Seminar: Pharmacogenomics of breast, colorectal, and pancreatic carcinomas

The RCSI Centre for Systems Medicine will host a seminar by Dr Pavel Souček (NIPH, Prague) on the molecular mechanisms of responses to major anticancer drugs by

Dr Pavel Souček

Head, Toxicogenomics Department & Group for Biotransformations, Centre of Occupational Medicine, National Institute of Public Health (NIPH), Prague, Czech Republic

Pharmacogenomics of breast, colorectal, and pancreatic carcinomas

Abstract: Response to anticancer therapy on the molecular level is limited by the inter-individual variability in drug metabolizing enzymes (e.g. cytochromes P450) and transporters as ATP-binding cassette (ABC) transporters or solute carrier (SLC) proteins. We followed associations of clinical features, including therapy outcome, with gene expression of more than 100 genes from pathways active in metabolism and transport of major anticancer drugs (anthracyclines, antimetabolites, taxanes) in sets of tumor and non-neoplastic tissues from breast, colorectal and pancreatic carcinoma patients.

We have found potential biomarkers of patient´s prognosis, e.g. ABCC11 in colorectal (Hlavata et al. Mutagenesis 2012) or ABCA12, ABCA13, ABCC1, ABCC8, and ABCD2 in breast carcinoma (Hlavac et al. Pharmacogenomics 2013). The observed, overexpression of multidrug-resistance connected exporters (ABC transporters) and downregulation of drug importers (SLCs) in pancreatic adenocarcinomas may contribute to the generally low treatment response of this cancer and suggests new drug targets (Mohelnikova-Duchonova et al. Pancreas 2013 and Cancer Chem Pharmacol. 2013).

Marked differences in expression profiles suggest that the followed carcinomas may differ in mechanisms of drug resistance. We are currently performing validation and mechanistic studies to verify the importance of the revealed biomarkers for cancer outcome.

All are welcome to the Albert LectureTheatre, RCSI 123 St Stephen’s Green on Tuesday August 26th at 4pm.

This seminar is supported by HRB funding to Dr David Hughes in the CSM

 

Low selenium levels are associated with colorectal cancer development

Low selenium levels are associated with colorectal cancer development

New evidence that the micronutrient selenium is involved in colorectal cancer (bowel cancer) has been discovered by Dr David Hughes from the Centre for Systems Medicine with colleagues in Emory University in Atlanta, Georgia, USA, the University of
Newcastle in England, the International Agency for Research on Cancer in Lyon,
France, and collaborators in the European Prospective Investigation of Cancer
and Nutrition Cohort (EPIC) study. The research is currently published online
(July 9th) in the International Journal of Cancer*

 The HRB funded research, led by Dr Hughes, indicates that selenium levels are suboptimal in many Western Europeans and suggest that higher serum selenium levels are associated with a decreased risk of colorectal cancer (CRC), which is more evident in women.

Many populations in Europe have intakes of selenium that are relatively low, especially compared with North America. The association of selenium status with CRC development is controversial due to conflicting results from both observational
studies and intervention trials.

The present study describes the results of the largest prospective analysis of the association of serum selenium status biomarkers [total serum Se levels and Selenoprotein P (SePP) protein concentrations] with risk of CRC in European populations. These are robust markers of Se status. The study was conducted within the EPIC cohort across ten European countries. This cohort provides a well-characterized, large set of participants in terms of diet and cancer risk.

The study shows that in many Western Europeans selenium levels are insufficient for adequate function of key proteins (such as SePP) that use selenium in important cellular processes. Higher selenium concentrations were inversely associated with CRC risk in women only while higher SePP concentrations were inversely associated with CRC risk in men and women combined. The results suggest that selenium intake/status is an important factor in affecting CRC risk in a population of marginally low
selenium status, such as in Europe.

The contrasting results of this study and those from the NPC and SELECT selenium intervention trials may be due to differences in baseline selenium levels of study participants. This likely helps to explain the controversy over outcomes from these selenium intervention trials in North America that has led to the prevalent perception among the scientific / medical community that increased selenium intake does not have any association with risk of CRC development. Our results suggest that in populations where selenium status is sub-optimal (e.g. Western Europe) increasing selenium intake may reduce CRC risk, especially for women. We believe our study provides a strong rationale for undertaking a selenium supplementation trial, including use of selenium status biomarkers, for CRC prevention in a population with sub-optimal Se availability.

