Clinical Scientist (St James's Hospital)
Adjunct Assistant Professor (TCD)
T: - Office: +353 1 8963620
T: - Lab: +353 1 8962134
Dr Martin Barr is a graduate of the University of Ulster, Coleraine, where he graduated in 1996 with a first-class honours degree in Biomedical Sciences and Diploma in Industrial Studies. During this time, he spent one year working in the Institute of Biology at INSERM, Central University Hospital of Nantes, France, where he worked as part of a cancer research group in characterising a chromosomal deletions (13q14.3) involved in B-cell lymphocytic leukaemia. In 1998, he qualified from the University of Nottingham, United Kingdom, with a Master’s Degree in Oncology (first-class honours) and was awarded a PhD in Cancer Research from the Department of Surgery, Royal College of Surgeons in Ireland in 2006. Under the supervision of Dr Judith Harmey and clinical direction of Professor Bouchier-Hayes, his PhD thesis examined the role of vascular endothelial growth factor (VEGF) and its receptors in metastatic breast cancer. Dr Barr is currently employed as a Clinical Scientist in the Thoracic Oncology Research Group, Institute of Molecular Medicine, St James’s Hospital & is an Adjunct Assistant Professor in Trinity College Dublin.
With a keen interest in Translational Biology, Dr Barr has a number of key research interests in non-small cell lung cancer (NSCLC). These include projects investigating the role of VEGF and its receptors in lung cancer cell signalling, miRNA profiling and gene signatures as potential markers in the treatment of lung cancer patients and the role of VEGF on lung cancer cell survival. In addition, Dr Barr has played a major role in the initiation of a research programme relating to chemoresistance and cancer stem cells through the generation and characterisation of a panel of isogenic cisplatin resistant NSCLC cell lines. As a Clinical Scientist, he provides scientific support to ongoing biomarker and other translational studies within the Clinical Trials Unit and Oncology Department at St. James’s Hospital. He played an active role in the establishment, and current maintenance of the Lung Cancer Biobank within the Thoracic Oncology Research Group which provides a valuable bioresource of patient biospecimens for translational research.
Since commencing employment in St. James’s Hospital in 2004, Dr Barr has been largely involved in the training and supervision of students (BSc, MSc, MD, PhD) pursuing both undergraduate and postgraduate degree programmes in the School of Clinical Medicine, TCD. He currently lectures in the area of Cancer & Treatments in a number of teaching programmes including the BSc in Molecular Medicine, MSc in Translational Oncology in addition to various Basic Medical Sciences programmes in TCD.
Dr Barr is a member of a number of professional bodies and organisations including the Irish Association for Cancer Research (IACR), American Association for Cancer Research (AACR), International Association for the Study of Lung Cancer (IASLC), Irish Thoracic Society (ITS) and the European Respiratory Society (ERS). He is a Fellow of the Institute of Biomedical Science (IBMS), a registered Chartered Scientist (Science Council, UK) and is a current Ambassador for the European Association for Cancer Research (EACR).
Dr Barr has received a number of awards for his research at both national and international conferences and was a recipient of the prestigious AACR Scholar-In-Training Award during the course of his PhD studies at RCSI. As part of ongoing collaborations within the Thoracic Oncology Research Group, Dr Barr was a Visiting Scientist in the laboratory of Professor John Minna, University of Texas Southwestern Medical Centre, Dallas, USA. He has published his research findings in international peer-reviewed medical and science journals, and has acted as a reviewer for international journals including; The Lancet Oncology, Journal of Thoracic Oncology, Lung Cancer, Cancer Investigation, Cancer Detection and Prevention, Molecular Cancer Therapeutics, Drug Design and Pharmacology, Annals of Surgical Oncology, International Journal of Cancer, Thorax, PLoS ONE, Cancer Research, Oncogene, Journal of Experimental & Clinical Cancer Research, International Journal for Biotechnology and Molecular Biology Research, Critical Reviews in Oncology/Haematology, Irish Journal of Medical Science, Journal of Cancer Therapy, Journal of Biomedical Research, Oncology, OncoTargets & Therapy, Experimental Lung Research, Biopreservation & Biobanking, Cancers, Clinical Investigation, Molecular Cancer, Annals of Clinical Pathology, BBA Cancer, BMC Cancer, Molecular Carcinogenesis, Current Medicinal Chemistry, Drug Design, Development & Therapy, OncoTarget, International Journal of Oncology, International Journal of Nanomedicine, Future Oncology, Cellular Physiology & Biochemistry.
He has also been successful in securing EU Seventh Framework Programme Funding (FP7) in collaboration with the King Hussein Cancer Centre in Jordan and European partners, Biostór Ireland and accelopment AG, Switzerland.
VEGF Survival Signalling in Non-Small Cell Lung Cancer
Angiogenesis is an essential pre-requisite for the growth and metastasis of many solid tumours, including non-small cell lung cancer (NSCLC). Vascular endothelial growth factor (VEGF) has been shown to correlate with a poor prognosis in NSCLC where increased tumour expression of VEGF is thought to play a central role in this process. Initially identified as an endothelial cell mitogen, VEGF has been shown to stimulate migration, survival, and induce vascular permeability. In addition, it has also been shown to promote tumour growth in vivo by inducing angiogenesis.
The biological effects of VEGF are mediated via binding to specific tyrosine kinase receptors including VEGFR-1 (Flt-1) and VEGFR-2 (KDR) in addition to non-tyrosine kinase receptors, Neuropilin-1 (NP1) and Neuropilin-2 (NP2). Neuropilins bind the VEGF165 isoform, where this interaction of VEGF165 with the NP receptors has been shown to enhance the biological effects of VEGF in vitro via VEGFR-2 signalling, thereby mediating endothelial cell migration, proliferation and angiogenesis. Co-expression of NP1 and NP2 in NSCLC tissue is significantly correlated with tumour progression and poor prognosis. NP1 has also been shown to be an independent predictor of cancer relapse and poor survival in NSCLC patients. In phase III trials, blocking VEGF using the recombinant humanised VEGF monoclonal antibody, Bevacizumab (Avastin®), has yielded improved progression-free and overall survival in NSCLC patients when combined with standard chemotherapy, demonstrating the use of VEGF as a target for therapy. Research interests in this area include, elucidating the role of VEGF as a tumour cell survival factor in NSCLC and the signalling pathways through which VEGF mediates this effect in vitro and in vivo (Barr et al., Mol Cancer, 2015).
Histone deacetylases (HDACs) are a growing family of enzymes that mediate the availability of chromatin to the transcriptional machinery. HDAC inhibitors have been shown to inhibit the proliferation and induce apoptosis of tumour cells and have demonstrated anti-angiogenic activity via targeting of the VEGF signalling pathway. To date, there is little research examining the epigenetic regulation of the VEGFR’s, particularly in NSCLC. Within the context of epigenetics, studies deciphering the epigenetic regulation of the VEGF receptors and their epigenetic targeting using HDAC inhibitors are on-going in our laboratory (Barr et al., Epigenomics, 2015).
Confocal microscopy imaging of the phosphorylation of the downstream PI3K signalling protein, Akt, in A549 lung adenocarcinoma cells in response to vascular endothelial growth factor (VEGF). Phosphorylation of the Akt protein is shown in green (Alexafluor 488) while cell nuclei are shown in blue (Hoechst 33342).
Mechanisms of Resistance to Chemotherapy in NSCLC
Cisplatin, or cis-diamminedichloro-platinum (II), is one of the most potent anti-cancer drugs, displaying significant clinical activity in a wide variety of solid tumours. The cytotoxic effects of cisplatin are mediated by its interaction with DNA, resulting in the formation of DNA adducts which activate several signal transduction pathways and culminate in the activation of apoptosis. While cisplatin has been the most effective systemic chemotherapy for NSCLC, the outcome of cisplatin therapy for NSCLC patients has reached a plateau due to resistance in a large number of patients. While 20-40% of patients with metastatic NSCLC experience a partial response to newly developed combination therapies, most responders relapse within six months. Within the population of patients that relapse, the selection of pre-existing resistant cells, and/or acquisition of resistant cells during treatment with chemotherapy has been proposed. Therefore, a better understanding of the molecular basis of cisplatin resistance is warranted in order to elucidate the mechanisms and markers underlying this drug-resistant phenotype, which at present radically limits the clinical utility of this drug in lung cancer patients. Research studies that may help improve our understanding of the molecular events associated with chemotherapy resistance in NSCLC, in addition to devising novel and more effective therapeutic approaches to reverse drug resistance to cisplatin in this disease is critical. We have previously generated and extensively characterised a panel of isogenic cisplatin resistant lung cancer sublines from corresponding, age-matched parental cells (Barr et al., PLoS One, 2013), providing a valuable in vitro model with which to investigate the molecular pathways and markers associated with this drug resistant phenotype in NSCLC.
Mechanisms by which tumour cells may become resistant to cisplatin. These include alterations in copper-transporters which decrease uptake of the drug by tumour cells, resulting in reduced intracellular drug levels. Tumour cells are also capable of enhancing their DNA repair capacity in addition to inducing alterations in pro- and anti-apoptotic proteins which result in decreased caspase activation and inhibition of apoptosis.
In addition to exploring the various molecular mechanisms implicated in the drug resistant phenotype in NSCLC such as drug uptake and drug efflux, we are also interested in the study of how lung cancer cells respond to DNA damage induced by cytotoxic chemotherapy and the repair mechanisms they use to overcome chemotherapy-induced cell death (O’Grady et al., Cancer Treat Rev., 2014).
Detection of DNA damage repair in H460 lung cancer cells in response to cisplatin. The gH2AX foci formation assay was used to detect cisplatin-induced DNA damage in NSCLC cells using an anti-human anti-phospho- histone 2AX (Ser139) antibody. Cells were imaged using the IN Cell Analyzer 1000.
Numerous studies have reported the potential role of microRNAs (miRNA) in resistance to various cancer treatments. MicroRNAs are a family of small non-coding RNAs that regulate gene expression by sequence-specific targeting of mRNAs causing translational repression or mRNA degradation. Evidence suggests that dysregulation of specific miRNAs may be involved in the acquisition of resistance to a number of cancer treatments, thereby modulating the sensitivity of cancer cells to such therapies. Therefore, targeting miRNAs may be an attractive strategy for developing novel and more effective individualized therapies, improving drug efficiency, and for predicting patient response to different treatments (MacDonagh et al., Cancer Treat Rev., 2015). Having identified a specific microRNA signature in cisplatin resistant NSCLC cells (unpublished), prospective studies examining the use of this microRNA signature in predicting response of NSCLC patients to cisplatin-based chemotherapy, is currently in progress. We are also interested in exploring the use of one or more of these microRNAs as potential diagnostic markers in NSCLC.
Drug resistance and Cancer Stem Cells
Recently, the cancer stem cell (CSC) theory was proposed where according to this model, tumours may be viewed as a result of abnormal tumorigenesis driven by CSC’s. These are self-renewing tumour cells that are able to initiate and maintain tumour growth through subpopulations of tumour cells with stem or progenitor cell characteristics. While conventional cytotoxic chemotherapy eliminates the bulk of tumour cells within the lung tumour cell population, residual CSCs continue to self-renew in the face of this cytotoxic challenge. We are interested in the characterisation of CSC subpopulations in chemoresistant NSCLC and the targeting of CSC-specific markers, aldehyde dehydrogenase (ALDH) activity and signalling pathways, using in vitro and in vivo models.
Original Peer-Reviewed Research Publications:
Hu L, Sun S, Jiang K, Lin G, Ma Y, Barr MP, Song F, Zhang G, Meng S. Oncolytic Newcastle Disease virus triggers cell death of lung cancer spheroids and is enhanced by pharmacological inhibition of autophagy. Am J Cancer Res, (In Press), 2015.
Barr MP & O’Byrne KJ, Al-Sarraf N, Gray SG. VEGF-mediated cell survival in NSCLC: Implications for epigenetic targeting of VEGF receptors as a therapeutic approach. Epigenomics, 7(6), 897-910, 2015.
Barr MP, Gray SG, Gately K, Hams E, Fallon PG, Davies AM, Richard DJ, Pidgeon GP, O’Byrne KJ. VEGF is an autocrine growth factor, signalling through Neuropilin-1 in non-small cell lung cancer. Mol Cancer, 14(1), 2015.
Dowling P, Pollard D, Larkin AM, Michael H, Meleady P, Gately K, O'Byrne K, Barr MP, Lynch V, Ballot J, Crown J, Moriarty M, O’Brien E, Morgan R, Clynes M. Abnormal levels of heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) found in tumour tissue and blood samples from patients diagnosed with lung cancer. Mol BioSyst, 11(3), 743-752, 2015.
Barr M, Souan L, MacGabhann P, Müller J, Al Ashhab M, Jasser M, Hamza K, Al Hassoon S, Kuhn U, Infante D, Lawlor D, Gately K, Amireh E, O’Byrne, KJ, Sughayer MA. The Establishment of an ISO Compliant Cancer Biobank for Jordan and its Neighbouring Countries Through Knowledge Transfer & Training. Biopreservation & Biobanking, 12(1):3-12, 2014.
Heavey S, Godwin P, Baird AM, Barr MP, Umezawa K, Cuffe S, Finn S, O’Byrne K, Gately K. Strategic targeting of the PI3K-NFkB axis in Cisplatin Resistant NSCLC. Cancer Biol Ther, 15(10):1367-1377, 2014.
Barr MP. Front Cover Image. Biotechniques, 56(4), 2014.
Peters S, Weder W, Dafni U, Kerr KM, Bubendorf L, Meldgaard P, O'Byrne KJ, Wrona A, Vansteenkiste J, Felip E, Marchetti A, Savic S, Lu S, Smit E, Dingemans AM, Blackhall FH, Baas P, Camps C, Rosell R, Stahel RA; ETOP Lungscape Investigators. Lungscape: resected non-small-cell lung cancer outcome by clinical and pathological parameters. J Thorac Oncol, 9(11), 1675-1684, 2014.
Barr MP, Fennell DA, O’Leary JJ, Gray SG, O’Flaherty JD, Reynolds JV, O’Byrne KJ. The generation and characterisation of cisplatin resistant non-small cell lung cancer cell lines displaying stem-like features. PLoS One, 8(1), 2013.
Paul I, Chacko AD, Stasik I, Busacca S, Crawford N, McCoy F, McTavish N, Wilson B, Barr M, O'Byrne KJ, Longley DB, Fennell DA. Acquired differential regulation of caspase-8 in cisplatin-resistant non-small-cell lung cancer. Cell Death Dis, 3:449, 2012.
Field JK et al. EUELC project: a multi-centre, multipurpose study to investigate early stage NSCLC, and to establish a biobank for ongoing collaboration. Eur Respir J, 34 (6):1477-86, 2009.
Barr MP, Bouchier-Hayes DJ, Harmey JH. Vascular endothelial growth factor (VEGF) is an autocrine survival factor for breast tumour cells under hypoxia. Int J Oncol, 32 (1): 41-48, 2008.
Barr MP, Byrne AM, Duffy A, Condron C, Devocelle M, Harriott P, Bouchier-Hayes DJ, Harmey JH. A peptide corresponding to the Neuropilin-1 binding site on VEGF165 induces apoptosis of Neuropilin-1-expressing breast tumour cells. Brit J Cancer, 92 (2):328-333, 2005.
Pidgeon GP, Barr MP, Harmey JH, Foley DA, Bouchier-Hayes DJ. Vascular endothelial growth factor (VEGF) upregulates Bcl-2 and inhibits apoptosis in human and murine mammary adenocarcinoma cells. Brit J Cancer, 85 (2):273-279, 2001.
Leon G, MacDonagh L, Finn SP, Cuffe S, Barr MP. Cancer Stem Cells in Drug Resistant Lung Cancer: Targeting Cell Surface Markers and Signalling Pathways. Pharmacol. Ther, (In Press), 2015.
MacDonagh L, Gray SG, Finn SP, Cuffe S, O’Byrne KJ, Barr MP. The emerging role of microRNAs in resistance to lung cancer treatments. Cancer Treat Rev, 41(2): 160-169, 2015.
O’Grady S, Finn SP, Cuffe S, Richard DJ, O’Byrne KJ, Barr MP. The Role of DNA repair pathways in cisplatin resistant lung cancer. Cancer Treat Rev, 40(10): 1161-1170, 2014.
Barr MP, Mac Donagh L, O’Byrne KJ. Markers of response to platinum-based chemotherapy in lung cancer. Lung Ca Management, 2(3): 1-13, 2013.
Godwin P, Baird AM, Heavey S, Barr MP, O’Byrne, KJ, Gately K. Targeting Nuclear Factor-kappa B to overcome resistance to chemotherapy. Front Oncol, (3)120, 2013.
O'Flaherty JD, Barr M, Fennell D, Richard D, Reynolds J, O'Leary J, O'Byrne K. The cancer stem-cell hypothesis: its emerging role in lung cancer biology and its relevance for future therapy. J Thorac Oncol, 7(12): 880-1890, 2012.
Gao Y, Baird AM, Barr M, Gately K, O’Byrne KJ, Gray SG. Epigenetic therapy for cisplatin resistance in non-small cell lung cancer: the way forward? Lung Ca Management, 2(1):1-4, 2013.
Kenneth J. O’Byrne, Martin P. Barr, Steven G. Gray. The role of Epigenetics in Resistance to Cisplatin Chemotherapy in Lung Cancer. Cancers, 3(1): 1426-1453, 2011.
Published Book Chapters
Barr MP & O’Byrne KJ. Molecular Mechanisms of Cisplatin Resistance in Lung Cancer. In: Lung Cancer: A Comprehensive Overview. Nova Science Publishers, New York, 2013.
For further information about Dr Martin Barr please view his CV Profile.
For further information on Thoraic Oncology Research please view the IMM website