NIHRDataInsights/HRCSData huggingface dataset:
Title: Structural analysis of the mTOR kinase domain by X-ray crystallography
Funder: Tenovus Cancer Care

Abstract: The mammalian target of rapamycin (mTOR) is a large protein kinase that represents an extremely attractive drug target for anti-cancer therapy. Indeed, rapamycin, which is a specific inhibitor of the mTOR complex, mTORC1, has potent anti-tumour properties. Rapamycin inhibits mTORC1 through its direct interaction with the FKBP12- rapamycin binding (FRB) domain, which lies proximal to the kinase domain of mTOR. Currently, there is no published inhibitor of mTOR that specifically binds to the kinase domain and this is partly due to the lack of detailed structural information available for mTOR. We propose to determine the structure of the mTOR kinase domain by X-ray crystallography and combine this approach with additional functional characterisation studies. In recent preliminary studies, we have been able to grow crystals from a discrete protein fragment that contains the kinase domain of mTOR with low conformation flexibility. We were able to enhance the speed and onset of crystal formation when the kinase domain of mTOR was incubated in the presence of PI3K inhibitors. PI3K inhibitors are known to non-specifically inhibit mTOR in vitro and in vivo. Interactions of the purified kinase domain of mTOR with PI3K inhibitors generated a more stable mTOR:inhibitor complex that favoured crystal formation due to lowered entropy. These preliminary studies now require further optimisation to identify better crystal growth conditions. We plan to prepare large amounts of recombinant mTOR protein, screen an array of crystallization conditions to generate protein crystals that are suitable for x-ray diffraction studies and solve the structure of the kinase domain. Interestingly, point mutations in TOR were previously shown to confer Rheb-independent growth in fission yeast and nutrient-independent activity in mammalian cells. One of these point mutations, E2419K, lies within the kinase domain of mTOR. Our structural studies will compare this activating mutation of mTOR within the kinase domain, E2419K, with that of wild-type mTOR. This analysis will reveal why the E2419K mutant has a higher kinase activity relative to wild-type. Based on the detailed information derived from these crystal structures, we will characterise the kinase domain by further mutation analysis. To examine the single point mutations that are generated, we will analyse the kinase activity of these mutants in cells, as well as utilising in vitro kinase assays against mTORC1 and mTORC2 substrates. Defining the precise atomic structure of the kinase domain of mTOR is of immense scientific and clinical interest that will dramatically aid the design of drugs that bind to and inhibit mTOR specifically.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS
Title: Advancing the Quality and Research-efficiency of economic evaluation alongside Cancer Trials in Wales: Application of Value of Information Theory
Funder: Tenovus Cancer Care

Abstract: Many trials in cancer have an economic analysis component to ascertain whether or not the technology under investigation is cost-effective. In our health economics unit’s recent experience, for the last 6 funded trials (cancer and non cancer), the budget for economic evaluation has averaged 6 percent of the total clinical trial budget. This seems relatively low given that the results of cost-effectiveness studies may have a direct impact on patient care through, for example, informing decisions by NICE and the All-Wales Medicines Strategy Group. Objective: To assess the trade-offs between precision of cost estimates, and research intensity of data collection, through modelling the research-efficiency of different approaches to the collection of patient service use data. Methods: The student will apply “value of information” theory in an innovative way to explore research -efficiency in economic evaluation alongside cancer trials. Value of information theory assesses the extra benefits of collecting additional information in terms of reducing error and weighs these up with the added research costs of collecting this information. S/he will (1) review current theory and guidance on how costs should be collected in clinical trials; (2) survey those leading or collaborating on cancer trials ( at both research centres and haematology/oncology units) with an economic component in Wales to find out how they are collecting service use and cost information in current trials; (3) design and undertake a number of modelling exercises using a cancer trial data set to demonstrate the impact on cost-effectiveness, of different approaches to collecting and costing drugs, inpatient stays, chemotherapy, and primary and community care; (4) conduct value of information analyses (expected value of perfect information, EVPI; and expected value of partial perfect information, EVPPI) to quantify the trade-off between the precision of cost estimates and the costs of data collection to assess the implications for health economics resourcing in this trial (and generalised to others); and (5) assist with the writing of a Standard Operating Procedure (SOP) for the collection and costing of service use for UK CRC trials unit use, initially specifically for NWORTH, the Bangor Trials Unit. This SOP will be made available publically via NWORTH’s website.


Research activity codes: 8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES);8.2 HEALTH AND WELFARE ECONOMICS
Health categories: CANCER AND NEOPLASMS
Title: Identifying genes associated with severe toxicities in the treatment of advanced colorectal cancer
Funder: Tenovus Cancer Care

Abstract: Each year in the UK, over 16,000 patients die from colorectal cancer (CRC). The treatment of CRC is rapidly improving; for advanced CRC (aCRC) average survival has increased from ~6 months with best supportive care alone, through 10-12 months with single agent 5FU regimens and up to 16-20 months in randomised trials using oxaliplatin as well as 5FU. Despite these advances, around half of all patients fail to respond to first line treatment and many suffer from the considerable side effects. Inherited genetic variations can affect a patient’s response to, and side effects from, chemotherapy. Here, we will use exome re-sequencing and subsequent validation analyses to attempt to identify novel genes associated with severe oxaliplatin-induced neurotoxicity and cetuximab-induced acneiform skin rash. Identification of these genes may lead to a better understanding of the mechanisms underlying more generalised toxicities and therapeutic efficacy (skin rash is a surrogate marker). Knowledge of these variations may help to ‘tailor’ therapy for improved response and reduced toxicity.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS
Title: Characterising the role of Cbx3/Hp1gamma in normal intestinal homeostasis and tumourigenesis
Funder: Tenovus Cancer Care

Abstract: Three heterochromatic protein 1 (HP1) proteins (alpha, beta and gamma) exist in mammals, each with non-redundant functions and capable of activating or suppressing gene transcription. The HP1 proteins recognise a specific post-translational modification of histone proteins (H3K9me), thereby having a critical role in interpreting epigenetic gene regulation. Accumulating evidence suggests that Hp1gamma, encoded by the gene Cbx3 (Chromobox Homolog 3), is involved in cell proliferation and differentiation and becomes mis-regulated in numerous cancer settings. We have shown that activation of Cbx3 expression occurs following Wnt signaling activation and during intestinal tumourigenesis. Wnt signaling is a key pathway in the regulation of intestinal stem cells ensuring homeostatic self-renewal of the intestine, while aberrant Wnt signaling activation results in expansion of the intestinal stem cell population and is also recognized as a key initiating event in intestinal tumourigenesis. Loss of the tumour suppressor gene APC (Adenomatious Polyposis Coli) results in activation of Wnt signaling and we propose that the subsequent mis-regulation of Cbx3 contributes to the neoplastic phenotype observed, potentially via modulation of the intestinal stem cell population. To directly test this hypothesis we propose to conditionally delete Cbx3 in isolation or together with Apc within the adult mouse intestine and study the effects on intestinal homeostasis, including analysing the impact on the intestinal stem cell population, and tumour predisposition and progression. Thereby, we will be able to elucidate the role of Hp1gamma protein in regulating normal intestinal homeostasis, tumour initiation and progression, and provide a critical understanding of the relationship between Wnt signalling and epigenetic gene regulation in these processes. The importance of Wnt signalling in colorectal cancer (CRC) is undisputed. We have performed expression analysis using samples from human CRC patients and confirmed over-expression of Cbx3 is a clinically relevant phenomenon occurring during human colorectal cancer development (Fig1). Furthermore, Cbx3 is over-expressed and ranked within the top 10% of gene changes in all but one of the colorectal cancer data sets on the online cancer microarray database, Oncomine. Understanding the importance of this over-expression would improve our knowledge of the mechanisms underlying neoplasia, and provide potential new pathways to target for therapeutic intervention.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS
Title: Analysing the acute effects of Axin loss in liver and colon cancer
Funder: Tenovus Cancer Care

Abstract: High quality 3D cell culture models that recapitulate tissue organization, stem cell behaviour and differentation should advance drug discovery by allowing early candidate compounds to be separately optimised for efficacy and in vivo stability. Here we propose developing a 3D tissue-culture model that recapitulates Axin1 and Axin2 loss of function in liver and intestinal cancer respectively. The culture systems that have been established are a recent breakthrough in 3D culture technology and maintain tissue stem cells in the absence of a supporting mesenchyme. Liver and stem cell cultures with and without oncogenic stimuli (loss of the Axin1 or Axin2 antioncogenes) will be exposed to inhibitors of the Wnt pathway to identify compounds that have potential as anti-cancer therapeutics.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS
Title: A longitudinal study exploring breast cancers survivors' experiences of remaining in or returning to paid employment during and after treatment in South Wales
Funder: Tenovus Cancer Care

Abstract: The aim of this research is to provide an in-depth exploration of participants’ experiences of remaining in or returning to paid employment during and after treatment for breast cancer. Consequently, a qualitative, phenomenological approach, informed by the philosophy of Heideggerian hermeneutics, will be used to conduct this study (Heidegger 1962, Walters 1995). Phenomenology is a research/philosophical approach used to understand the lived experiences of participants (Crotty 1996). It is an inductive, descriptive method that attempts to study phenomena as they are consciously experienced (Beck 1994). The focus of Heideggerian hermeneutics is the ‘interpretation’ of ‘lived experiences’. Researchers subscribing to Heideggerian philosophy acknowledge that they can only interpret something according to their own beliefs, experiences and preconceptions, which are a legitimate part of the research process and should not be left out (Lowes and Prowse 2001). Therefore, in practice, researchers using this approach, acknowledge their own background and preconceptions and constructively use them to ‘co-create data’ with their participants, both in the collection and analysis phase.The longitudinal approach will allow the researcher to explore participants’ experiences as they progress through different stages of their cancer treatment and recovery (Parahoo 2006).


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: CANCER AND NEOPLASMS
Title: Characterisation of the prognostic role of embryonic stem cell marker expression in circulating tumour cells from patients with metastatic cancer.
Funder: Prostate Cancer UK

Abstract: The mainstay of treatment for advanced prostate cancers is androgen deprivation. It is difficult to predict the success of this treatment and many patients relapse within 24-36 months, developing castration resistant prostate cancer (CRPC). Recent studies looking at capturing circulating tumour cells (CTCs) from patients with prostate cancer have shown that the number of CTCs at diagnosis is a known predictor of survival. Gene expression within CTCs is also being explored as a prognostic tool. Emerging data propose that individual expression of embryonic stem cell (ESC) markers in prostate cancer correlate with clinical histological grade and survival. Pilot data from our lab, based on immunohistochemistry, has shown has shown that in 74 patients with CRPC, those with high levels of all three ESC markers Oct4, Sox2 and Nanog (OSN) have significantly reduced survival. The role of ESC genes as candidate biomarkers in determining outcomes in advanced prostate cancer treatment therefore warrants further investigation. We hypothesise that the expression of OSN in CTCs from patients with advanced prostate cancer correlates with clinical outcomes in patients receiving hormone treatment. In this study we will prospectively evaluate the above ESC markers in CTCs in advanced prostate cancers; characterise key regulatory pathways associated with clinical OSN expression to identify targets, and validate putative targets using prostate cancer cell lines. We aim to identify patients less likely to benefit from hormone treatment, to provide a personalised medicine approach. Characterisation of the molecular pathways in the cancers of these patients will also help us to identify potential new treatment targets.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: CUP RFA: Development of systematic review methodology for mechanistic studies
Funder: World Cancer Research Fund

Abstract: Background: Systematic reviews are acknowledged as the most rigorous way to synthesise data which have addressed a common question. Methods for conducting and reporting rigorous systematic reviews of epidemiological studies have been developed, but remain


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: CANCER AND NEOPLASMS
Title: Feasibility of reduction in Right Sided Bowel cancer through Contrast enhanced Colonoscopy - The CONSCOP RIGHT SIDE study
Funder: Division for Social Care and Health Research (Wales)

Abstract: The Bowel Cancer Screening program was implemented to address the important issue of prevention and early detection of bowel cancer. Results from the first few years of screening and previous smaller studies show that while in its current form it will save many lives, there continue to be polyps and cancers in the upper large bowel (right side) that may be difficult to detect. There is some evidence that these types of polyps (serrated polyps) may be at least partly responsible for cancers missed at the initial colonoscopy and have a faster rate of growth to cancer compared to conventional polyps (adenomas). We propose to examine participants undergoing screening colonoscopy with the addition of a contrast dye ( a safe food colouring agent base already used in various bowel camera procedures in standard clinical practice). This has been shown to improve detection of conventional polyps significantly even though it is considered by some to be more time consuming (possibly taking a few minutes longer) and requiring specific training to undertake. We hope to study the feasibility of undertaking these procedures to improve detection and removal of these polyps within the bowel screening program and potentially inform further studies to assess the impact of improved detection and consequent potentially reduced incidence of interval or missed bowel cancers in longer term follow up. Thus the main aims of this feasibility study are to assess if this type of procedure would be feasible to implement and acceptable to participants, colonoscopists and the screening program and also assess any additional time or costs involved to inform the question of if a larger study should then be undertaken to conclusively prove or disprove the merits of this approach in terms of health economics, cancer detection and survival.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Creating a rapid diagnostic pathway for patients with pancreatic cancer
Funder: Pancreatic Cancer UK

Abstract: Pancreatic cancer has a 5 year survival of less than 4% which has remained unchanged over the last 40 years. Despite advances in diagnostic technology, pancreatic cancer is usually diagnosed late and at an incurable stage, whilst early diagnosis is directly linked to improved survival. Although numerous biomarkers for pancreatic cancer have been reported, none have been adopted into routine clinical practice and alternative diagnostic strategies are urgently required. Our on-going research efforts have identified promising early biomarkers of pancreatic cancer, and have also shown that early symptoms are often not recognised. In the proposed study, we aim to provide primary care physicians with a rapid diagnostic pathway for patients with pancreatic cancer by implementing early detection tests in symptomatic, ‘at-risk’ patients. This will be achieved by: (i) validating promising early biomarkers in pre-diagnosis blood samples for a screening or diagnostic test, (ii) refining and validating an early symptoms tool to identify individuals ‘at-risk’ of pancreatic cancer, and (iii) trialling the rapid diagnostic pathway within the North London Cancer Network. We will also test promising candidate biomarkers specifically for the detection of pancreatic neuroendocrine tumours (PNETs), using newly collected patient samples and those collected from women prior to their diagnosis. Building on the work and progress so far, this project will for the first time bring together the resources of the NIHR UCLH Biomedical Research Centre, the Liverpool NIHR Pancreas BRU, the UCL Early Symptoms Study, UKCTOCS, EUROPAC and London Cancer to deliver a screening tool for the early detection of pancreatic cancer.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: The role of Eps8 in αv-β6-dependent functions in pancreatic cancer invasion
Funder: Pancreatic Cancer UK

Abstract: Pancreatic adenocarcinoma (PC) has one of the worst outcomes of any cancer; only 3.7% of patients survive for more than 5 years. Patients usually present with advanced disease, less than 20% of patients are suitable for surgical treatment, mainly because at the time of diagnosis the tumour has already spread into adjacent tissues, making surgery impossible. The spread of malignant cells locally (tumour invasion) is fundamental to cancer development and progression. Integrins are a family of cell surface receptor proteins that play a variety of roles in cancer. The integrin αvβ6 is not found on healthy cells but is upregulated in cancer. We and others have found that high levels of !vβ6 are seen in more than 70% of PCs and that αvβ6 can promote tumour invasion directly by increasing cell movement and indirectly by activating a signalling protein called TGF-β. TGF-β is critical to the formation of the characteristic fibrous supporting tissue surrounding the cancer cells which is known to promote tumour progression. We have identified a novel link between αvβ6 and the protein Eps8. Eps8 is also upregulated in more than 70% PCs and plays a role of changing cell shape allowing cells to move and invade. We have found that a high level of Eps8 promotes αvβ6-dependent cell movement, yet inhibition of Eps8 promotes αvβ6-dependent TGF-β activation. αvβ6 is an exciting potential target for PC therapies however the activation of TGF-β by αvβ6 can have both positive and negative effects on PC progression. It is essential therefore that we understand the mechanisms underlying these critical functions of αvβ6, and Eps8 warrants further investigation as a potential molecular switch controlling these functions in PC. Understanding this process will give crucial insight into the biology of tumour cell invasion, and may uncover novel targets for the treatment of PC.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: microRNAs as biomarkers of chemotherapy sensitivity in pancreatic cancer
Funder: Pancreatic Cancer UK

Abstract: Background: Advanced Pancreatic cancer has a dismal prognosis with a low rate of curability. Increased response rate and survival advantage is achieved by combination regimes such as FOLFIRINOX, which, however, have an unfavourable toxicity profile. Predictive biomarkers of response to this regime are lacking, making the selection of patients more challenging. The decision process is even more complicated when FOLFIRINOX is given pre-operatively in borderline resectable cancers, in which cases a good tumour response is warranted but toxicity may preclude surgical intervention. Therefore biomarkers of response to this chemotherapy are needed to better personalize treatment and carefully assess the balance between the risk of side effect and the chance of success. Detection of circulating microRNAs is a promising area of investigation as represents a reproducible, non-invasive and cost/effective tool. Aims: I. To identify circulating microRNAs that predict response to chemotherapy in advanced pancreatic cancer patients. II. To cross-compare miRNAs expression in pancreatic cancer tissues and sera from patients with borderline resectable disease. III. To study the mechanisms of miRNA mediated sensitivity/resistance to chemotherapy. Methods: We will profile circulating miRNAs by real-time PCR-array in sera of patients with metastatic and locally advanced pancreatic cancer before starting chemotherapy with FOLFIRINOX and will correlate miRNA-expression with response rate and clinical outcome. We will then assess the expression of selected microRNAs in the sub-group of T3N1R1 pancreatic cancer patients by Taqman assays and will match miRNA expression between pancreatic adenocarcinoma tissues and sera. miRNA-mediated mechanisms of resistance to FOLFIRINOX will be assessed in pancreatic cancer cell lines by studying drug sensitivity after transfection with miRNA-precursor/inhibitors. How the result of this research will be used: These studies aim to identify circulating microRNAs that can predict the sensitivity/resistance to FOLFIRINOX-chemotherapy and can be used as a non-invasive tool to decide the appropriate treatment for each patient. Although circulating miRNAs showed promises as diagnostic tool, they have never been studied as predictive biomarkers of response in pancreatic cancer. Thus, findings from these studies may open the way for a prospective multi-centre clinical trial for the stratification of patients undergoing FOLFIRINOX chemotherapy.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS