Professor John O’Leary delivers his Inaugural Lecture as Chair of Pathology at TCD on Cancer: Genes, Proteins and Stemness’
Posted on: 18 May 2007
Major Research in the Development of New Treatments for Ovarian, Cervical, Thyroid and Prostate Cancers at TCD
“Irish scientists will make a significant contribution to unlocking the mystery of cancer, its causes and outcomes through the formation of strategic translational cancer networks. New molecular biology tools have revolutionised the way in which we view cancer and how we can investigate the causes of cancer,” stated Professor John O’Leary, TCD who is leading major research of international significance in the development of new therapeutic approaches in the treatment of ovarian, thyroid, prostate and cervical cancer.
Delivering his Inaugural Lecture as Chair of Pathology today on ‘Cancer: Genes, Proteins and Stemness’ in Trinity College Dublin, Professor O’Leary examined the role of new technologies in the diagnosis and management of cancer. He highlighted, in particular, the use of recently discovered genetic biomarkers of disease and the new theory of ‘cancer stem cell biology’ and how the isolation of cancer stem cells may provide new therapeutic approaches in cancer.
Professor O’ Leary presented current research topics that are being investigated by the molecular pathology research group which he heads up at the Department of Histopathology, Trinity College Dublin and which has gained an international reputation in the areas of cervical, ovarian, thyroid, prostate and virally-driven cancers.
Professor O’Leary presented research highlights from consortia in which his research group is involved and explored gender restricted cancers (cervix, ovary, prostate) and thyroid cancer.¹
In cervical cancer, he described the identification of a novel set of molecular biomarkers which have direct diagnostic and prognostic value in cervical pre-cancer and cancer diagnosis ².
The TCD research group which includes Dr Cara Martin and Dr Orla Sheils, now advocates the use of a gene and protein expression ‘molecular traffic light’ for the management of women with cervical pre-cancer, which has recently been introduced in hospitals associated with the research and is now used by many international centres of excellence working in the area of cervical pre-cancer and cancer.
Professor O’Leary described a recently discovered gene signature pattern for chemoresistant ovarian cancer³.
Using a novel human protein expression array system in collaboration with Professor. Dolores Cahill of the Conway Institute, Dr Sharon O’Toole and Professor Brian Sheppard, TCD, the group has now assembled a protein signature for advanced ovarian cancer. Many of these novel proteins have important functions related to cell kinesis, apoptosis and resistance to commonly used ovarian chemotherapeutic agents.
In collaboration with Professor Marek Radomski, School of Pharmacology, TCD, the TCD ovarian cancer group is examining the role of novel therapeutic agents in ovarian cancer through the activation of apoptosis cascades to bring about tumour cell death. In collaboration with Professors Luke Lee and Brian MacCraith, Dublin City University, the group is developing a novel lab-on-a-chip device and oxygen sensing nanoparticle technology for patient disease monitoring and therapeutic decision formulation in ovarian cancer patients.
Professor O’Leary discussed significant advances in thyroid cancer and highlighted many of the important discoveries made by the molecular pathology research group led by Dr Orla Sheils, TCD. The group has formulated a bio-algorithm for radiation and non-radiation associated thyroid cancer and has identified significant gene pathways that are involved in the pathogenesis of thyroid cancer. The group has also recently formulated an miRNA regulatory map in thyroid cancer based on the predominant gene pathways that are dysregulated in thyroid cancer, offering for the first time a novel molecular diagnostic approach to thyroid cancer diagnostics.
In prostate cancer, the TCD group has been involved in describing the use of a novel protein AMACR in prostatic cancer diagnostics. It has recently shown that the amplification and over-expression of the important cancer gene Topoisomerase II alpha is seen to correlate with patient survival and improves on the routinely used PSA (prostatic specific antigen) screening test used in prostatic cancer patients. As part of the prostate research consortium in collaboration with TCD’s Professor Mark Lawler, Professor Bill Watson of the Conway Institute, UCD, Professor Richard O’Kennedy, DCU and Professor Elaine Key, RCSI, the group will examine the phenomenon of epithelial-stormal cross talk in prostate pre-cancer and cancer and will critically examine the role of gene expression dysregulation and transcriptional and translational control in prostate pre-cancer and cancer.
Cancer Stem Cell Biology
Professor O’Leary’s talk also dealt with cancer stem cell biology and explored this concept in relation to the definition of cell renewal, proliferation and differentiation in cancer. Professor O’Leary presented data on murine (mice) and human systems and provided compelling data in relation to what constitutes a cancer stem cell and how this differs from murine embryonic stem cells and adult stem cells. The cancer stem cell group has used embryonal carcinoma (EC) as a model system to examine cancer stem cell biology. This model has recently been accepted internationally as a paradigm for cancer stem cell biological evaluation. Professor O’Leary presented data in relation to well characterised stem cell genes (Oct 4, Nanog, Shh, Notch etc.) and critically evaluated their role in cancer stem cell renewal, maintenance of renewal and in cell differentiation. The findings indicate that there are several gene pathways that are potential targets for new chemotherapeutic and gene targeting therapies including oxidative stress genes, WNT signalling genes and hedgehog proteins.
The expanding role of short interfering RNA (siRNA) technology in gene knockdown experiments in cancer research and miRNA translational regulation in cancer systems was also explored. Gene knockdown is where synthetic nucleic acid sequences are used to knock out the effect of a particular gene.
Notes to the Editor
Professor John O Leary was recently awarded the St Luke’s medal by The Royal Academy of Medicine in Ireland (RAMI) and St Luke’s Hospital. It is awarded in recognition of a substantial contribution to cancer research in Ireland.
1.The molecular pathology research group at TCD currently hosts or participates in several research consortia including:
– CERVIVA (The Irish Cervical Screening Research Consortium: a 5year programme funded by the HRB: www.cerviva.ie);
– DISCOVARY (an all Ireland ovarian cancer research discovery programme);
– PREG consortium (Proteomics Research Enhancing Gestation) – an all Ireland proteomic and transcriptomic research initiative in pregnancy and pregnancy related disorders;
– Prostate Cancer Research Consortium (funded by the Irish Cancer Society);
– Microactive (an EU 6th FP funded international biochip research consortium)¹.
CERVIVA: €1.35 million has been received from the HRB and an additional €300,000 from other sources.
DISCOVARY: industrial collaboration and part of SFI CSET hosted by Professor Brian MacCraith, Biomedical Devices Institute, DCU.
PCRC (prostate cancer research consortium): €1.2 million (Irish Cancer Society – phase I and II).
MICROACTIVE (EU 6th FP grant): €3.4 million in funding.
2. These markers include: p16, mcm 2,3 5,7, geminin, topoisomerase II alpha and nfu-2 (a novel replisome protein) and a unique set of regulatory micro RNAs (miRNAs) discovered by the Dublin group to be significantly dysregulated in cervical cancer.
3. This includes genes in the S-100, tight junction, EGFR-L (epidermal growth factor) ligand and interleukin signalling pathways.