NIHRDataInsights/HRCSData huggingface dataset:
Title: Investigations into the role of glycogen synthase kinase-3 in non small cell lung carcinoma.
Funder: Cancer Research UK

Abstract: BACKGROUND<br/>Lung cancer is the most common cause of cancer-related death. In the U.K. 70% of people die within a year of diagnosis and after five years this rises to 92%. There remains, therefore, a major unmet need for effective treatments for this disease. New targeted drugs, such as erlotinib and gefitinib, have started to change this but they are only effective at improving survival in a relatively small proportion (~10%) of patients with non-small cell lung cancer (NSCLC). We have found that one third of patients with early stage (I/II) NSCLC have tumours which exhibit hyperactivation of glycogen synthase kinase-3 (GSK3). We have additionally found that a selective GSK3 inhibitor blocks the growth of NSCLC cell lines expressing high but not low levels of GSK3 activity. <br/><br/>AIMS AND OBJECTIVES<br/>The objective of this proposal is to further validate our observations and to build a case for progressing GSK3 inhibitors towards a clinical trial in NSCLC.<br/><br/>METHODS<br/>We will further confirm our observations in our collection of biopsies from human early stage NSCLC, extend the study to an examination of biopsies of tumours we are collecting from late stage human NSCLC, and explore the consequences of manipulating GSK3 activity in a panel of normal lung and NSCLC tumour cells using pharmacological and genetic approaches in cell culture and in murine tumour xenograft models. We will also investigate the mechanism of action of GSK3 inhibitors and role of GSK3 in NSCLC. The Tavar&#233; and Seckl laboratories will bring together their combined expertise to undertake these studies, and all the methodologies required are already in routine use.<br/><br/>HOW THE RESULTS OF THIS RESEARCH WILL BE USED<br/>Several orally available GSK3 inhibitors have been developed by the pharmaceutical industry for the treatment of type 2 diabetes. The principal goal of our proposal, therefore, is to reevaluate these compounds for lung cancer treatment and so provide a compelling case for progressing them towards a clinical trial.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: A Phase 1b/randomised Phase II trial of vascular disrupting agent OXI4503 combined with pazopanib, a VEGFR/TK inhibitor, in relapsed ovarian cancer
Funder: Cancer Research UK

Abstract: Vascular disruptive agents (VDAs) are able to induce central necrosis of many tumours but due to preservation of a viable rim of cancer cells, there is rapid tumour re-growth and minimal single agent activity. OXi4503 is a phosphate prodrug of combretastatin A1 with a dual mechanism of action involving antivascular effects and direct cytotoxicity towards tumor cells. As well as being the most potent VDA it has also shown single agent activity against ovarian cancer in a phase 1 trial. There are several pre-clinical studies that show that combining an anti angiogenic agent with a VDA leads to significantly enhanced tumour growth delay, probably by preventing the re-growth of the viable rim after VDA therapy alone. It has been shown that the combination of a less potent VDA, combretastatin A4 Phosphate (CA4P) with bevacizumab, results in a more sustained antivascular response in humans and was well tolerated. It therefore makes sense to investigate the combination of a VEGF inhibitor with the potent VDA OXI4503. Pazopanib has been selected as the VEGF inhibitor to be combined with OXI4503 as it multi-targeted receptor tyrosine kinase inhibitor of VEGFR-1, 2, & 3, PDGFR-a/ß, and c-kit, which has activity against ovarian cancer and GSK is supportive of this proposal. They both share the side effect of hypertension but the time course of the hypertension after OXI4503 is only 2-6 hours and is well tolerated in patients without pre-existing hypertension. This will be a two-stage trial. The first stage will be a dose escalation study to determine the maximum tolerated dose. While the primary endpoint will be based on toxicity, our goal is to use imaging and circulating biomarkers to determine the dose level that is associated with a biomarker effect that exceeds that seen by either single agent. In the second stage patients will be randomised to start treatment with OXI4503 alone, pazopanib alone or the combination to examine whether the biomarker signature associated with the combination exceeds that induced by either agent alone. The arms would only differ during the first week of therapy so the DCR-MRI could examine the effect of the single drugs or combination. Thereafter all patients would receive both drugs so that the tolerability and anti-tumour effect could be adequately examined. The obvious group of patients to study are those with relapsed ovarian cancer as both pazopanib and OXI4503 have activity for this tumour type.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: CRUK/11/056: A randomized phase IIb trial of BEvACizumab added to Temozolomide ± IrinOtecan for children with refractory/relapsed Neuroblastoma - BEACON-Neuroblastoma Trial
Funder: Cancer Research UK

Abstract: Background Neuroblastoma is a highly vascular tumour. Preclinical evidence suggests that angiogenesis inhibition with monoclonal antibodies produces anti-tumour response. Bevacizumab is a monoclonal antibody against Vascular Endothelial Growth Factor. Adult studies have established its safety profile with manageable toxicity both as a single agent and in combination. Paediatric evaluation has shown no severe unexpected toxicities. Furthermore, Bevacizumab has shown a survival advantage in several adult malignancies. Irinotecan-Temozolomide is a widely used tolerable combination for the treatment of relapsed or refractory neuroblastoma. However trials to date have provided no evidence that Irinotecan adds to the activity of Temozolomide. There is a strong rationale for combining an effective backbone second line regimen with an antiangiogenic monoclonal antibody in order to improve the outcome of patients with relapsed/refractory neuroblastoma. Aims The primary aim is to evaluate whether Bevacizumab, added to a backbone chemotherapy regimen (Temozolomide or Irinotecan-Temozolomide), demonstrates sufficient activity in children and young adults with relapsed/refractory neuroblastoma to warrant further investigation in a larger Phase III trial. Similarly, the trial will evaluate whether or not Irinotecan, added to Temozolomide, shows evidence of increased activity compared to single agent Temozolomide. It will allow evaluation of the effect of angiogenesis inhibition on pharmacodynamic biomarkers (DCE-MRI changes in tumour vasculature and circulating angiogenic cytokines) in addition to the role of tumour profiling and circulating mRNA levels for TH, PHOX2B and DCX as prognostic/predictive biomarkers for neuroblastoma. Methods This is an open-label, multicentre, randomized phase II trial. 120 patients aged 1-21 years with relapsed/refractory neuroblastoma will be randomised to receive therapy with 1 of 4 arms: Arm T: 200mg/m2 of Temozolomide on days 1-5 of each 28 day cycle. Arm BT: 10mg/kg of Bevacizumab on days 1 and 15 and 200mg/m2 of Temozolomide on Days 1-5 and of each 28 day cycle. Arm IT: 50mg/m2 of Irinotecan and 100mg/m2 of Temozolomide on days 1-5 of each 21 day cycle. Arm BIT: 10mg/kg Bevacizumab on day 1 and then every 14 days after this, in addition to 50mg/m2 of Irinotecan and 100 mg/m2 of Temozolomide on days 1-5 of each 21 day cycle. Response will be assessed after the second cycle of treatment and after every 2 subsequent cycles. Patients may receive up to 6 cycles of therapy in the absence of disease progression. Outcome This trial will show whether Bevacizumab and/or Irinotecan are sufficiently active to be taken forward into larger phase III trials in neuroblastoma.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Defining an early transcriptional response to histone deacetylase inhibitors: regulation by chromatin and effects on cell survival.
Funder: Cancer Research UK

Abstract: Background Histone deacetylase (HDAC) inhibitors are remarkably effective drugs for treatment of certain leukaemias and lymphomas, but less effective against other cancers. We propose to test the novel hypothesis that human cells have inbuilt, perhaps evolutionarily ancient, defence mechanism(s) that allow them to survive the toxic effects of HDAC inhibitors (HDACi). Our early evidence suggests that these mechanisms operate through enzyme-catalysed modifications to chromatin structure, and consequent effects on gene expression, triggered shortly after exposure to HDACi. Aims We will explore the hypothesis that cells respond to HDACi by rapidly changing the expression of a set of functionally related genes. We will determine how the response differs from one HDACi to another and how it exerts downstream effects on cell behaviour and survival. We will define the enzymes, chromatin modifications and metabolic changes that regulate the early response and its progression. Finally, we will ask whether disruption of the response can explain the sensitivity of some tumour types to HDACi and, if so, will identify the genes responsible. Methods Gene expression will be assayed by microarray using Nimblegen HD2 high-density arrays. We will characterise the genes whose activities are changed most rapidly after exposure to HDACi using time course analyses (0, 30, 60, 120min) in triplicate, for which the 12-array per slide format is ideally suited. We will test different primary cell types and cell lines (both normal and cancer-derived) and correlate the transcriptional response with sensitivity to HDACi. We will test fatty acid-derived and hydroxamic acid-derived HDACi (valproic and butyric acids, SAHA and TSA). Chromatin changes induced by HDACi will be assayed by chromatin immunoprecipitation linked to microarrays or Next Generation sequencing (IBR Technology Hub). We will map the spread of chromatin changes across the genome over time and identify regions that show rapid changes and those that are sheltered. Metabolic changes in response to HDACi will be assayed by NMR (Biomolecular NMR Facility, U.Birmingham). Genes responding early to HDACi and whose activities correlate with cell survival will be validated by siRNA mediated knockdown. How the results of this research will be used Several HDAC inhibitors are in clinical trials and two have been approved by the FDA. Understanding how cells respond to or resist HDACi will improve both the applicability and effectiveness of these valuable drugs. Our work will reveal new biomarkers for monitoring responses to HDACi and for predicting sensitivity or resistance.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Core funding for Wellcome Trust / Cancer Research UK Gurdon Institute
Funder: Cancer Research UK

Abstract: The Gurdon Institute brings together about 18 research groups in the areas of developmental biology and cancer research with the goal of producing world class research at the interface between these two fields. Our main research topics are DNA repair and replication, the regulation of the cell cycle, chromatin modification and transcriptional control, stem cell biology, the role of cell polarity in epithelial organization and morphogenesis, nuclear reprogramming, and the roles of small non-coding RNAs in gene regulation and genome stability, all of which are highly relevant to cancer.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: CANCER AND NEOPLASMS
Title: CRUK/12/021: A phase II trial of vinflunine in locally-advanced and metastatic carcinoma of the penis (VinCaP)
Funder: Cancer Research UK

Abstract: Background: Cancer of the penis is rare with an annual incidence of 1.3 cases per 100,000 UK men. This rarity means there are very few prospective clinical trials investigating its management. Patients are predominantly over 60 years of age with various co-morbidities and a treatment is needed that improves quality of life and overall disease control with manageable toxicity. Distant metastatic disease is incurable. Combination chemotherapy in this setting is indicated primarily for symptomatic patients with good performance status with a view to improving symptom control. Vinca alkaloids (e.g. vincristine) have been used as part of combination chemotherapy for penis cancer since the mid-1970 with mixed results. Their use is limited by their associated toxicity. Vinflunine is a new vinca alkaloid that has been shown to be well-tolerated by patients with poor-prognosis bladder cancer in phase III trials. Aims: To determine the activity, safety and tolerability of single agent Vinflunine chemotherapy in cancer of the penis and thus determine whether this regimen warrants further research. Methods: VinCaP is a limited non-randomised multi-centre phase II study to gain insight into the potential activity of single agent vinflunine. This trial has a single stage Fleming A’Hern design (alpha=0.05, 80% power). 22 patients will receive Vinflunine 320mg/m2 every 21 days. Four doses (cycles) will be administered prior to formal re-staging. The primary endpoint is clinical benefit (i.e. objective response + stable disease). Patients with clinical benefit will continue on treatment until disease progression. How the results of this research will be used: This trial will provide valuable information on how to treat the more elderly, more infirm patients with penis cancer who are not suitable for complex combination chemotherapy. If 7 or more responses or disease stabilizations are observed in 22 evaluable patients then we would conclude that the rate of clinical benefit is not 15% (and is more likely to be 40% or greater) and, if it was also shown that delivering this drug is feasible in terms of toxicity, tolerability and acceptability, further research would be warranted. If it is not feasible to give this drug to this patient group or if 7 responses or stabilizations are seen (and we thus concluded that the true clinical benefit rate was not 40%), further trials would not be recommended.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Structural Biology of DNA Damage Response and Repair Mechanisms and its Exploitation for Drug Discovery
Funder: Cancer Research UK

Abstract: BACKGROUND For a cell to retain normal function following damage to its DNA, it requires a concerted response in which the damage is repaired as accurately as possible, and the cell cycle arrested to allow repair to occur or to trigger apoptosis if damage is too severe. Failures or inadequacies in this DNA damage response provide the genetic instability that underlies the acquisition of the changes that lead to cancer. The central importance of this concept is underlined by the observation that many of the genes found to be mutated in cancers are components of DNA damage response systems Understanding the molecular basis of DNA damage responses is therefore essential to understanding the process of carcinogenesis, but is also important to the development of new therapeutic approaches that take advantage of cancer-associated defects in DNA damage responses to achieve specific targeting of cancer cells. AIMS We wish to understand the structural basis for assembly, specificity and mechanism of the proteins and complexes that mediate repair of single-strand and double-strand DNA breaks, and signal DNA damage to the cell - central systems of genome stability and maintenance that are emerging as prime targets for therapeutic intervention in cancer. We aim to provide the detailed mechanistic insight essential to understanding how these systems work, how mutations in their component proteins contribute to carcinogenesis, and how these systems can be successfully exploited as targets for novel cancer therapeutics. METHODS To achieve these aims we will determine detailed molecular structures of proteins and multiprotein complexes involved in single-strand and double-strand DNA break repair and DNA damage signalling, primarily using techniques of X-ray crystallography and single-particle electron microscopy. These structural data, together with data from biochemical and biophysical techniques, will help us define the conformational mechanics of the proteins and the specificity and energetics of their interactions, providing a rational basis for targeted mutagenesis and functional studies to define their roles in the biology of the system in vivo, and furnishing detailed molecular templates for the discovery of novel drugs. HOW THE RESULTS OF THIS RESEARCH WILL BE USED Our work will provide a basic mechanistic understanding that will facilitate drug discovery and assist the functional interpretation of cancer-associated mutations in tumours, thereby allowing clinicians to make rational choices in the use of synthetic-lethal therapeutic approaches targeted to DNA damage responses.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS
Title: Interaction between NRG1/Neuregulin-1/heregulin and the ERBB family in epithelial cancers
Funder: Cancer Research UK

Abstract: Background. NRG1 encodes ligands for the ERBB/HER receptor family. These ligands can be mitogenic to neighbouring cells but, in the transmembrane precursor form, powerfully proapoptotic to the expressing cell. Apparently contradictory roles have been suggested for NRG1 in cancer: we and others have concluded that NRG1 is an important tumour suppressor gene, mutated or silenced by methylation in many breast cancers and responsible for the loss of 8p in 25 - 50% breast and presumably other epithelial cancers; but NRG1 is also claimed to be oncogenic, forming an NRG1-ERBB3 autocrine loop in some ovarian cancers. Aims: We hypothesize that both these scenarios occur and that they represent alternative routes to cancer that may be taken by individual cases of both breast and ovarian cancer. Our principal questions are: Do both the silencing and autocrine loop mechanisms occur, as alternative routes to cancer? How is the autocrine loop normally avoided in normal cells, i.e. how are NRG1 isoforms and ERBB-family kept apart, and how does this change in tumours? How does NRG1 signal into the expressing cell, since this is likely to mediate tumour suppression, induction of apoptosis, and/or prevention of co-expression with ERBB3. Methods: Working primarily with a panel of breast and ovarian cancer cell lines we will identify cases in both tumour types that show NRG1 inactivation or the NRG1-ERBB autocrine loop, by measuring expression of NRG1 and the ERBB family and using overexpression and knockdown. We will investigate whether normal cells avoid the autocrine loop by segregating expression, primarily using fluorescence; whether there is mutual regulation of expression, by altering and monitoring expression; and whether this regulation is broken in cases that have the autocrine loop. We will investigate intracellular signaling that may result in tumour suppression and apoptosis, using ChIP-seq, and immunoprecipitation with mass spec, to identify targets of the NRG1 cytoplasmic domain. How the results of this research will be used: This will improve our understanding of the role of signalling through the ERBB/HER family pathway in epithelial cancer, and whether NRG1 is a key tumour suppressor or oncogene or both.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Regulation of the estrogen receptor-a (ERa) by a new kinase, LMTK3
Funder: Cancer Research UK

Abstract: Background: Therapies targeting estrogen receptor-a (ERa) have transformed the treatment of breast cancer. However, many women relapse, highlighting the need for new regulatory targets modulating ERa pathways. An siRNA screen identified kinases whose silencing alters the genomic estrogen response including those previously implicated in regulating ERa activity (eg. MAPK/AKT). Amongst the most potent regulators was lemur tyrosine kinase-3 (LMTK3), for which a role has not previously been assigned. In contrast to other ERa modulators, LMTK3 has undergone Darwinian positive selection, a noteworthy result given the unique susceptibility of humans to ERa(+) breast cancer. LMTK3 phosphorylates ERa, protecting it from proteasomal degradation in vitro. Silencing of LMTK3 reduces tumour volume in an orthotopic mouse model and abrogates proliferation of ERa(+) but not ERa(-) cells, indicative of its role in ERa activity/signallilng. In humans, LMTK3 abundance and intronic polymorphisms in 2 large separate cohorts is significantly associated with disease-free and overall survival and predicts response to endocrine therapies. These findings yield insights into the natural history of breast cancer in humans and reveal LMTK3 as a new therapeutic target. Aims and methods: We wish to understand ERa regulation by LMTK3. The objectives are: a) To understand transcriptional regulation of LMTK3 and the identification of LMTK3 regulated genes as follows: i) First, we will investigate the mechanism(s) by which LMTK3 is regulated by ERa, and conversely the regulation of ERa by LMTK3. We wish to establish potential genomic binding sites of LMTK3, that these sites are functional and establish transcription factors that may be LMTK3 regulated, ii) As we have previously described the set of microRNAs (miRNAs) induced by ERa14, we will investigate miRNAs that target LMTK3 and examine their effects on the regulatory pathways we have described. b) Establish post-transcriptional mechanisms of LMTK3 activity on ERa: iii) We will determine the exact ERa phosphorylation sites of LMTK3 in vitro and in vivo, and study their biochemical and functional consequences including effects on proliferation/apoptosis, ERa stability, function and sub-cellular localisation, iv) We aim to identify the LMTK3-ER? interacting domain and investigate the involvement of LMTK3 in the ERa transcriptional machinery (co-activators and co-suppressors) and, v) Importantly we will investigate the clinical relevance of our findings by correlating identified LMTK3-driven ERa phosphorylation sites with single nucleotide polymorphisms and clinical outcomes in large well described cohorts. Use of results: Together, these data aim to establish the mechanism of ERa regulation by LTMK3 in breast cancer.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS