NIHRDataInsights/HRCSData huggingface dataset:
Title: Isolation, culture and analysis of murine ovarian surface epithelial cells and ovarian stem cells.
Funder: Cancer Research UK

Abstract: Ovarian epithelial cancer is a heterogeneous disease with several histological subtypes. Therefore the current ‘one treatment regime for all’ is outdated and a key step in the treatment of this disease is the customisation of treatment for the various subtypes. Several studies indicate that epithelial ovarian tumours are the end result of a complex sequence of events involving multiple genetic alterations in key signalling pathways. Understanding these molecular mechanisms in the various subtypes of ovarian cancer and the pathways that contribute to the metastatic spread of this cancer therefore has important implications in the development of new therapeutic targets and eradicating this life-threatening disease. Unfortunately the biology that drives spontaneous epithelial ovarian cancer is poorly understood, partially due to a lack of appropriate experimental models reflecting human disease, therefore the majority of what is known about the cellular changes in the ovarian surface as it becomes cancerous or metastatic is based almost entirely on examination of clinical tumour specimens or immortalised ovarian cancer cell lines grown in culture. Consequently the progression of the disease from benign lesions to clinical carcinoma has not been clearly demonstrated as early stage malignancy is infrequently detected in patients. In particular we wish to define the influence of key signalling pathways upon the ovarian stem cell population, and to potentially address the hypothesis that the mutation of key regulators could result in expansion of the stem cell population and subsequent tumour development, a hypothesis termed the cancer stem cell (CSC) theory. Although little is known about the ovarian cancer stem cell this cell population is thought to be a subset of cells capable of dictating invasion, metastasis, heterogeneity, therapeutic resistance and disease recurrence all of which make the treatment of this disease a difficult challenge. Therefore an understanding of the regulation of the ovarian cancer stem cell is vital to the development of new therapeutic strategies in the treatment of ovarian cancer, and the hope of eradicating this cancer cell population is a new insight in the treatment of this disease. Using Cre-lox based mouse models, we will mutate key signalling pathways alone and in combination within the ovarian epithelium and will subsequently define the effects of these mutations upon the ovarian cancer stem cell population and ovarian tumour development. In this proposal we aim to establish key experimental techniques in order to develop and characterise our novel, clinically relevant mouse models of ovarian tumorigenesis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: 'Towards a smoke-free generation' - building on ASH Wales's collaborative tobacco control campaigns programme This project will be led by ASH Wales's Head of Communications and Public Affairs
Funder: Cancer Research UK

Abstract: ASH Wales is seeking to build on its successful tobacco control campaigns of 2012-2014 with an ambitious new 2-year programme: 'Towards a Smokefree Generation'. The role of ASH Wales's Head of Communications and Public Affairs has been instrumental in positioning the organisation as a major player in public health in Wales through high profile campaigning and influencing. ASH Wales has developed a significant political and media profile and was awarded Gold at the CIPR Cymru awards in October 2013 for its successful campaign against the Welsh Government’s proposal to exempt the TV and film industry from the smoking ban. In the last 12 months ASH Wales’s smoke free playgrounds campaign has also resulted in 21 out of 22 local authorities committing to implementing smoking bans in play areas - up from just 1 in 2012 - and we have generated widespread support for standardised packaging across Welsh public life. The Head of Communications and Public Affairs also chairs the Wales Tobacco Control Alliance and increased its membership from 30 to 34 organisations in 2012/2013. The profile of the Alliance has been raised considerably as an effective and collaborative campaigning body which holds the Welsh Government to account on its national tobacco control targets. It will have a crucial role to play in ensuring Wales meets its 16% smoking prevalence target by 2020. The aim of the project is to develop our vision of a ‘Smokefree generation' which places the future of our young people at the heart of our campaigns. We will: 1.Press for implementation of Wales's national tobacco control strategy 2.Lobby for further legislation including a Public Health Bill and a ban on smoking in cars carrying children 3.Work with local councils to develop a ‘smokefree spaces charter' to include sports grounds, beaches and school perimeters 4.Develop a campaign to highlight the impact of illicit tobacco on Wales’s most deprived communities 5. Build on the success of the Wales Tobacco Control Alliance as an influential campaigning Alliance


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION)
Health categories: CANCER AND NEOPLASMS
Title: UKCTAS Communications and Research Network Manager
Funder: Cancer Research UK

Abstract: Background The UK Centre for Tobacco and Alcohol Studies (UKCTAS), a continuation and expansion of its successful predecessor, the UK Centre for Tobacco Control Studies, has recently been launched involving 13 Universities (12 in the UK and one in New Zealand at Massey University). Communication and public engagement activities undertaken by an experienced communications manager underpinned the success of the UKCTCS Aims To continue the Communications and Research Network Manager post and its associated activities in order to establish UKCTAS as a leading international centre of tobacco and alcohol research and policy excellence. Methods Using her unique skill set and vast experience, the Communications Manager will underpin the work and policy impact of the UKCTAS by undertaking the following roles: Public Engagement: manage the smokers’ panel based in Bath; assist colleagues in Nottingham in managing a second panel there; establish a public engagement panel for alcohol research. Event Management: managing numerous research and policy events including, the annual UKCRC Research Centres of Excellence Conference in Leeds and the 2015 Global Alcohol Policy Conference; communicating and implementing a UKCTAS policy on excluding the tobacco industry and its representatives from Centre events and developing and implementing a similar policy for alcohol. Dissemination and Communication: managing lines of communication across the 13 universities involved in the centre and building a sense of community; expanding the previously established research network to include alcohol researchers; prepare internal and external newsletters; disseminating research findings to key stakeholders including via the media; working with UKCTAS academics to enhance knowledge exchange and policy impacts of research. Capacity Building: managing and marketing the previously established CPD module ‘Tobacco Control in Practice’ and establishing an equivalent module for alcohol, supporting the development of a new masters module on alcohol at Kings College London; organising an annual early career researchers’ event. How the results will be used Through the activities outlined above it is anticipated that this post ensure that opportunities for research collaboration, engagement of the public and communication of research and policy developments to specialist and lay audiences from the UKCTAS are maximised


Research activity codes: 8.2 HEALTH AND WELFARE ECONOMICS;3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION)
Health categories: CANCER AND NEOPLASMS
Title: Adult Tobacco Policy Survey
Funder: Cancer Research UK

Abstract: While most tobacco advertising, promotion and sponsorship is banned in the UK, tobacco companies continue to use displays in shops and tobacco packaging to promote their products. In response to this, governments across the UK have taken two key actions: 1) banned the open display of tobacco products in large shops, with a ban in smaller shops due in 2015; and 2) supported the use of the new and larger pictorial health warnings on tobacco packaging, due to be introduced between 2015 and 2016. In addition, the Scottish Government has announced plans to introduce plain packaging in 2015, which would standardise the appearance of tobacco packaging apart from the brand name. We propose a web-based survey with smokers in the UK, aged 16 and over, called the Adult Tobacco Policy Survey (ATPS), so as to respond to the rapidly changing tobacco control environment. The main aim would be to evaluate the impacts of forthcoming tobacco control policies (plain packaging, new pictorial health warnings on packs and the tobacco display ban) among smokers in the UK. We would also aim to assess the impact of any other tobacco control policies introduced during the lifetime of the study. This could include, for instance, a ban on smoking in cars with children or regulation of electronic nicotine delivery systems such as e-cigarettes. The ATPS would draw on, and benefit from, the experience of other tobacco surveys which we are involved with, including the YTPS (Youth Tobacco Policy Survey) and the ITC (International Tobacco Control) project survey. The web-based survey would involve a cohort of 7500 adult smokers surveyed in 2015 and followed-up in 2016, at times that will allow us to capture a pre- and post-measure of the display ban, new health warnings and also plain packaging. The ATPS would be specifically designed with these tobacco policies in mind so as to ensure timely implementation, analysis and dissemination of results. The findings will be disseminated primarily via publications, presentations and meetings. They will also be shared with interested parties, both nationally and internationally, and via the wider media. The applicants have extensive research, policy and advocacy networks, and are therefore well placed to ensure findings are widely disseminated and drive effective policy development.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION)
Health categories: CANCER AND NEOPLASMS
Title: Investigating a curcumin-binding protein as a potential druggable target in colorectal cancer stem-like cells
Funder: Cancer Research UK

Abstract: Background: Data within our group has shown that curcumin is able to inhibit proliferation of cancer stem-like cells (CSCs) obtained from colorectal cancer (CRC) cell lines and primary patient samples (identified by phenotype via sphere formation and cell surface markers e.g. high aldehyde dehydrogenase). Preliminary data supports an interaction with a target protein required to maintain key features of CSCs as the basis of anti-tumour activity. Importantly, an early phase trial is currently underway to assess clinical efficacy of curcumin in patients with CRC at our centre. Suppression of the target protein (via indirect pathways) has been proposed as a possible therapeutic strategy for cancer, but we are not aware of any small molecules that directly target the protein. Aims: We aim to investigate the interaction between curcumin and the target protein, confirm binding and go on to narrow down the binding site to individual domains. Methods: 1) Cloning and Expression 2) Detection of ligand binding to individual protein domains 3) Interference of curcumin binding with key mechanisms of action of the protein 4) Flow Cytometry and RT-PCR How the results of this research will be used: The work outlined in this proposal aims at providing a detailed analysis of the binding of the putative cancer chemopreventive agent curcumin to a target protein that is critically involved with the self-renewal of cancer stem cells. This analysis will help clarify the extent to which the multi-facetted anti-tumour activity of curcumin is mediated via its effects on this protein and contribute to the ongoing development of curcumin as an agent for the prevention and treatment of CRC and other solid tumours. The results will also allow the development of a screening system for identifying novel small molecule inhibitors of the target protein. Overall, the project could lead to the development of cancer stem cell-targeted agents which may provide potential benefit via chemoprevention of cancer or as a targeted cancer therapy.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Investigating ASPP2/Notch/p53/p63 interplay in oesophageal cancer development and prognosis
Funder: Cancer Research UK

Abstract: Oesophageal cancer is highly invasive and metastatic and is the sixth most common cause of cancer death with 5 year survival of ~15% globally. Oesophageal adenocarcinoma (OAC) and oesophageal squamous cell carcinoma (OSCC) are two major oesophageal cancer (OC) types with striking geographical distribution. OSCC and OAC are highest in northern China and in UK respectively. Importantly, the incidence of OAC has risen by 5 fold in the Western world over the last 30 years. Lack of suitable animal and human organotypic models and a shortfall of molecular insight into the cause of oesophageal cancer (OC) have resulted in the late diagnosis and lack of effective treatments. Notch was recently identified as the second most mutated tumour suppressor in OC after p53. In contrast to p53, the mutation frequency of Notch varies dramatically between American and Chinese OSCC and OAC. How Notch functions together with p53 to suppress OC and why Notch mutation differs geographically are fundamental questions. Recently we identified ASPP2, a common regulator of p53 and p63, as a novel haploinsufficient tumour suppressor of SCC. ASPP2 is mutated in human OC with low frequency. This application therefore aims to investigate whether ASPP2/Notch/p53/p63 could be the molecular cause of the striking differences in the geographic and anatomical distributions of OSCC and OAC among Chinese and western populations.


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: Combining TLR agonists with ChiLob 7/4 anti-CD40 mAb in neuroblastoma and lymphoma
Funder: Cancer Research UK

Abstract: Background Recent clinical results with immunomodulatory monoclonal antibodies (mAb) have revitalised the belief that the adaptive immune system can be harnessed to provide long term cures for cancer patients. The novel agonistic immunomodulatory human IgG1 mAb ChiLob7/4 targets the CD40 co-stimulatory receptor found on antigen presenting cells. It was developed in Southampton in partnership with Cancer Research UK and is currently in Phase I trial. Although well tolerated by patients it is clear that combination strategies will likely be required to maximise patient outcomes. We have recently demonstrated that the potency of anti-CD40 activity is dependent upon mAb isotype due to isotype-dependent differences in Fc receptor engagement required for mAb cross-linking and that no human isotype is ideal. We have also found that activity can be augmented through appropriate manipulation of Fc gamma receptor expression. In pre-clinical models, co-administration of toll like receptor (TLR) agonists that augment Fc?R expression can enhance anti-CD40 activity with synergistic immunostimulatory outcome. In this study we will investigate the therapeutic potential of the co-administration of ChiLob 7/4 with select TLR ligands for the treatment of two distinct malignancies: neuroblastoma and lymphoma. Aims To determine the clinical potential of combining ChiLob 7/4, an agonistic immunomodulatory anti-CD40 mAb with the adjuvant effects of selected toll-like receptor (TLR) agonists to augment therapeutic responses in neuroblastoma and lymphoma. Methods We will utilise transplantable congenic neuroblastoma (TH-MYC-N) and lymphoma (Eu-Myc) tumour models to establish the immune modulatory effects of Lob7/4 mIgG2a (equivalent of ChiLob7/4 huIgG1) in the presence and absence of three selected TLR agonists (TLR 1/2-Pam3CSK4/ TLR 3-Hiltonol(Poly(I:C))/ TLR7/8-Resiquimod(R848)), determining the optimal combinations and strategies to maximise the therapeutic potential of ChiLob 7/4 in these settings. These investigations will be carried out in parallel with in vitro proliferation and antigen presentation studies using ChiLob7/4 and TLR agonists with human monocyte derived dendritic cells, macrophages and T cells to increase the likelihood of translating our findings into successful Phase I trials. How the results of this research will be used The results will be used to design phase I trials of ChiLob7/4 and TLR agonists in children (neuroblastoma + other CD40+ tumours) and adults (lymphoma). Our results will be used to guide the selection, scheduling and dosing of the most potent combination, as well as to identify appropriate immune endpoints / biomarkers for these studies.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Does the activity of the PAK-PI3K signaling nexus promote pancreatic cancer tissue invasion?
Funder: Cancer Research UK

Abstract: Background Each year more than 8000 people are diagnosed with pancreatic cancer in the United Kingdom and even early stage disease is associated with poor 5 year overall survival rates. These figures highlight the urgent need for a greater understanding of the disease and the development of effective novel therapeutics. Metastatic spread requires reorganisation of the actin cyto-skeleton3, a process dependent on proteins belonging to the Rho family GTPases ; Rho, Rac and Cdc-41. and growing evidence supports the theory that the p21-actiavted kinase family (PAK1-6) may play a key role in cell migration, cell survival and regulation – key hallmarks of the development and progression of cancer. Published reports and our preliminary data suggest that PAK1, PAK4, PAK5 and PAK6 may be active and that PAK4 may be required for invasion. However, the role of other PAK isoforms has not been investigated. In addition, the Wells laboratory at KCL recently demonstrated that somatic PAK4 mutation increased activity and PAK5 mutations have been identified in pancreatic cancer. Aims Establish if PAK mutations are present in pancreatic cancer patient samples Establish the requirement for PAK-PI3K signaling in pancreatic cancer cell invasion Test our key findings using an 3D organotypic model of pancreatic cancer cell invasion Methods Using both tissue from patients with pancreatic cancer and organotypic models we plan to characterise the PAK/PI3K interaction and in particular assess their role in cancer growth and metastatic spread,. This will build on preliminary work that this group has performed that has already demonstrated the role of PAK 4 in prostate cancer and ongoing research with pancreatic cancer cell lines. We will use Patu8988T and Capan-1 cells for our migration and invasion analysis as these cells have previously been used by our group and others in migration and invasion studies. Using 2D cell migration assays, we will monitor the migratory behaviors of cells in a random migration chamber using digital time-laparoscopy. Results The preliminary data from this project will be used to apply for further funding for a PhD that will continue to focus on the PAK/PI3K interaction in pancreatic cancer. After ascertaining the role of PAK/PI3K interaction in the development and spread of metastatic pancreatic cancer, we hope to develop therapeutic targets that will be used to treat this disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: RHYTHM-2: modulation of Radiotherapy according to HYpoxia: exploiting changes in the Tumour Microenvironment to improve outcome in rectal cancer using PF-05212384.
Funder: Cancer Research UK

Abstract: Background: Activation of PI3K/Akt/mTOR is common in CRC. PI3K/Akt/mTOR Pathway inhibition is radiosensitising. Pre-clinical experiments with PI3K or PI3K / mTORi have shown tumour cell radiosensitisation in vitro. Specifically in CRC lines with mutant KRAS (HCT116, DLD) with and without additional mutations of PI3Kinase, inhibition of PI3K showed down regulation of AKT phosphorylation at Ser473 and resulted in radiosensitisation when PI-103 was added to radiation. In xenograft models, PI3K/mTORi cause marked reduction in tumour hypoxia after seven days of treatment mediated through prolonged vascular normalisation and reduced oxygen consumption. Radiosensitisation has been shown in pancreatic xenografts treated with radiation and BEZ235 compared. PF-05212384 is a PI3K-mTOR inhibitor with MTD of 154 mg administered as a once weekly iv infusion, suitable for inclusion in a radiotherapy schedule. It is currently entering phase 1 combination studies with chemo/novel agents. No radiotherapy studies are currently planned. Aims: To evaluate whether the PI3K-mTOR inhibitor PF-05212384 causes radiosensitisation in colorectal cancer cell lines, and the effect on tumour vasculature and radiosensitivity in xenograft models of CRC. Methods: authentic Pfizer compound is available free of charge. •In vitro: Assays in 4-6 cell lines to test effects on radiosensitivity and oxygen consumption and target inhibition. •In vivo: Two cell lines for in vivo studies will be chosen based on in vitro studies. We will assess the impact of PF-05212384 +/- chemoradiation on (i) tumour vasculature and oxygenation by non-invasive imaging, and (ii) on antitumour efficacy by assessing tumour growth delay. In vivo studies will include pharmacodynamic measures of unrepaired DNA damage and hypoxia. How the research will be used: To provide preclinical support for a trial proposal submitted to Pfizer global to assess PF-05212384 in rectal cancer: Cohort 1: proof of principle in Operable rectal cancer patients: does PF-05212384 change tumour physiology and reduce hypoxia in rectal cancer? (n= 10). Cohort 2: Dose escalation study in locally advanced rectal cancer for pre-operative chemoradiotherapy followed by resection at 6-12 weeks to assess safety and toxicity (DLTs and determine RP2dose) of PF384 in combination with Cohort 3: Expansion cohort (with imaging) n = 10.


Research activity codes: 6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS