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Trinity College Dublin

Personal Information
College Photo Name Pidgeon, Graham
Main Department Surgery
College Title Associate Professor
E-mail pidgeong@tcd.ie
College Tel +353 1 896 4097
Web http://people.tcd.ie/pidgeong
Fax + 353 1 4546534
 
Biography
Dr. Graham Pidgeon graduated from DCU with a degree in Analytical Science and obtained a Ph.D. in Cancer Research from the Dept. Surgery, RCSI/DCU in 2000. Awarded an American Cancer Foundation Fellowship, he worked as research fellow at Wayne State University, Michigan with Prof. Kenneth Honn on the regulation of prostate cancer survival by bioactive lipids. In 2002 he returned to Ireland as a senior postdoctoral fellow in the Dept. Clinical Pharmacology at RCSI. He was awarded a HRB postdoctoral fellowship in 2004, and joined Dr. Ken O’Byrne in the Thoracic Oncology Research Group at the Institute of Molecular Medicine at TCD/St. James as research lecturer. He developed his own research group focused on the regulation of VEGF-mediated survival pathways by COX and LOX in lung cancer and combining inhibitors of these pathways with conventional chemotherapy. He was appointed senior lecturer in Dept. Surgery at TCD/St.James in Jan 2007 and has expanded these research areas into other prevalent solid malignancies, including oesophageal cancer. He has published in a number of high impact journals including Cancer Research and Circulation, and was awarded the IJS doctor award 2005 for Cardiology. His current research is focused on the role of bioactive lipid enzymes including cycloxygenase and lipoxygenase in the growth and metastasis of lung and oesophageal cancer. Dr. Graham Pidgeon’s group have a strong interest in the molecular processes regulating the growth and survival of oesophageal and lung cancer. Work in the past months has concentrated on the development of an adipose biobank from patients undergoing oesophageal and colorectal resections, to investigate the role of visceral fat in the progression of these malignancies. Recent scientific literature highlights the importance of central obesity and metabolic syndrome (MetS) as negatively impacting on cancer risk, tumour size, metastatic potential, and both disease free and overall survival. The group are prospectively investigating the incidence of central adiposity, metabolic syndrome and adipocyte secretion amongst newly diagnosed patients with these cancers to determine the link between these parameters and tumour size, metastases, treatment pathways, and survival.
 
Membership of Professional Institutions, Associations, Societies
Details Date From Date To
Honarary Fellow of the IBS (Institute of Biomedical Sciences), RCSI. 2004 Current
Member of the Irish Association of Cancer Research 1997 Current
Member of the American Association of Cancer Research 1998 Current
 
Awards and Honours
Award Date
Health Research Board PostDoctoral Fellowship 2004
Cancer Research Foundation of America Research Fellowship 2001
 
Description of Research Interests
My research interests focus on the regulation of vascular function and angiogenesis by bioactive lipids/prostanoids. Biologically active products derived from cyclooxygenase (COX) and lipoxygenase (LOX) mediated metabolism of arachidonic acid are involved in a range of clinical conditions, including arthritis, cancer and heart disease. One area of my research is in the examination of the role of the different COX isoforms, and their downstream products in pulmonary disease. There are reports that drugs which selectively inhibit COX-2 have detrimental effects on cardiac function, to date our results confirm that selective inhibition of COX-2 in models of hypoxia-induced pulmonary hypertension aggravates the problem. We are currently examining the mechanisms whereby cyclooxygenase isozymes regulate pulmonary hypertension and lung cancer, with an emphasis on COX-mediated angiogenesis and thrombosis in these diseases. A second area of research involves examining the role of bioactive lipids as survival factors in cancer. We are currently examining the role of 12-lipoxygenase, COX-2 and thromboxane synthase as survival factors in lung cancer and mesothelioma. The goal of this research is to identify the mechanisms whereby these enzymes facilitate tumour survival under conditions found within the tumour microenvironment, including hypoxia and serum deprivation. My third area of research interest is in the Vascular Endothelial Growth Factor receptors and their expression in lung cancer and mesothelioma. I am particularly interested in the Neuropilin family of receptors, their role in cell survival and regulation by bioactive lipids. We are currently examining the expression profile of VEGF receptors in cell lines and retrospective human lung cancers, to correlate their expression with tumour grade and stage.
 
Research Interests
Angiogenesis Anticancer therapies Apoptosis Apoptosis, molecular control
Biological Markers Breast Cancer Breast cancer Cancer Biology
Cancer genetics and cell biology including metastasis Cancer/Carcinogenesis Cardiology Cardiovascular Diseases
Cardiovascular System Cardiovascular and molecular pharmacology Cardiovascular disease, pharmacology Cardiovascular regulation and hypertension
Cell Communication Cell Components Cell Lines Cell cycle control
Clinical research, trials Coronary artery ischaemia Cytoskelton, cell division DNA transcription and translation
Drug development and evaluation Extracellular Matrix Gene therapy Gene transcription in human cancer
Genomic structure and function, molecular approaches to gene function Growth Factors Immunology Inflammation and coagulation syndromes
Intra and intercellular signalling Lipids, steroids, membranes Lung Cancer Metabolism, Lipid
Molecular Biology Molecular Genetics Nutrition/Dietetics Oncogenes, apoptosis and tumour development
Oncology Pathogenesis Pathology Pharmacology
Platelet activating agents Prostaglandins Prostate Cancer Prostate cancer
Proteomics Pulmonary Diseases Radiotherapy, Biological response modifiers and chemoprevention Receptors
Regulatory methods of gene expression Respiratory System Therapeutic and Clinical oncology Thrombosis
Thrombosis and haemostasis Tissue Culture Transgenic Animals Tumour immunology and immunotherapy
Vascular Biology Vascular Biology, Thrombosis
 
Research Projects
Project title An investigation of the thromboxane and prostacyclin synthase pathways in non-small cell lung cancer.
Summary This research project will provide significant insights into the potential mechanisms whereby the balance between the expression of thromboxane synthase and prostacyclin synthase in lung cancer may confer a survival advantage on tumour cells directly. The series of experiments will examine the potential correlation between tumour expression of these PGH2 metabolising enzymes and clinical parameters, including thrombotic events, tumour angiogenesis and overall survival. These pathways have been implicated in various forms of malignancies and a number of specific inhibitors of TXS have shown promise in clinical trials, suggesting the translation of the research proposed here into future clinical applications in lung cancer should be rapid. The in vitro experiments are carefully designed to explore the potential survival mechanisms at the cellular protein level, by generating NSCLC clones with overexpression or silenced expression of these targets using molecular strategies. These clones will be thoroughly characterised both invitro and invivo for their effect on tumour cells. Direct clinical relevance will be highlighted by retrospectively examining the expression of TXS and PGIS expression in a series of resected lung tumours with varying stage and type of disease and also in frozen normal / tumour samples taken from the EU biobank at St. James Hospital. By furthering our knowledge of these critical regulatory mechanisms controlling tumour cell survival, it is anticipated that new interventional therapies may be designed to target lung cancer, either alone or in combination with conventional radiotherapy and chemotherapy.
Funding Agency Cancer Research Ireland
Programme Project Grant Scheme
Type of Project Research - Post-doctoral
Date from 2008
Date to 2011
Person Months


Project title Neuropilin-1 expression and regulation by 12-Lipoxygenase in lung cancer.
Summary This research project will provide significant insights into the potential mechanisms whereby neuropilin-1 expression in lung cancer may confer a survival advantage on tumour cells directly. The series of experiments will examine the potential correlation between tumour expression of the arachidonic acid metabolising enzyme 12-LOX and neuropilin-1 receptor expression in lung cancer. Each of these pathways have been implicated in various forms of malignancies and a number of specific inhibitors of LOX pathways have shown promise in clinical trials, suggesting the translation of the research proposed here into future clinical applications in lung cancer should be rapid. These experiments are carefully designed to explore the potential survival mechanisms at the cellular protein level, by overexpression of 12-LOX while targeting NRP-1 pathways by a neutralising or RNA silencing approach. Direct clinical relevance will be highlighted by retrospectively examining the expression of 12-LOX and NRP-1 expression in a series of resected lung tumours with varying stage and type of disease. By furthering our knowledge of these critical regulatory mechanisms controlling tumour cell survival, it is anticipated that new interventional therapies may be designed to target lung cancer, either alone or in combination with conventional radiotherapy and chemotherapy.
Funding Agency Cancer Research Ireland
Programme Project Grants
Type of Project Research - PhD student
Date from 2005
Date to 2008
Person Months


Project title COX-isoforms and prostaglandins in an hypoxia-induced model of pulmonary hypertension.
Summary Altered regulation of the cyclooxygenase (COX) signalling pathway underlies the development and progression of many diseases. The PGI2/TXA2 ratio is of particular importance in-vivo, with the corresponding synthases being shown to be differentially regulated. COX-derived prostanoids have been implicated in the development of PH, and an imbalance between the generation of thromboxane A2 (TXA2) and prostacyclin (PGI2) has been reported in both primary and secondary forms of the disease. These prostanoids have directly opposing effects; PGI2 is a potent vasodilator, is anti-proliferative, and inhibits platelet activation and aggregation, while TXA2 is a vasoconstrictor, is mitogenic and activates platelets and their aggregation. COX-2 is the main isoform responsible for the generation of PGI2, while TXA2 is mainly derived from platelets, where COX-1 is the main isoform. Exogenous PGI2 is effective in reducing pulmonary vascular resistance in some forms of human pulmonary hypertension (PH). To examine whether endogenous prostanoids played a similar role in PH, we examined the effect of deleting COX-gene isoforms in a chronic hypoxia model of the disease. An experimental model of pulmonary hypertension (PH) was generated using COX-gene disrupted mice. PH was induced by 3 weeks of hypobaric hypoxia, and was confirmed by direct measurement of right ventricular end systolic pressure (RVESP), right ventricular hypertrophy (RVH) and increased haematocrit. RVESP was increased in wild-type (WT) hypoxic mice compared to normoxic controls, while COX-2 knock-out (KO) mice showed a further increase in RVESP following hypoxia. Urinary TXB2 excretion increased following hypoxia, an effect that was exacerbated following COX-2 gene disruption. In contrast, the increase in 6-keto-PGF1á excretion following hypoxia was reduced by COX-2 gene disruption. Tail-cut bleed times were reduced following hypoxia, and there was (immunohistochemical) evidence of intravascular thrombosis in lung vessels that was exacerbated by disruption of COX-2 and reduced by deletion of COX-1. The thromboxane receptor antagonist, ifetroban (50mg/kg/day) offset the effect of COX-2 gene deletion, by attenuating the hypoxia-induced rise in RVESP and intravascular thrombosis. In addition to pulmonary vascular thrombosis, a second characteristic feature of pulmonary hypertension is the development of pulmonary vascular remodelling an angiogenesis. Real-time PCR analysis of vascular remodelling in the disease implicated a number of genes to be altered in the disease including VEGFC, EphB2, TNFá, TNFaip2, and CCl2. Genes of particular interest included VEGFC, EphB2, TNFá and TNFaip2, which are all pro-angiogenic factors that were down-regulated following COX-2 gene disruption. Further work is required to determine whether these changes in gene expression profile represent a beneficial or detrimental adaptation to chronic hypoxia exposure. In conclusion, the findings of this research demonstrate that COX-2 gene deletion exacerbates the pathogenesis of pulmonary hypertension, enhances sensitivity to TXA2 and induces intravascular thrombosis in response to hypoxia. COX-2 gene deletion also down-regulated the expression of a number of angiogenic genes in response to hypoxia, suggesting that expression of these genes may have a beneficial effect in the pathogenesis of the disease. Our data provides evidence that endogenous prostanoids modulate the pulmonary response to hypoxia.
Funding Agency Health Research Board
Programme Post-doctoral Fellowship Scheme
Type of Project Research
Date from 2004
Date to 2007
Person Months 36


 
Publications and Other Research Outputs
Peer Reviewed
Cathcart MC, Tamosiuniene R, Chen G, Neilan TG, Bradford A, O' Byrne KJ, Fitzgerald DJ, Pidgeon GP., COX-2-Linked Attenuation of Hypoxia-Induced Pulmonary Hypertension and Intravascular Thrombosis., Journal of Pharmacology and Expreimental Therapeutics, 2008
Pidgeon GP, Lysaght J, Krishnamoorthy S, Reynolds JV, O'Byrne K, Nie D, Honn KV., Lipoxygenase metabolism: roles in tumor progression and survival., Cancer Metastasis Reviews, 3-4, 2007, p503 - 524
G.P. Pidgeon, R. Tamosiuniene, G. Chen, I. Leonard, O. Belton, A. Bradford, D.J. Fitzgerald, Intravascular thrombosis after hypoxia-induced pulmonary hypertension: regulation by cyclooxygenase-2., Circulation, 110, (17), 2004, p2701 - 2707
URL
G.P. Pidgeon, K. Tang, Y.L. Cai, E. Piasentin, K.V. Honn., Overexpression of platelet-type 12-lipoxygenase promotes tumor cell survival by enhancing alpha(v)beta(3) and alpha(v)beta(5) integrin expression., Cancer Research, 63, (14), 2003, p4258 - 4267
TARA - Full Text  DOI
G.P. Pidgeon, M. Kandouz, A. Meram, K.V. Honn., Mechanisms controlling cell cycle arrest and induction of apoptosis after 12-lipoxygenase inhibition in prostate cancer cells., Cancer Research, 62, (9), 2002, p2721 - 2727
TARA - Full Text  URL
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