*Manuscript reference:

Hughes DJ, Fedirko V, Jenab M, Schomburg L, Méplan C,
Freisling H, Bueno de Mesquita HB, Hybsier S, Becker NP, Czuban M, Tjønneland
A, Outzen M, Boutron-Ruault MC, Racine A, Bastide N,  Kühn T, Kaaks R,
Trichopoulos D, Trichopoulou A, Lagiou P, Panico S, Peeters PH, Weiderpass E,
Skeie G, Dagrun E, Chirlaque MD, Sánchez MJ, Ardanaz E, Ljuslinder I, Wennberg
M, Bradbury KE, Vineis P, Naccarati A, Palli D, Boeing H, Overvad K, Dorronsoro
M, Jakszyn P, Cross AJ, Ramón Quirós  J, Stepien M, Kong SY, Duarte-Salles
T, Riboli E, Hesketh JE.<a href=”http://www.ncbi.nlm.nih.gov/pubmed/25042282
target=”_blank”> Selenium Status is Associated with Colorectal
Cancer risk in the European Prospective Investigation of Cancer and Nutrition
Cohort.</a> Int J Cancer. 2014 Jul 9. [Epub ahead of print] PMID:
25042282

APO-DECIDE Project

Link

At the threshold of personalised cancer treatment

Published by newsroom editor on Friday, 16/05/2014

New tumour profiling methods developed by EU-funded researchers aim to help doctors adjust treatments for colorectal cancer to the specific needs of an individual patient. The methods are currently at the trial stage and could be in use in clinics within three years.

Worldwide, colorectal cancer is responsible for around 694 000 deaths each year, according to the World Health Organization. Decision making on treatment in the clinic currently depends largely on factors such as how much the tumour has grown and the age of a patient. As each patient is unique, the success of such treatments is largely unpredictable.

To replace the ‘one size fits all’ approach, the APO-DECIDE project, led by Professor Jochen Prehn at the Royal College of Surgeons in Ireland, is developing new clinical decision-making tools to help doctors categorise patients on the basis of their individual biological and genetic characteristics.

Read More:http://ec.europa.eu/programmes/horizon2020/en/news/threshold-personalised-cancer-treatment

Common Gut Bacterium Associated with Colorectal Cancer

HRB-funded research in the Centre for Systems Medicine could lead to a new biomarker for colorectal cancer.

New evidence that a common gut bacterium is involved in colorectal cancer has been published by researchers in the Centre for Systems Medicine, RCSI (first author is Dr Lorna Flanagan and study PI is Dr David Hughes). The manuscript* is currently available online in the European Journal of Clinical Microbiology & Infectious Diseases.

The HRB funded research found a significantly increased presence of a common microbe Fusobacterium nucleatum (Fn) in tissue and stool samples of patients with colorectal cancers and colorectal adenomas. Additionally Fn infection levels were related with adenoma progression from early to advanced stages and the transition from an adenoma to cancer, highlighting the potential of Fn detection as a possible indicator of colorectal cancers. The research further found that cancer patients with low bacterial levels had significantly longer survival times than patients with moderate and high levels of the bacterium.

The research suggests that screening for Fn levels may be used as a new colorectal cancer detection method or to further inform existing screening strategies. Efforts to combat Fn infection could be considered for colorectal cancer patients with high levels of the bacterium to improve the survival prospects for these patients. Fn levels may be used to classify adenomas that may have a higher risk of disease progression to colorectal cancers with implications for increasing follow-up and at the possible use of anti-microbial treatments. Potentially, any impact of Fn infection on adenoma development and progression to more serious stages will be considerable, because 95% of all colorectal cancers arise from adenomas, but only a small number of them become cancerous. Currently, there are no reliable predictive markers of whether an adenoma will advance to cancer.

Seminar by Prof. Borner on use of viruses and funghi in apoptosis research

The Centre for Systems Medicine is pleased to announce another speaker to our seminar series,

Prof Dr Christoph Borner

Professor in Medical Cell Research, Institute of Molecular Medicine,
Albert Ludwigs University Freiburg, Germany

Use of viruses and funghi to uncover novel apoptosis signaling pathways

The primary interest of his laboratory is the elucidation of the function of multidomain anti- and pro-apoptotic Bcl-2 family members (Bcl-2, Bcl-xL, Mcl-1, Bax and Bak), the characterization of components of caspase-independent and RNA-virus (SFV)-induced apoptosis signaling, and the mathematical modelling of apoptotic and mitogenic FasL signaling pathways in primary hepatocytes.

Find more details on his homepage.

Recent publications:

  • A Novel Mitochondrial MAVS/Caspase-8 Platform Links RNA Virus-Induced Innate Antiviral Signaling to Bax/Bak-Independent Apoptosis. El Maadidi S, Faletti L, Berg B, Wenzl C, Wieland K, Chen ZJ, Maurer U, Borner C. J Immunol. 2014 Jan 3.
  • Apoptosis induced by the fungal pathogen gliotoxin requires a triple phosphorylation of Bim by JNK. Geissler A, Haun F, Frank DO, Wieland K, Simon MM, Idzko M, Davis RJ, Maurer U, Borner C. Cell Death Differ. 2013 Oct;20(10):1317-29. doi: 10.1038/cdd.2013.78. Epub 2013 Jul 5.
  • TNFα-induced lysosomal membrane permeability is downstream of MOMP and triggered by caspase-mediated NDUFS1 cleavage and ROS formation. Huai J, Vögtle FN, Jöckel L, Li Y, Kiefer T, Ricci JE, Borner C. J Cell Sci. 2013 Sep 1;126(Pt 17):4015-25. doi: 10.1242/jcs.129999. Epub 2013 Jun 20.
  • Non-canonical function of Bax in stress-induced nuclear protein redistribution. Lindenboim L, Ferrando-May E, Borner C, Stein R. Cell Mol Life Sci. 2013 Aug;70(16):3013-27.

The talk is open to everyone and will be held in Houston Lecture Theater, RCSI on 28th of January 2014 at 1:30 pm.

Seminar by Lou Philipson: New Insights into Insulin Secretion

The Centre for Systems Medicine is pleased to announce another speaker to our seminar series,

Prof. Lou Philipson,
Professor of Medicine, Director, Kovler Diabetes Center, The University of Chicago

New Insights into Insulin Secretion

Louis Philipson, MD, PhD, is an endocrinologist and a leading world authority on diabetes mellitus. His clinical interests include type 1 diabetes, complicated type 2 diabetes, monogenic diabetes and hypoglycemia.

Recognized for unmatched expertise in the treatment of diabetes that is difficult to manage, Dr. Philipson’s multisciplinary team frequently accepts referrals and provides consultations. Under his leadership, Kovler Diabetes Center has been recognized as a one of only seven National Institutes of Health (NIH) Diabetes Research and Training Centers in the U.S.

For more than 25 years, Dr. Philipson has tirelessly explored the biophysical, molecular and genetic aspects of insulin secretion, and the genetics of diabetes. He and his colleagues discovered rare insulin gene mutations that produce beta cell ER stress and, in turn, cause neonatal diabetes.

In addition, Dr. Philipson and his colleagues are among the nation’s leading experts on monogenic diabetes, following more than 100 patients diagnosed with neonatal diabetes and many others with maturity onset diabetes of the young (MODY) type diabetes. He also serves as co-director of the Human Islet Transplantation project at the University of Chicago.

Dr. Philipson has served as principal investigator on numerous research projects. His work is widely published in biomedical journals, including the Proceedings of the National Academy of Sciences, Science, Nature, Diabetes, American Journal of Physiology and the Journal of Biological Chemistry.

http://www.uchospitals.edu/physicians/louis-philipson.html

The talk is open to everyone and will be held in Houston Lecture Theater, RCSI on the 16th of January 201 at 4:30 pm.

Irish Cancer Society Research Fellowship awarded to Amanda Tivnan

Congratulations to Dr. Amanda Tivnan from the Centre for Systems Medicine, Royal College of Surgeons in Ireland. She is awarded a Research Fellowship by the Irish Cancer Society.

AmandaTivnan receives Irish Cancer Society Research Award

Dr Amanda Tivnan with Professor John Fitzpatrick, Head of Research, Irish Cancer Society, Mr Dermot Breen, Tesco, and Ray D’Arcy, Broadcaster at Today FM receiving the Irish Cancer Society Research Fellowship Award Certificate

Dr. Amanda Tivnan at the Irish Cancer Society Research Fellows and Scholars Awards Ceremony in Dublin at which six new cancer research grants were awarded, said, “Although any form of brain cancer is serious, diagnosis of a patient with glioblastoma multiforme (GBM) currently holds the worst outcome, with an average survival of only 12-15 months. It is a highly aggressive brain cancer due to increased numbers of ‘pumps’, called transporters, on the cancer cells surface that rapidly remove the chemotherapy from the cell, not allowing it enough time to act and kill the brain cancer.”

“My research aims at targeting these pumps, so allowing the chemotherapy a longer time within the cancer cells and hopefully increasing its killing abilities. It will also focus on developing novel technologies to remove these pumps from the cancer cells, and then reassessing the response of these glioblastoma cells to chemotherapy, providing us with hope for patient survival in the future.”

Speaking at the Ceremony, Prof. John Fitzpatrick, Head of Research, Irish Cancer Society said, “The Irish Cancer Society’s vision for cancer research is based on achieving world-class discoveries across all cancer types to improve outcomes for the thousands of patients that are diagnosed each year in Ireland. We are extremely proud to announce our next round of Fellows and Scholars that will join the battle against cancer by applying their great knowledge and skills- to finding new ways to improve patient outcomes.”

“Over the past 50 years, the Irish Cancer Society has contributed €33 million to advance high-quality cancer research in Ireland. This funding has gone towards research grants, such as the Scholarship and Fellowship programmes, and the country’s first Collaborative Cancer Research Centre BREAST-PREDICT, which aims to predict the best treatment options for breast cancer patients. None of this would have been made possible without the general public’s ongoing support and commitment to fundraising for cancer research.” The Society’s Fellows and Scholars are also supported by the Tesco Charity of the Year Partnership 2010-2011 and the Movember Foundation.

Women race to pay tribute to friend who died of brain cancer and raise almost €30K for Irish Cancer Society research grants

An inspiring group of 47 women self-titled the Rainbow Runners raced to the finish line at the Flora Women’s Mini Marathon this year to pay tribute to their dear friend Gayle Warnock, who died from an inoperable brain tumour in 2012 aged 38, and raised almost €30K for Irish Cancer Society Research.

Caroline Reay said the women had chosen the Irish Cancer Society “as Gayle wanted to run the marathon herself, and donate the money to the Society to encourage new research discoveries that might one day benefit thousands of patients battling cancer in Ireland.” Their contribution will go towards the Irish Cancer Society’s total €33 million investment in cancer research over the past 50 years, making them Ireland’s largest voluntary funder of cancer research.

The Society’s Research Fellows and Scholars awards are designed to foster home-grown cancer research talent in Ireland and to ensure new research projects are commenced in a range of cancers including brain tumours, colorectal, oesophageal, prostate and breast cancers. The research projects span a wide range of research areas and will investigate a number of potentially important topics, such as novel technologies that could increase the length of time that chemotherapy can act inside cancer cells, novel targets to develop drugs against and broadening treatment options.

Workshop on light sheet fluorescence microscopy was full success

CSM successfully hosted the first Irish/UK light sheet fluorescence microscopy workshop organized by Dr Emmanuel G. Reynaud (UDC) and Dr Heiko Dussmann (RCSI). Lectures given by Malte Wachsmuth (21st Nov 2013), Bill Chaudry, Chris Power, Ellen Barker, and Emmanuel Reynaud drew a clear picture in the morning sessions (25th Nov 2013) of the new dimensions of imaging possibilities, which were then demonstrated in the hands on training sessions in the afternoon.

Thank you to the speakers agreeing to offer presentations for download:

Here are some impressions of the event:

Seminar: Fiona Ginty, GE Global Research Centre

Dr. Fiona Ginty

Principal Scientist, Life Sciences and Molecular Diagnostics, General Electric Global Research Center

Tumor heterogeneity revealed using high-order in situ multiplexing

The Centre for Systems Medicine is pleased to announce a seminar by Dr. Fiona Ginty from General Electric Global Research Center, Niskayuna, NY.

Abstract: Protein analysis in formalin-fixed, paraffin-embedded tissues is typically limited to 1-2 markers per tissue slide using chromogenic stains, or up to four markers using immunofluorescence. The increasing demands on tissue for predictive and prognostic biomarker testing presents significant challenges for pathologists and oncologists to ensure that the most important markers are selected for patient care. Coupled with this, tumor and cellular heterogeneity may confound genomic results. To address these challenges, GE scientists have developed a multiplexed immunofluorescence technology that allows measurement of up to 60 markers at single cell level in a 5 um FFPE tissue section (MultiOmyx™). DNA FISH analysis may also be conducted on the same sample, following multiplexed protein analysis. Image processing and visualization tools allow interactive assessment cellular biomarkers in context of tumor histology and microenvironment.  In addition to sparing precious sample, multiplexed analysis allows quantitation and visualization of extensive biomarker heterogeneity within the tumor, stroma, blood vessels and other cellular features. This platform will provide new opportunities for redefining and understanding biological mechanisms for basic and drug discovery research.

Please see also the publication Highly multiplexed single-cell analysis of formalin-fixed, paraffin-embedded cancer tissue PNAS 2013 110 (29) 11982-11987; published ahead of print July 1, 2013

The talk is free and open to everyone and will be held in Houston Lecture Theater, RCSI on the 16th of December 2013 at 4 pm.

This seminar is supported by the RCSI seed fund program.

Seminar: Real-Time Near Infrared Fluorescence Imaging

Prof. Donal O’Shea

Head of the Department of Pharmaceutical and Medicinal Chemistry,
Royal College of Surgeons in Ireland

Real-Time Near Infrared Fluorescence Imaging – from chemistry to mice and the potential for beyond

Fluorescence imaging, utilizing molecular fluorophores, often acts as a central tool for the investigation of fundamental biological processes.  It also offers huge future potential for human imaging coupled to therapeutic procedures such as fluorescence guided surgery. We have recently developed a new class of near infrared (NIR) fluorophore from which excellent in vitro and in vivo imaging probes can be developed.1 But in spite of the advantages offered by longer wavelength NIR emissions a common limitation with fluorescence imaging is the difficulty in discriminating non-specific fluorescence from fluorescence localized at a specific region of interest. This can restrict imaging to individual time points at which non-specific background fluorescence has been minimized.  It would be of significant advantage if the fluorescence output could be modulated from off to on in response to specific biological events as this would permit imaging of such events in real time without background interference. Two approaches (one molecular and one nanoparticle based) to achieve this using cellular endocytosis as the NIR-fluorescence switching trigger will be described.2  Both approaches permit continuous real-time imaging of the cellular uptake, trafficking and efflux processes as extracellular fluorophore is non-fluorescent. The principles behind the NIR-fluorescence off/on switching will be explained and illustrated in vitro and in vivo. In addition, a theranostics approach using the combination of NIR fluorescence imaging and photodynamic therapy will also be shown.3

Please feel welcome to attend on the 6th of December 2013 at 9:10 am. The talk will be held in Cheyne Lecture Theatre at RCSI, St. Stephen’s Green.

1.         (a) Tasior, M.; O’Shea, D.F. Bioconjugate Chem. 2010, 21, 1130. (b) Wu Dan, O’Shea D.F. Org. Lett. 2013, 15, 3392.

2.         (a) Palma, A.; Alvarez, L.A.; Frimannsson, D.O.; Grossi, M.; Quinn, S.J.; O’Shea, D.F. J. Am. Chem. Soc. 2011, 133, 19618. (b) http://www.youtube.com/watch?v=FjipbGTf8w4.

3.         O’Connor, A. E.; McGee, M. M.; Likar, Y.; Ponomarev, V.; Callanan, J. J.; O’Shea, D. F.; Byrne, A. T.; Gallagher, W. M. Intern. J. Cancer, 2012, 130, 705.