NIHRDataInsights/HRCSData huggingface dataset:
Title: Pharmacological inhibition of monocarboxylate transporter-4: Pre-clinical evaluation in combination with radiotherapy.
Funder: Cancer Research UK

Abstract: Cancer cells have an increased reliance on glycolysis for survival and this manifests itself by increased utilization of glucose and the accumulation of lactate. As such, the glycolytic phenotype has been identified as an emerging hallmark of cancer, with both glycolytic rate and lactate concentration having been suggested to predict an increase in the likelihood of metastasis, resistance to radiotherapy and reduced survival. Our work has recently focused on lactate transport in tumour cells. This is carried out by members of the monocarboxylate transporter (MCT) family, notably MCT1 and MCT4. We first established the importance of these transporters in Head and Neck (H&N) cancer. We were able to show an association between the protein expression of MCT4, but not MCT1, and treatment outcome following radiotherapy. Survival analysis indicated that those patients with high MCT4 expression had a poorer outcome following radiotherapy than those with low MCT4 expression, suggesting that MCT4 expression is an adverse prognostic indicator. We subsequently validated MCT4 as a potential therapeutic target by down-regulating MCT4 in H&N cancer cells and showing that they become more sensitive to treatment with radiation. The purpose of this project is to establish the effectiveness of proprietary drugs as inhibitors of MCT4 and thereby potentially improve the efficacy of radiotherapy for the treatment of H&N cancer and other malignancies.


Research activity codes: 6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Plk1 inhibitors as a therapy for glioblastoma
Funder: Cancer Research UK

Abstract: Background: Glioblastoma multiforme (GBM) is the most common form of primary brain cancer. Current treatments are ineffective and median survival is only ~14 months. There is an urgent need to improve our understanding of the biology of GBM and translate this into novel treatment approaches. New in vitro models of the human disease have been developed through application of neural stem (NS) cell culture techniques. We recently carried out a phenotypic screen of 160 known kinase inhibitors against GBM-derived neural stem (GNS) cells. We identified a sensitivity of GNS cells to inhibition of Polo-like kinase 1 (Plk1) compared to genetically normal NS cells._x000D_ Aims: The overall hypothesis is that Plk1 inhibitors will be effective against GBM. We will model this in vivo using orthotopic xenotransplantation of GNS cells. The objective is to generate sufficient preclinical data to stimulate new clinical trials. There are four major aims:_x000D_ 1. In vitro screening of GSK461364 and 23 additional structural analogues against normal neural stem cells and GBM-derived neural stem cells for differential sensitivities and blood-brain barrier (BBB) permeability._x000D_ 2. For the five best inhibitors determine their ability to induce mitotic arrest in vivo using human orthotopic xenograft tumours._x000D_ 3. For the best two candidates, analyse pharmacokinetics within both the xenograft tumour mass and surrounding ‘normal brain tissues’._x000D_ 4. Survival analysis of inhibitor treated mice harbouring xenograft tumours representative of three major molecular subtypes of disease._x000D_ _x000D_ Methods: In vitro assessment of inhibitor responses will be performed using live cell imaging, flow cytometry and immunocytochemistry/immunoblotting for mitotic markers. BBB permeability will be modeled using an in vitro porcine brain endothelial cell co-culture assay (collaboration with Prof Joan Abbott). The major in vivo model is the orthotopic transplantation of GNS cells into the adult brain of immunocompromised mice. We will assess in vivo responses using immunohistochemistry for mitotic and spindle markers. HPLC/LC-MS will be used for the PK analysis. Bioluminescence imaging technologies will be used in Aim 4._x000D_ _x000D_ How the results of this research will be used: The results of these preclinical studies will help stimulate, guide and support new clinical trials to determine the efficacy of Plk1 inhibitors as a treatment for GBM. Upon completion of the project an internal steering group and clinical collaborators will discuss possibilities for new trials and explore potential funding streams from the CRUK drug Discovery Office, Samantha Dickson Brain Tumour Trust and/or GSK._x000D_


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: MLN4924, targeting a key regulator in merlin deficient tumours- target validation
Funder: Cancer Research UK

Abstract: Merlin is a tumour suppressor and is lost in a variety of tumours including schwannomas, meningiomas, ependymomas, glioblastomas, mesotheliomas and breast cancers. In all schwannomas, the majority of meningiomas and 1/3 of ependymomas merlin loss is causative. In Neurofibromatosis type 2 (NF2), a dominantly inherited tumour disease, due to the loss of Merlin, patients suffer from multiple nervous system tumours and die on average at age of 40. Chemotherapy is not effective and tumour localisation and multiplicity make surgery and radiosurgery challenging and morbidity is often considerable. Thus, a new therapeutic approach is needed for these tumours. We have established and validated a human in vitro model for NF2 and have shown that it adequately reflects major aspects of NF2 related tumours, have characterised new drug targets in vitro and translated them into early clinical trials. However quite a large number of abnormal signalling pathways and potential drug targets have been identified by us and others in these tumours. In collaboration with a group at the Memorial Sloan-Kettering Institute we have discovered a potentially unifying disease mechanism in these tumours: merlin interacts and inhibits Cullin 4-Ring E3 Ubiquitin ligase (CRL4-DCAF1) which regulates transcription of signalling pathways like RTKs and downstream pathways previously show to be activated in these tumours. Millenium pharmaceuticals have developed a first in class inhibitor of the activation of Cullin 4-Ring E3 Ubiquitin ligase (CRL4-DCAF1). As a proof of principle we have shown MLN4924 dose dependently reduced proliferation of primary human (merlin deficient) schwannoma cells but not normal merlin expressing Schwann cells. We hypothesize that MLN4924 has the potential to correct an abnormal master regulator pathway in NF2 and tumours in which merlin is lost. Thus we aim to validate MLN4924 for treatment of merlin deficient tumours using our established preclinical human schwannoma in vitro model. We will use established relevant cell biological read outs, proliferation/apoptosis/adhesion to determine IC50. To understand MLN 4924 action incl. potential feedback mechanisms we will analyse relevant signalling pathways downstream of Cullin 4-Ring E3 Ubiquitin ligase (CRL4-DCAF1). If MLN4924 reduces proliferation and/or increases apoptosis progress at reasonable IC50 we will apply to the New Agents Committee to do a feasibility/tolerability study of MLN4924 in NF2 patients. We plan to validate the PD biomarker as part of this feasibility/tolerability study.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Hedgehog acyltransferase: a therapeutic target in pancreatic cancer
Funder: Cancer Research UK

Abstract: • Background_x000D_ The hedgehog (Hh) signalling pathway is implicated in the aetiology of many cancers. The pathway can act in both an autocrine manner and a juxta/paracrine manner to surrounding stroma, causing it to produce a microenvironment supporting tumour growth and drug resistance. In some cases, the pathway is activated in the tumour cells by mutation of signal transducers such as Smo and Gli, promoting growth and metastasis; in others it is due to overproduction of Hh proteins. Therapeutics have been developed by pharma companies to target Smo and Gli and are in clinical trials, but these suffer from development of mutations in the targets which render them resistant. There is therefore an unmet need for inhibitors which have different targets. This is particularly true for PDAC for which there are currently no really effective treatments, and which is almost invariably rapidly fatal following diagnosis._x000D_ During biosynthesis, Hh proteins undergo addition of N-terminal palmitate which is required for their function and is catalysed by the highly specific multipass transmembrane enzyme Hedgehog acyltransferase (Hhat). We and others have shown that Hhat knockdown reverts the transformation of PDAC and other tumour cells._x000D_ • Aims_x000D_ Here we propose to further validate Hhat as a target in PDAC by analysing its expression in tumour samples. We plan to develop an effective antibody against Hhat for this purpose, and to express and purify the protein both for biochemical analysis and structural studies. We have developed in vitro and cell based assays for Hhat that we will take forward with our collaborators to medium and high throughput scales in order to screen large compound libraries to ultimately identify leads for therapeutic application in PDAC._x000D_ • Methods_x000D_ - Develop and validate an effective antibody against Hhat with a commercial company_x000D_ - Express Hhat in insect cells and purify the protein following detergent lysis_x000D_ - Attempt crystallisation of Hhat for structural studies with the MPL/DLS_x000D_ - Optimise in vitro peptide-based enzyme assay and cell based reporter assays for Hhat with our collaborators for medium and high throughput scales_x000D_ - Screen large compound libraries with our collaborators to identify hits and validate them as leads for therapeutic application in PDAC. _x000D_ • How the results of this research will be used._x000D_ Hhat inhibitors could be efficacious in PDAC and other tumour types dependent on Hh overexpression, and could be used in combination with Smo/Gli inhibitors and conventional anti-cancer agents.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Control of mitotic commitment and progression
Funder: Cancer Research UK

Abstract: Anti-microtubule reagents are believed to be effective in cancer therapy because the disruption of mitotic spindle function they invoke arrests cell cycle progression in mitosis. Prolonged mitotic arrest often triggers an apoptotic pathway that eradicates the cell. This view has fuelled considerable interest in finding alternative ways to impose a mitotic arrest that entraps cells in this state from which they will be predisposed to suicide. In part this effort is motivated by the fact that microtubule disruption does not induce apoptosis each time it invokes a cell cycle arrest. Sometimes cells slip out of the mitotic block to survive. Additionally, the other functions executed by microtubules mean that microtubule disruption has side effects, most notably neuro-toxicity. Therefore, agents that target the spindle alone should have greater potency and fewer side effects. The programme we propose explores the underlying biology of three fertile areas for exploitation in the bid to find novel ways to trap cells in mitosis; mitotic commitment, mitotic exit and mitotic regulators. The potency of force cells into division from any point in the cell division cycle into mitosis in pre-clinical models via Wee1 inhibition suggests that greater insight into the switch will uncover new opportunities for this effective approach. Considerable effort in anti-mitotic drug development is invested in the mitotic kinases that drive mitotic progression. Without the activity of these kinases, cells get stuck in mitosis. We will address this area through global phosphoproteomics of cells in which kinase function is abolished or enhanced. More recently it has been proposed that blocking mitotic exit is likely to be extremely effective in trapping cells in mitosis. Our programme contributes to this area by characterising the means by which the PP2A protein phosphatase complexes that drive mitotic exit are reactivated within mitosis to drive exit. We use fission yeast as a simple model system because all the mitotic switches we analyse are conserved and many involve extensive feedback loop controls that require mutation of endogenous loci at multiple points to dissect out the contributions of different signalling pathways to the integrated signal that governs cell cycle progression. We seek support for one of these three aims from CRUK; the control of mitotic commitment. We will seek support from other sources for activity in the other two areas. Specifically, with CRUK support, we will address how signalling scaffolds on the centrosome regulate the timing of mitotic commitment.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/12/047: Randomised phase 2 study of afatinib penetration into cerebral metastases for patients undergoing neurosurgical resection, both with and without prior low-dose, targeted radiotherapy (CamBMT1) (jointly funded with The Brain Tumour Charity)
Funder: Cancer Research UK

Abstract: Failure of drugs to cross the blood brain barrier (BBB) can be a major reason for treatment failure for patients with brain tumours. For most patients who don't respond to treatment, it is not known whether this is due to inadequate drug concentrations in the tumour, or due to drug resistance. Preliminary preclinical and clinical data suggest that low-dose radiotherapy may disrupt the BBB, and could facilitate increased drug delivery into brain tumours. This trial has been designed to address two main questions: 1) What concentration of afatinib is detected in resected brain metastases after 11 days of afatinib 40mg given once daily?, and 2) Does a single fraction of low-dose targeted radiotherapy given prior to afatinib increase drug delivery to brain metastases? If so, does a single 4Gy fraction have a greater effect than a single 2Gy fraction? 78 patients with operable brain metastases from breast or lung primaries, will be recruited to receive 11 days preoperative treatment with afatinib, a potent, irreversible pan-HER inhibitor. During the safety run-in phase, the safety of increasing doses of afatinib (10mg, 20mg, 30mg, 40mg dose levels), will be assessed following a single fraction of targeted radiotherapy. There will be two parallel safety run-in arms: one combining afatinib with a single 2Gy of targeted radiotherapy, and the other with a single 4Gy fraction of targeted radiotherapy. Using the maximum safe doses identified in Part A, 46 patients will be recruited to the randomised Part B, with three treatment arms: i) afatinib alone (n=20) ii) afatinib plus 2Gy single fraction of radiotherapy (n=20) iii) afatinib plus 4Gy single fraction of radiotherapy (n=20) The primary endpoint of the study is the steady-state afatinib concentration detected in resected brain metastases compared to serum levels. Secondary endpoints will be: toxicity of afatinib following targeted low-dose radiotherapy; functional magnetic resonance imaging to detect changes in perfusion, vascular density and interstitial pressure. Exploratory endpoints will be molecular profiling of reflected brain tumours focusing on lipid and tyrosine kinomes, for comparison with primary lung and breast cancers.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Epigenetic silencing of Wnt antagonists in prostate cancer
Funder: Cancer Research UK

Abstract: Background: Prostate cancer is the most common male cancer, accounting for 25% of cancer diagnoses and over 10,000 annual cancer deaths in men in the UK. There are many unmet clinical needs regarding the management of prostate cancer including more specific tests to identify individuals who need to undergo prostate biopsy and improved risk stratifying of patients with early prostate cancer needing direct therapy. Epigenetic changes play a more significant role in early tumour development than previously thought. Hypermethylation patterns, a marker of epigenetic change, of tumour suppressor genes may provide useful risk stratification for patients with early tumours. Hypermethylation of secreted Wnt antagonist genes has been demonstrated in a wide range of tumours, indicating that silencing is a common feature of solid tumourigenesis. Silencing of the Wnt antagonists has been reported in prostate cancer as well. Aims: The purpose of this project is to analyse epigenetic changes in secreted Wnt antagonist genes that occur in prostate cancer and to determine whether these events can be exploited to provide supplementary biomarkers for prostate cancer staging and prognosis. How the results of this project will be used: If this preliminary study shows promising evidence, the data will be used to expand our research into the role of epigenetic changes in prostate cancer with a follow-up project.


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: Understanding age inequalities and inequities in cancer diagnosis, treatment and outcomes in brain, colorectal and ovarian tumours, sarcoma and Hodgkins lymphoma
Funder: Cancer Research UK

Abstract: Background Evidence suggests there are age related inequalities in cancer treatment and outcomes but there is insufficient information to provide a complete picture of the situation. There are known inequalities in cancer treatment and outcomes nationally and work to address this has become a key focus of the NHS and cancer bodies in recent years. Aims This study aims to exploit routine health data to quantify, understand and describe the influence of age on the incidence, tumour characteristics, diagnosis, treatment, survival and long-term outcomes of brain, colorectal and ovarian tumours, sarcoma and Hodgkin lymphoma at a population level. It also intends to develop understanding of the root cause of age related variation and to examine the total healthcare experience of patients. The final objective is to produce a robust, replicable methodology for the assessment of inequalities in relation to age. Methods Data from the National Cancer Data Repository (NCdr) will be used alongside additional data sources to perform a descriptive and statistical analysis of patient and tumour characteristics, co-morbidity, method of presentation to secondary care, treatment and outcomes (including survival) using age as a continuous variable. International collaboration facilitated by the International Agency for Research on Cancer (IARC) will be used for international comparison and allow for the determination of the UK’s position in an international setting. How the results of this research will be used The results from this project will be disseminated through routine pathways, peer reviewed journals and conference presentations. The results will also be used to inform service delivery and commissioning. The Cancer Equalities Portal, run by the National Cancer Intelligence Network (NCIN), provides a useful resource for the dissemination of results. Observations will also be distributed through the National Cancer Survivorship Initiative. The methodologies produced during collaboration with IARC to utilise stage and survival data will be used to supplement the international data already held. The production of a dataset including multiple data sources will create a valuable resource for use in other projects and also will produce a generic ethics model which can be used for similar projects in the future.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: CANCER AND NEOPLASMS
Title: Harm reduction and smoking: smokers’ understandings and experiences
Funder: Cancer Research UK

Abstract: Background: Smoking is the most important cause of preventable death and disease in the UK. The UK is at the forefront in implementing comprehensive tobacco control policies designed to prevent smoking initiation and to help smokers to quit, having employed various successful population-level interventions and developed internationally unique NHS stop smoking services. However, there are growing concerns that the decline in adult smoking prevalence may be levelling off. Whilst most smokers try to quit, the majority are not successful. Some experts have therefore argued for the use of harm reduction approaches to reduce smokers' health risks. Generally, harm reduction approaches suggest that smokers who are unable to or do not want to quit should be advised to switch from smoking cigarettes to less harmful nicotine delivery devices - devices that deliver nicotine without inhaling tobacco smoke, such as nicotine replacement therapies or electronic cigarettes (e-cigarettes). Despite the fact that harm reduction approaches have divided the international tobacco control community, they have recently become influential in the UK, particularly in English tobacco control policy. However, we know very little about how smokers view harm reduction. Aims: To explore how tobacco harm reduction approaches and alternative nicotine delivery devices, including e-cigarettes, are understood and experienced by smokers and recent ex-smokers, and to consider the implications for tobacco control policy and practice. Methods: This qualitative study will focus particularly on groups of smokers who either may find it harder to quit or for whom quitting is particularly important and are, therefore, considered most likely to benefit from harm reduction i.e. those with low socio-economic status, smoking-related diseases, mental health issues and young adults. We will undertake focus groups and semi-structured individual interviews with purposively selected smokers from these four groups. The analysis will explore what considerations and criteria smokers draw upon when evaluating health risks and smoking-related choices. We will examine how smokers conceptualise nicotine as a substance and how they understand the risks and benefits of different nicotine delivery devices. How the results will be used: The study findings will be discussed with two expert panels of key stakeholders to identify implications for tobacco harm reduction policy and practice. A research briefing will then be produced and disseminated to relevant academic, policymaker and practice stakeholders. Presentations will be given to tobacco control networks and at relevant Scottish and UK conferences. Peer-reviewed papers will be prepared for publication in high quality academic journals.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: CANCER AND NEOPLASMS