Publications
75 results found
Cunnea P, Curry E, Nixon K, et al., 2019, MOLECULAR AND PHENOTYPIC CHARACTERISATION OF INTRA-TUMOURAL HETEROGENEITY IN HIGH GRADE SEROUS OVARIAN CANCER, Publisher: BMJ PUBLISHING GROUP, Pages: A50-A51, ISSN: 1048-891X
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- Citations: 1
Hall M, Savvatis K, Nixon K, et al., 2019, Maximal-effort cytoreductive surgery for ovarian cancer patients with a high tumor burden: variations in practice and impact on outcome, Annals of Surgical Oncology, Vol: 26, Pages: 2943-2951, ISSN: 1068-9265
BackgroundThis study aimed to compare the outcomes of two distinct patient populations treated within two neighboring UK cancer centers (A and B) for advanced epithelial ovarian cancer (EOC).MethodsA retrospective analysis of all new stages 3 and 4 EOC patients treated between January 2013 and December 2014 was performed. The Mayo Clinic surgical complexity score (SCS) was applied. Cox regression analysis identified the impact of treatment methods on survival.ResultsThe study identified 249 patients (127 at center A and 122 in centre B) without significant differences in International Federation of Gynecology and Obstetrics (FIGO) stage (FIGO 4, 29.7% at centers A and B), Eastern Cooperative Oncology Group (ECOG) performance status (ECOG < 2, 89.9% at centers A and B), or histology (serous type in 84.1% at centers A and B). The patients at center A were more likely to undergo surgery (87% vs 59.8%; p < 0.001). The types of chemotherapy and the patients receiving palliative treatment alone were equivalent between the two centers (3.6%). The median SCS was significantly higher at center A (9 vs 2; p < 0.001) with greater tumor burden (9 vs 6 abdominal fields involved; p < 0.001), longer median operation times (285 vs 155 min; p < 0.001), and longer hospital stays (9 vs 6 days; p < 0.001), but surgical morbidity and mortality were equivalent. The independent predictors of reduced overall survival (OS) were non-serous histology (hazard ratio [HR], 1.6; 95% confidence interval [CI] 1.04–2.61), ECOG higher than 2 (HR, 1.9; 95% CI 1.15–3.13), and palliation alone (HR, 3.43; 95% CI 1.51–7.81). Cytoreduction, of any timing, had an independent protective impact on OS compared with chemotherapy alone (HR, 0.31 for interval surgery and 0.39 for primary surgery), even after adjustment for other prognostic factors.ConclusionsIncorporating surgery into the initia
Nixon K, Wulandari R, Curry E, et al., 2019, Describing intratumoural heterogeneity in high-grade serous ovarian cancer, Publisher: WILEY, Pages: 87-88, ISSN: 1470-0328
Rinne N, Curry E, Fotopoulou C, et al., 2019, Targeting AKT and DNA-PK as a therapeutic strategy in platinum-resistant high-grade serous ovarian cancer, Publisher: WILEY, Pages: 88-89, ISSN: 1470-0328
Lu H, Arshad M, Thornton A, et al., 2019, A mathematical descriptor of tumour mesoscopic structure from computed tomography images annotates prognostic and molecular phenotypes of epithelial ovarian cancer, Publisher: WILEY, Pages: 89-89, ISSN: 1470-0328
Lu H, Arshad M, Thornton A, et al., 2019, A mathematical-descriptor of tumor-mesoscopic-structure from computed-tomography images annotates prognostic and molecular-phenotypes of epithelial ovarian cancer, Nature Communications, Vol: 10, ISSN: 2041-1723
The five-year survival rate of epithelial ovarian cancer (EOC) is approximately 35–40% despite maximal treatment efforts, highlighting a need for stratification biomarkers for personalized treatment. Here we extract 657 quantitative mathematical descriptors from the preoperative CT images of 364 EOC patients at their initial presentation. Using machine learning, we derive a non-invasive summary-statistic of the primary ovarian tumor based on 4 descriptors, which we name “Radiomic Prognostic Vector” (RPV). RPV reliably identifies the 5% of patients with median overall survival less than 2 years, significantly improves established prognostic methods, and is validated in two independent, multi-center cohorts. Furthermore, genetic, transcriptomic and proteomic analysis from two independent datasets elucidate that stromal phenotype and DNA damage response pathways are activated in RPV-stratified tumors. RPV and its associated analysis platform could be exploited to guide personalized therapy of EOC and is potentially transferrable to other cancer types.
Kreuzinger C, von der Decken I, Wolf A, et al., 2019, Patient-derived cell line models revealed therapeutic targets and molecular mechanisms underlying disease progression of high grade serous ovarian cancer, CANCER LETTERS, Vol: 459, Pages: 1-12, ISSN: 0304-3835
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- Citations: 15
Cunnea P, Gorgy T, Petkos K, et al., 2018, Clinical value of bioelectrical properties of cancerous tissue in advanced epithelial ovarian cancer patients, Scientific Reports, Vol: 8, Pages: 1-12, ISSN: 2045-2322
Currently, there are no valid pre-operatively established biomarkers or algorithms that can accurately predict surgical and clinical outcome for patients with advanced epithelial ovarian cancer (EOC). In this study, we suggest that profiling of tumour parameters such as bioelectrical-potential and metabolites, detectable by electronic sensors, could facilitate the future development of devices to better monitor disease and predict surgical and treatment outcomes. Biopotential was recorded, using a potentiometric measurement system, in ex vivo paired non-cancerous and cancerous omental tissues from advanced stage EOC (n = 36), and lysates collected for metabolite measurement by microdialysis. Consistently different biopotential values were detected in cancerous tissue versus non-cancerous tissue across all cases (p < 0.001). High tumour biopotential levels correlated with advanced tumour stage (p = 0.048) and tumour load, and negatively correlated with stroma. Within our EOC cohort and specifically the high-grade serous subtype, low biopotential levels associated with poorer progression-free survival (p = 0.0179, p = 0.0143 respectively). Changes in biopotential levels significantly correlated with common apoptosis related pathways. Lactate and glucose levels measured in paired tissues showed significantly higher lactate/glucose ratio in tissues with low biopotential (p < 0.01, n = 12). Our study proposes the feasibility of biopotential and metabolite monitoring as a biomarker modality profiling EOC to predict surgical and clinical outcomes.
Antony J, Zanini E, Kelly Z, et al., 2018, The tumour suppressor OPCML promotes AXL inactivation by the phosphatase PTPRG in ovarian cancer, EMBO Reports, Vol: 19, ISSN: 1469-221X
In ovarian cancer, the prometastatic RTK AXL promotes motility, invasion and poor prognosis. Here, we show that reduced survival caused by AXL overexpression can be mitigated by the expression of the GPI-anchored tumour suppressor OPCML Further, we demonstrate that AXL directly interacts with OPCML, preferentially so when AXL is activated by its ligand Gas6. As a consequence, AXL accumulates in cholesterol-rich lipid domains, where OPCML resides. Here, phospho-AXL is brought in proximity to the lipid domain-restricted phosphatase PTPRG, which de-phosphorylates the RTK/ligand complex. This prevents AXL-mediated transactivation of other RTKs (cMET and EGFR), thereby inhibiting sustained phospho-ERK signalling, induction of the EMT transcription factor Slug, cell migration and invasion. From a translational perspective, we show that OPCML enhances the effect of the phase II AXL inhibitor R428 in vitro and in vivo We therefore identify a novel mechanism by which two spatially restricted tumour suppressors, OPCML and PTPRG, coordinate to repress AXL-dependent oncogenic signalling.
Boutelle MG, Gowers SAN, Hamaoui K, et al., 2018, High temporal resolution delayed analysis of clinical microdialysate streams, Analyst, Vol: 143, Pages: 715-724, ISSN: 1364-5528
This paper presents the use of tubing to store clinical microdialysis samples for delayed analysis with high temporal resolution, offering an alternative to traditional discrete offline microdialysis sampling. Samples stored in this way were found to be stable for up to 72 days at −80 °C. Examples of how this methodology can be applied to glucose and lactate measurement in a wide range of in vivo monitoring experiments are presented. This paper presents a general model, which allows for an informed choice of tubing parameters for a given storage time and flow rate avoiding high back pressure, which would otherwise cause the microdialysis probe to leak, while maximising temporal resolution.
Nixon K, Cunnea P, Wulandari R, et al., 2017, DESCRIBING INTRA-TUMOURAL HETEROGENEITY IN HIGH GRADE SEROUS OVARIAN CANCER, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: 516-516, ISSN: 1048-891X
Lu H, Fotopoulou C, Rockall A, et al., 2017, PRE-OPERATIVE RADIOMIC MODELS ANNOTATE EPITHELIAL OVARIAN CANCER PROGNOSTIC PHENOTYPES, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: 1490-1490, ISSN: 1048-891X
Lu H, Fotopoulou C, Rockall A, et al., 2017, PRE-OPERATIVE RADIOMIC MODELS ANNOTATE EPITHELIAL OVARIAN CANCER PROGNOSTIC PHENOTYPES, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: 502-502, ISSN: 1048-891X
Nixon K, Cunnea P, Wulandari R, et al., 2017, DESCRIBING INTRA-TUMOURAL HETEROGENEITY IN HIGH GRADE SEROUS OVARIAN CANCER, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: 1613-1613, ISSN: 1048-891X
Athanasiou D, Edgar LT, Jafarnejad M, et al., 2017, The passive biomechanics of human pelvic collecting lymphatic vessels, PLOS One, Vol: 12, ISSN: 1932-6203
The lymphatic system has a major significance in the metastatic pathways in women’s cancers. Lymphatic pumping depends on both extrinsic and intrinsic mechanisms, and the mechanical behavior of lymphatic vessels regulates the function of the system. However, data on the mechanical properties and function of human lymphatics are lacking. Our aim is to characterize, for the first time, the passive biomechanical behavior of human collecting lymphatic vessels removed at pelvic lymph node dissection during primary debulking surgeries for epithelial ovarian cancer. Isolated vessels were cannulated and then pressurized at varying levels of applied axial stretch in a calcium-free Krebs buffer. Pressurized vessels were then imaged using multi-photon microscopy for collagen-elastin structural composition and fiber orientation. Both pressure-diameter and force-elongation responses were highly nonlinear, and axial stretching of the vessel served to decrease diameter at constant pressure. Pressure-diameter behavior for the human vessels is very similar to data from rat mesenteric vessels, though the human vessels were approximately 10× larger than those from rats. Multiphoton microscopy revealed the vessels to be composed of an inner layer of elastin with an outer layer of aligned collagen fibers. This is the first study that successfully described the passive biomechanical response and composition of human lymphatic vessels in patients with ovarian cancer. Future work should expand on this knowledge base with investigations of vessels from other anatomical locations, contractile behavior, and the implications on metastatic cell transport.
Flanagan JM, Wilson A, Koo C, et al., 2017, Platinum-based chemotherapy induces methylation changes in blood DNA associated with overall survival in ovarian cancer patients, Clinical Cancer Research, Vol: 23, Pages: 2213-2222, ISSN: 1557-3265
PURPOSE: DNA damage repair can lead to epigenetic changes. DNA mismatch repair proteins bind to platinum DNA adducts and at sites of DNA damage can recruit the DNA methylating enzyme DNMT1, resulting in aberrant methylation. We hypothesised that DNA damage repair during platinum-based chemotherapy may cause aberrant DNA methylation in normal tissues of patients such as blood. EXPERIMENTAL DESIGN: We used Illumina 450k methylation arrays and bisulphite pyrosequencing to investigate methylation at presentation and relapse in blood DNA from ovarian cancer patients enrolled in the SCOTROC1 trial (n=247) and in a cohort of ovarian tumour DNA samples collected at first relapse (n=46). We used an ovarian cancer cell line model to investigate the role of the DNA mismatch repair gene MLH1 in platinum induced methylation changes. RESULTS: Specific CpG methylation changes in blood at relapse are observed following platinum-based chemotherapy and are associated with patient survival, independent of other clinical factors (HR=3.7; 95%CI 1.8-7.6, p=2.8x10-4). Similar changes occur in ovarian tumours at relapse, also associate with patient survival (HR=2.6; 95%CI 1.0-6.8, p=0.048). Using an ovarian cancer cell line model, we demonstrate that functional mismatch repair (MMR) increases the frequency of platinum-induced methylation. CONCLUSION: DNA methylation in blood at relapse following chemotherapy, and not at presentation, is informative about ovarian cancer patient survival. Functional DNA mismatch repair increases the frequency of DNA methylation changes induced by platinum. DNA methylation in blood following chemotherapy could provide a non-invasive means of monitoring patients' epigenetic responses to treatment without requiring a tumour biopsy.
Cunnea P, Gowers S, Moore JE, et al., 2017, Novel technologies in the treatment and monitoring of advanced and relapsed epithelial ovarian cancer, Convergent Science Physical Oncology, Vol: 3, ISSN: 2057-1739
Epithelial ovarian cancer (EOC) is the fifth most common cause of cancer death in females in the UK. It has long been recognized to be a set of heterogeneous diseases, with high grade serous being the most common subtype. The majority of patients with EOC present at an advanced stage (FIGO III–IV), and have the largest risk for disease recurrence from which a high percentage will develop resistance to chemotherapy. Despite continual advances in diagnostics, imaging, surgery and treatment of EOC, there has been little variation in the survival rates for patients with EOC. In this review we will introduce novel bioengineering advances in modelling the lymphatic system and real-time tissue monitoring to improve the clinical and therapeutic outcome for patients with EOC. We discuss the advent of the non-invasive 'liquid biopsy' in the surveillance of patients undergoing treatment and follow-up. Finally, we present new bioengineering advances for palliative care of patients to lessen symptoms of patients with ascites and improve quality of life.
Cunnea P, Fernandes AP, Capitanio A, et al., 2016, Increased expression of specific thioredoxin family proteins;: A pilot immunohistochemical study on human hepatocellular carcinoma, INTERNATIONAL JOURNAL OF IMMUNOPATHOLOGY AND PHARMACOLOGY, Vol: 20, Pages: 17-24, ISSN: 0394-6320
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- Citations: 21
Menezes KA, Cunnea P, Lawton P, et al., 2015, Targeting genomic instability to identify molecular drivers of poor prognosis in cancer, AACR Special Conference on Translation of the Cancer Genome, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Cheraghchi-Bashi A, Parker CA, Curry E, et al., 2015, A putative biomarker signature for clinically effective AKT inhibition: correlation of in vitro, in vivo and clinical data identifies the importance of modulation of the mTORC1 pathway, Oncotarget, Vol: 6, Pages: 41736-41749, ISSN: 1949-2553
Our identification of dysregulation of the AKT pathway in ovarian cancer as a platinum resistance specific event led to a comprehensive analysis of in vitro, in vivo and clinical behaviour of the AKT inhibitor GSK2141795. Proteomic biomarker signatures correlating with effects of GSK2141795 were developed using in vitro and in vivo models, well characterised for related molecular, phenotypic and imaging endpoints. Signatures were validated in temporally paired biopsies from patients treated with GSK2141795 in a clinical study. GSK2141795 caused growth-arrest as single agent in vitro, enhanced cisplatin-induced apoptosis in vitro and reduced tumour volume in combination with platinum in vivo. GSK2141795 treatment in vitro and in vivo resulted in ~50-90% decrease in phospho-PRAS40 and 20-80% decrease in fluoro-deoxyglucose (FDG) uptake. Proteomic analysis of GSK2141795 in vitro and in vivo identified a signature of pathway inhibition including changes in AKT and p38 phosphorylation and total Bim, IGF1R, AR and YB1 levels. In patient biopsies, prior to treatment with GSK2141795 in a phase 1 clinical trial, this signature was predictive of post-treatment changes in the response marker CA125. Development of this signature represents an opportunity to demonstrate the clinical importance of AKT inhibition for re-sensitisation of platinum resistant ovarian cancer to platinum.
Curry E, Cheraghchi-Bashi-Astaneh A, Chen M, et al., 2015, DNA-PKcs is amplified in high grade serous ovarian cancer (HGSC), correlates with poor outcome and drives resistance to platinum therapy via the AKT signaling pathway, 10th Biennial Ovarian Cancer Research Symposium, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 1078-0432
Curry E, Cheraghchi-Bashi-Astaneh A, Chen M, et al., 2015, DNA-PKcs is amplified in high-grade serous ovarian cancer (HGSC), correlates with poor outcome and drives resistance to platinum therapy via the AKT signaling pathway, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 1535-7163
Fotopoulou C, Cunnea P, Rama NR, et al., 2015, Characterising phenotypically relevant intratumoural heterogeneity in high grade serous ovarian cancer., Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) / Clinical Science Symposium on Predicting and Improving Adverse Outcomes in Older Adults with Cancer, Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X
Stronach EA, Cunnea P, Turner C, et al., 2015, The role of interleukin-8 (IL-8) and IL-8 receptors in platinum response in high grade serous ovarian carcinoma, Oncotarget, Vol: 6, Pages: 31593-31603, ISSN: 1949-2553
Platinum based drugs are the cornerstone of chemotherapy for ovarian cancer, however the development of chemoresistance hinders its success. IL-8 is involved in regulating several pro-survival pathways in cancer. We studied the expression of IL-8 and IL-8 receptors in platinum sensitive and resistant cell lines. Using qRT-PCR and immunohistochemistry, both platinum sensitive (PEA1, PEO14) and resistant (PEA2, PEO23) show increased expression of IL-8 and IL-8 receptors. IL-8RA shows nuclear and cytoplasmic expression, whilst IL-8RB is present solely in the cytoplasm. Knockdown of IL-8 increased sensitivity to cisplatin in platinum sensitive and reversed platinum resistance in resistant cell lines, decreased the expression of anti-apoptotic Bcl-2 and decreased inhibitory phosphorylation of pro-apoptotic Bad. IL-8 receptor antagonist treatment also enhanced platinum sensitivity. Nuclear localisation of IL-8RA was only detected in platinum resistant tumours. Inhibition of IL-8 signalling can enhance response in platinum sensitive and resistant disease. Nuclear IL-8RA may have potential as a biomarker of resistant disease.
Wu W, Vitharana K, Gorgy T, et al., 2015, A Method for Voltage Measurements of Cancerous vs Non-cancerous Omentum, 37th Annual International Conference of the IEEE-Engineering-in-Medicine-and-Biology-Society (EMBC), Publisher: IEEE, Pages: 7514-7517, ISSN: 1557-170X
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- Citations: 2
Fotopoulou C, Cunnea P, Rama N, et al., 2014, CHARACTERISING PHENOTYPICALLY RELEVANT INTRATUMOURAL HETEROGENEITY IN HIGH GRADE SEROUS OVARIAN CANCER, INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER, Vol: 24, Pages: 443-444, ISSN: 1048-891X
Fotopoulou C, Gorgy T, Paterson A, et al., 2014, Molecular physiology monitoring of ovarian cancer ex vivo., Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) / Clinical Science Symposium on Predicting and Improving Adverse Outcomes in Older Adults with Cancer, Publisher: LIPPINCOTT WILLIAMS & WILKINS, 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA, ISSN: 1048-891X
Cunnea P, Stronach EA, 2014, Modeling platinum sensitive and resistant high-grade serous ovarian cancer: development and applications of experimental systems, Frontiers in Oncology, Vol: 4, ISSN: 2234-943X
High-grade serous ovarian cancer remains the most common sub-type of ovarian cancer and, characterized by high degrees of genomic instability and heterogeneity, is typified by a transition from early response to acquired resistance to platinum-based chemotherapy. Conventional models for the study of ovarian cancer have been largely limited to a set of relatively poorly characterized immortalized cell lines and recent studies have called into question the validity of some of these as reliable models. Here, we review new approaches and models systems that take into account advances in our understanding of ovarian cancer biology and advances in the technology available for their generation and study. We discuss primary cell models, 2D, 3D, and organotypic models, and "paired" sample approaches that capture the evolution of chemotherapy failure within single cases. We also overview new methods for non-invasive collection of representative tumor material from blood samples. Adoption of such methods and models will improve the quality and clinical relevance of ovarian cancer research.
FitzGerald U, McMahon J, Ni Fhlathartaigh M, et al., 2013, CALRETICULIN: A NEW TWIST IN THE ENDOPLASMIC RETICULUM AND MULTIPLE SCLEROSIS TALE, 11th European Meeting on Glial Cell Function in Health and Disease, Publisher: WILEY-BLACKWELL, Pages: S25-S26, ISSN: 0894-1491
Roche M, Cunnea P, Walsh MY, et al., 2012, Variations in <i>SEPT6</i> expression reflect progression of melanoma, Spring Meeting of the Irish-Association-of-Dermatologists, Publisher: WILEY-BLACKWELL, Pages: E27-E27, ISSN: 0007-0963
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