2014 and is entitled "From target to disease: modelling stratified approaches in oncology". Through this we plan to assess the latest use of in vitro and in vivo cancer models to help identify new targets, define the response to novel therapeutic agents, develop patient selection hypotheses, and where possible to examine the translatability of such data to the clinic. We will also conclude with an example of the issues involved in employing stratified cancer therapies in clinical practice.? These meetings typically attract around 80 - 100 participants and in the past have provided a very interactive platform in which to discuss these issues including six invited lectures, a poster session and six proffered papers. The proffered papers give younger researchers the opportunity to present their work which is not always possible at larger conferences.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: CANCER AND NEOPLASMS
Title: Short term fellowship to develop murine model of NRas-induced senescence
Funder: Cancer Research UK

Abstract: Oncogene-induced senescence (OIS) is a conserved tumour suppressor mechanism that leads to proliferative arrest in response to oncogene activation. Previous work has identified OIS within several human premalignant lesions. It is an attractive diagnostic target for the early detection of cancer. However, current markers for OIS are unsuitable for in vivo use. We hypothesized that differentially regulated cell surface proteins in OIS may represent diagnostic or mechanistic targets. I have performed an unbiased quantitative proteomic screen on an in vitro model of OIS and identified 148 differentially expressed proteins. Notch1, a receptor involved in cell-fate decisions was found to be up-regulated and responsible for controlling the secretome composition of senescent cells. Inhibition of Notch1, using a dominant negative form of MAML1 in vitro, promotes a pro-inflammatory secretome. We have confirmed the OIS-associated up-regulation of Notch1 in 3 independent murine models, including one from the laboratory of Prof Zender in Tuebingen. They have developed a methodology for inducing hepatocyte senescence utilizing tail-vein injection of transposon-based oncogenic NRas. This model allows the study of the role of OIS within the microenvironment. I wish to validate and extend our findings utilizing functional manipulation of OIS-associated Notch1 signalling in vivo. This short-term research travel award would allow me to travel to Tuebingen in order to achieve 3 goals: (1) Receive training to perform a dnMAML1-mediated manipulation of OIS-associated Notch1 signalling; (2) to import this mouse model to the CRUK Cambridge Institute to facilitate validation of future senescence work; (3) develop a longer-term collaboration with the Zender laboratory to perform an in vivo¬ shRNA screen on up-regulated targets from our proteomic data. To achieve these goals I wish to apply for funding to support this visit to Tuebingen including laboratory costs. We believe that the proposal detailed here is important, timely and deliverable. The skills and knowledge gained through this visit will be vital in my development as a clinical scientist with a long-term goal of developing senescence-associated biomarkers for the early detection of cancer.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: CANCER AND NEOPLASMS
Title: Assessment of small retailer preparations for tobacco point of sale display removal and longer-term tobacco disinvestment
Funder: Cancer Research UK

Abstract: Background In England, the tobacco point of sale display ban is being implemented in two stages: 1) by 6 April 2012 displays had to be removed from large shops; and 2) by 6 April 2015 displays in small shops must be removed. Most smokers buy their cigarettes from small retailers and the majority of smokers support the removal of tobacco displays at point of sale. It is therefore critically important that the second phase of legislation is implemented smoothly. No recent research in England has been carried out with small retailers to assess their preparations for point of sale removal. With the rapidly increasing popularity and increase in use of electronic cigarettes, we will also assess where and how e-cigarettes are being displayed at point of sale. Aims The main aim is to assess small retailers’ plans and intentions regarding the second phase of tobacco point of sale display removal in two geographically distinct disadvantaged areas in England, as well as electronic cigarette displays at point of sale and longer term plans of retailers with regard to tobacco and nicotine sales. 1.To identify preparations by small retailers for point of sale display removal and tobacco industry support 2.To assess current display of electronic cigarettes at point of sale and plans for display of electronic cigarettes when tobacco displays are removed 3.To identify options for small retailers to disinvest from tobacco sales 4.To assess type and accuracy of communications on point of sale display removal in the retailer trade press Methods We will map all small retailers selling tobacco in two disadvantaged areas from the North and South of England. We will select at random approximately equal numbers from different categories of small retailers, in total assessing 100 retail outlets, 50 from each area. For every identified premise the researcher will visit and complete a short audit questionnaire. We will subsequently carry out a semi-structured interview with the most senior retailer assistant or manager available. We will also systematically assess all trade magazines published from April 2014 to September 2014 for mentions of tobacco point of sale displays. How the results of the research will be used The results will be used to inform the funders and other stakeholders and help to drive effective implementation of the second phase of the law.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE;3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION)
Health categories: CANCER AND NEOPLASMS
Title: Immuno Surveillance Laboratory
Funder: Cancer Research UK

Abstract: This research focuses on a novel from of immune response that his team has termed lymphoid stress-surveillance . In this process, lymphocytes provide a rapid response to infection and to incidences known as sterile dysregulation , which is when tissues are subject to physico-chemical damage or irradiation, without the obvious involvement of pathogenic microbes or viruses. The response bolsters tissue integrity during challenge, but if it occurs coincident with infection or expsure to allergens, it may also greatly affect the specific immune responses to those agents. Thus, lymphoid stress-surveillance has implications for tumour immunology; allergy; and vaccination. Moreover, some of its features make it particularly attractive for clinical application. However, this a novel area of Immunobiology, and as such is relatively poorly understood. Reflecting this, the research seeks to identify key molecular processes and mechanisms that regulate lymphoid stress surveillance, particularly via a better understanding of the lymphocytes that mediate it. His research involves some highly international, long-term collaborations, and spans the development of the novel reductionist molecular models to the formulation of clinical trials. The team is generously supported by peer reviewed funding from the Wellcome Trust and the Medical Research Council, and is part undertaken at Cancer Research UK's London Research Institute (LRI).


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: National Lung Matrix Trial: Multi-drug, genetic marker-directed, non-comparative, multi-centre, multi-arm phase II trial in non-small cell lung cancer
Funder: Cancer Research UK

Abstract: There has been a recent revolution in the management of non-small cell lung cancer (NSCLC), not least in the area of precision medicine. The list of potential actionable genetic changes continues to grow. Crucial to the efficient testing of multiple biomarker/drug combinations is a screening platform designed to detect the genetic changes in samples typically obtained from patients with advanced NSCLC. CR-UK’s Stratified Medicine Programme 2 (SMP2) will undertake large volume national molecular pre-screening using an Illumina NGS platform, which will integrate with a national clinical trial to further test the principle of precision medicine in NSCLC and identify new bona fide targeted treatments. The National Lung Matrix Trial consists of a series of parallel, multi-centre, single-arm phase II trials, each arm testing an experimental targeted drug in a population stratified by multiple pre-specified target biomarkers. There are currently 8 targeted drugs and 21 different drug-biomarker combinations. The aim is to determine whether there is sufficient signal of activity in any drug-biomarker combination to warrant further investigation. The study will be open at all ECMCs and will be carried out under a single clinical trial protocol and regulatory submission. The study is adaptive allowing rapid incorporation of new biomarker/drug combinations via substantial amendment. All arms incorporate comprehensive ctDNA analysis, supplemented with pre-and post-therapy tissue biopsy, for detection of predictive biomarkers, early detection of resistance and determination of mechanisms of resistance. The National Lung Matrix Trial is the largest precision trial in NSCLC. Sustainability will be ensured by inclusion of formal phase Ib testing of novel combinations, the potential to assess biomarker specificity in biomarker negative patients and the introduction of new pharma partners to the SMP-2/National Lung Matrix Trial consortium.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/MRC Oxford Institute for Radiation Oncology : Metastatic Disease Meeting
Funder: Cancer Research UK

Abstract: • Background The CRUK/MRC Oxford Institute: Metastatic Disease Meeting is being held at Wolfson College in Oxford on 9th and 10th September 2014. • Aims The meeting will provide scientific stimulus to those working in the field of metastasis research. It will encompass experimental, clinical and translational aspects of a number of important current issues, covering mechanisms, diagnosis and therapy. We aim to use this event to showcase high quality UK science, and to enable UK researchers to learn from international leaders in the field. • Methods The meeting is spread over two days, and has a strong cancer theme running through it. We aim for cancer scientists to be fully engaged, with a stimulating mix of high profile talks by international cancer experts alongside proffered papers and poster sessions. Session topics will include the role of the immune system, importance of the premetastatic niche, detection of circulating tumour cells, novel imaging approaches, advances in the use of radiotherapy, and targeting angiogenesis. • How the results of this research will be used. The meeting is designed to allow specialist cancer science to be presented and discussed in detail, alongside sessions focussed on supporting technologies. Overall we aim to fertilise high quality scientific innovation by encouraging new insights and providing networking opportunities. We prioritise the involvement of younger scientists and provide free registration for PhD students - that is one of the central reasons why CRUK support is vitally important to us. In addition your support will make an essential contribution towards accelerating scientific progress in the field and improving comprehensive science-led and ethical evaluation of new technologies in the clinic.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS