Centre for Systems Medicine

Seminar: Radiotherapy, Neural Stem Cells and Cognitive Function

Jasmin Schmid — Tue, 16 Apr 2013 13:44:35 +0000

Dr. Juergen Zanghellini

Austrian Centre of Industrial Biotechnology (ACIB)

From metabolic engineering to combinational drug therapy

The Centre for Systems Medicine is pleased to announce another speaker of our seminar series. Dr. Juergen Zanghellini received his masters in electrical engineering at the Vienna University of Technology. During his PhD he moved to Ottawa, ON, Canada where he modeled laser driven ionization processes in atoms and small molecules. He received his PhD in theoretical physics in 2004. After returning to Austria he joined the Institute of Chemistry (Graz University, Austria) and focused his work on modeling fat metabolism in yeast. In 2010 he did a post-doc at the Australian Centre for Plant Functional Genomics (ACPFG), Adelaide, SA.
Since 2011 Juergen Zanghellini is leading the junior group on metabolic modeling at Austrian Centre of Industrial Biotechnology (ACIB). His research interest focuses on the analysis of (metabolic) networks using methods from systems biology.
He will introduce the concept of elementary flux modes, show applications thereof and explain that both, the minimal metabolic intervention strategies and efficient drug cocktails can be efficiently predicted. Finally he will discuss the potential of such an approach for the prediction and identification of drug targets in cancer research.

The talk will be held in the Albert Lecture Theatre, RCSI on Tuesday 7th of May 2013 at 4.30 pm.

Seminar by Andrew Kung

Jasmin Schmid — Fri, 09 Nov 2012 18:53:35 +0000

Professor Andrew L. Kung

Columbia University Medical Center, New York, USA

Identification of novel therapeutic strategies for brain tumors

The Centre for Systems Medicine is pleased to announce another speaker of our seminar series. Professor Andrew L. Kung is Chief of the Division of Pediatric Hematology, Oncology, and Stem Cell Transplantation at the Columbia University Medical Center in New York City. Professor Kung earned his MD and PhD degrees from Stanford University School of Medicine in 1994, and did his post-graduate medical training at the Boston Children’s Hospital and the Dana-Farber Cancer Institute (DFCI). Professor Kung was on staff at the DFCI and Harvard Medical School for 12 years, and recently assumed a leadership position at Columbia University. His research program is focused on novel cancer target discovery and drug development.

The talk will be held in the Albert Lecture Theatre, RCSI on Monday 3^rd of December 2012 at 4.30 pm.

Seminar by Anthony Letai

Jasmin Schmid — Tue, 06 Nov 2012 13:32:55 +0000

Anthony Letai, MD, PhD

Associate Professor in Medicine, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA

Mitochondria: cancer’s crystal ball

The Centre for Systems Medicine is pleased to announce the latest speaker in our seminar series.

Dr. Letai’s research aims to bring a detailed, mechanistic understanding of how the BCL-2 family of proteins governs commitment to apoptosis and chemosensitivity in cancer cells to improving and personalizing cancer therapy in patients. He has applied studies across many types of cancers, including lung, breast, ovarian, lymphoma and leukemia. To this end, he developed a unique tool, BH3 profiling, that measures sensitivity of mitochondria to pro-death signals. BH3 profiling has proved very useful in understanding and predicting response to chemotherapy in vitro and in the clinic. Given that many target therapies also utilize the mitochondrial apoptotic pathway to kill cancer cells, he continues to explore ways to utilize BH3 profiling as a predictive biomarker for response to targeted therapies in vitro and in vivo.

Dr. Letai earned his PhD in biochemistry and molecular biology in 1993 and his MD in 1995 from the University of Chicago, Chicago, IL, USA. He then commenced a fellowship in Hematology and Oncology at Dana-Farber Cancer Institute, and was introduced to apoptosis and BCL-2 family proteins as a post-doctoral researcher in the laboratory of the late Stanley Korsmeyer.

The talk will be held in the Albert Theatre, RCSI on Thursday 08^th of November 2012 at 4 pm.

Familial Colorectal Cancer Genetic Study Published

davidhughes — Thu, 19 Jul 2012 15:47:56 +0000

Lynch Syndrome (LS) is an inherited predisposition to a range of cancers, notably uterine cancer in females and colorectal cancer (CRC) in both sexes, caused by a deficiency in mismatch repair (MMR). Germline mutations in several MMR genes predispose carriers to a high risk of CRC. Dr David Hughes (CSM / RCSI) collaborates with Mr Michael Farrell, a medical genetics counsellor at the Mater Private Hospital in Dublin, on studies of familial CRC such as LS and they have a new study recently accepted in the journal Familial Cancer that details the likely deleterious effect of a variant in one of these MMR genes*. Genetic counselling of at-risk individuals is optimally based on identification of the underlying deleterious germline mutation in an appropriate family member who has developed cancer. Approximately 25% of mismatch repair (MMR) variants are exonic nucleotide substitutions. Some result in the substitution of one amino acid for another in the protein sequence, so-called missense variants, while others are silent. The interpretation of the effect of missense and silent variants as deleterious or neutral is challenging. Pre-symptomatic testing for clinical use is not recommended for relatives of individuals with variants classified as ‘of uncertain significance’. These relatives, including non-carriers, are considered at high-risk as long as the contribution of the variant to disease causation cannot be determined. This results in continuing anxiety, and the application of potentially unnecessary screening and prophylactic interventions. This study details a large Irish Lynch syndrome kindred that carries the c.544A>G (p.Arg182Gly) alteration of uncertain significance in the MLH1 MMR gene. A systems approach is used to help define the likely significance of this variant by extensive testing of relevant family members in one kindred, immunohistochemical and molecular analysis of the effect of the variant change, a review of cancer incidence within three other LS kindreds carrying the same variant, and the use of in-silico prediction tools of likely harmfulness of a genetic change. The study results indicate that the hMLH1 p.Arg182Gly (c.544A>G) change causes LS and strongly supports reclassification of the variant as pathogenic.

*Clinical correlation and molecular evaluation confirm that the MLH1 p.Arg182Gly (c.544A/G) mutation is pathogenic and causes Lynch syndrome. Farrell MP, Hughes DJ, Berry IR, Gallagher DJ, Glogowski EA, Payne SJ, Kennedy MJ, Clarke RM, White SA, Muldoon CB, Macdonald F, Rehal P, Crompton D, Roring S, Duke ST, McDevitt T, Barton DE, Hodgson SV, Green AJ, Daly PA. Familial Cancer. 2012 Jul 7. [Epub ahead of print] PMID: 22773173

Activation of apoptosis executor BAX is mediated by intra-molecule charge transfer

heinhuber — Mon, 18 Jun 2012 07:22:19 +0000

Results of a collaboration between the Centre for Systems Medicine (CSM) and the Central European Institute of Technology (CEITEC), Masaryk University, Brno have been recently published in the highly respected theoretical journal PLOS Computational Biology (Ionescu et al., Plos CB 2012).

The collaboration led by Prof Jaroslav Koca (CEITEC) and Dr. Heinrich Huber (CSM) investigated structural data of BAX activation by a functional peptide of its natural activator protein (Bim) that were provided by the Walensky Group (Gavathiotis, Mol. Cell 2010). Using methods from quantum chemistry, researchers from CEITEC and CSM provided insigths into how activation information can be processed through the entire molecule, given that the activation site and the site of biological effectivity are at the opposite side of the Bax molecule and separated by a distance of more than 25 A°.

Results of the study are putting forward the notion of intra-molecule signal transduction that may process through changes in partial charges of amino-acid residues. In addition, the study identified novel potential targets for therapeutic drugs that may restore or attenuate apoptosis.

Ref: Ionescu CM, Svobodova-Varekova R, Prehn JHM, Huber HJ, Koca J, Plos Comp. Biol. 2012

http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002565

Seminar: Clinical & Molecular Oncology

Jasmin Schmid — Tue, 05 Jun 2012 10:50:51 +0000

Seminar by invited speaker:

Professor Dr Peter Daniel

Charité Campus Virchow-Klinikum, Humboldt University
& Max-Delbrück-Center for Molecular Medicine, Berlin, Germany

Unexpected findings in the regulation of the Bak pathway in apoptosis

The Centre for Systems Medicine is pleased to announce another speaker of our seminar series. Professor Dr Peter Daniel is Group Leader for Clinical and Molecular Oncology at the Max Delbrück Center for Molecular Medicine, Chairman of the Section Molecular Oncology and Tumor Genetics at Charité Campus Virchow Klinikum and Vice Chairman of the Department of Hematology and Oncology at the University Medical School Charité, Berlin, Germany. Professor Dr Peter Daniel earned his MD and PhD in Internal Medicine in 1987 from the University of Tübingen, Germany. During his postdoctoral training at the German Cancer Research Center, Heidelberg, he investigated the role of the CD95 (APO-1/Fas) death receptor in the regulation of T and B-lymphocyte apoptosis and immune tolerance.
His research is aimed at defining genetic defects in cancer that result in aggressive disease, poor prognosis, and resistance to clinical cancer therapy.

The talk will be held in RCSI on Thursday 07^th of June 2012.

Major international study to improve treatment for colorectal cancer patients

Jasmin Schmid — Fri, 25 May 2012 12:26:51 +0000

The Centre for Systems Medicine at the Royal College of Surgeons in Ireland (RCSI) is leading an international team of scientists on a major research study which aims to predict colorectal cancer patients’ response to the angiogenesis inhibitor class of anti-cancer drug which prevents growth of tumour blood vessels. The study will facilitate a more focused therapeutic approach thus limiting side-effects in patients.

The researchers have secured approximately 6 million EUR in competitive non-exchequer funding for the “AngioPredict” project which is supported by the European Commission’s Seventh Framework ‘Health’ Programme (FP7).

The project will focus on patients with metastatic colorectal cancer. At present, an important treatment for these patients is the ‘angiogenesis inhibitor’ drug Avastin (bevacizumab), which inhibits tumour blood vessel formation and thus prevents tumour growth.

This research project will investigate ways to predict how a patient will respond to Avastin, by identifying biomarkers which are found in the patient’s tumour tissue or blood and developing tests to identify these biomarkers. The ability to predict how a patient will respond to this drug would prevent unnecessary treatment, save critical time in patient care and improve quality of life.

The project is led by Dr Annette Byrne, Department of Physiology and Medical Physics & Centre for Systems Medicine, RCSI. “The ability to predict response will mean that more focused and personalised therapies can be delivered to cancer patients. Non-responding patients will be thus spared the side-effects of therapy and are more likely to receive optimal treatment with a minimum of delay,” Dr Byrne commented.

In the developed world, colorectal cancer is the third most commonly diagnosed cancer in males and the second in females [1]. 50% of colorectal cancer patients develop metastatic cancer for which Avastin is a key component of therapy [2].

AngioPredict is combining cutting-edge molecular biology, multi-centre clinical trials and optimised in-vitro diagnostic discovery approaches to establish new tests that will enable prediction of patient response to Avastin. The ‘AC-Angiopredict’ clinical trial will recruit 225 patients over two years from multiple centres across the island of Ireland and from Germany.

Other RCSI investigators working on the project are Prof Jochen Prehn, Prof Bryan Hennessy and Dr Heinrich Huber in collaboration with academic partners at University College Dublin, The Irish Co-operative Oncology Research Group, Vesalius Research Centre Leuven, University of Heidelberg, Vrei University Medical Centre Amsterdam and Industry partners at Oncomark Ltd (Ireland), Epigenomics (Germany), Somantix BV (The Netherlands) and Pintail Ltd (Ireland).

References

Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90. PMID: 21296855.
Strickler JH, Hurwitz HI. Bevacizumab-based therapies in the first-line treatment of metastatic colorectal cancer. Oncologist. 2012;17(4):513-24. PMID: 22477726.

Reviews on multi-protein interplay and drug synergies during apoptotic cell death published

mrehm — Fri, 13 Apr 2012 09:40:57 +0000

The Centre of Systems Medicine has published two review articles which describe key molecular processes and signalling network topologies coordinating apoptosis signal transduction. Christian T Hellwig and Markus Rehm published a review on synergistic TRAIL-based multidrug treatments in the AACR journal Molecular Cancer Therapeutics. TRAIL and agonistic TRAIL receptor antibodies are the only therapeutically relevant anti-cancer death ligands. Synergies have been reported in various scenarios of TRAIL-based multidrug treatments, and these can be used to potentiate the efficacy of therapies targeting TRAIL death receptors. The review structures the current knowledge on the diverse molecular mechanisms that are thought to give rise to these synergies and describes how different signaling features evoking synergies can be associated with distinct classes of drugs used in TRAIL-based combination treatments. In a second review article, Maximilian L. Würstle, Maike A. Laussmann, and Markus Rehm describe the latest developments in the understanding of caspase-9 activation. Caspase-9 is an essentially required cell death protease mediating apoptosis execution through the mitochondrial pathway. The review discusses recent structural and kinetic studies on caspase-9 signalling, and describes an emerging model for the regulation of caspase-9 activation and activity that arise from the complexity of multi-protein interactions at the apoptosome. This review is available ahead of print through the journal Experimental Cell Research, and will be part of a special edition on cell death signaling to be published later this year. Both reviews can be accessed online:

http://mct.aacrjournals.org/cgi/pmidlookup?view=long&pmid=22234808

http://www.sciencedirect.com/science/article/pii/S0014482712000894

Systems Modelling identifies key switches between cell death and survival during neuronal energy crisis

heinhuber — Wed, 04 Apr 2012 06:06:09 +0000

A study by David Davila, Niamh M. C. Connolly, Helena Bonner, Petronela Weisová, Heiko Dussmann, Caoimhín G. Concannon, Heinrich J. Huber and Jochen H. M. Prehn was accepted to the high profile journal Cell Death and Differentiation in March 2012. The study involved collaboration between the Centre for Systems Medicine (computational modelling) and the Centre for the Study of Neurological Disorders (biological experimentation). The authors investigated the molecular signalling pathways mediating the apoptotic response of neurons undergoing excitotoxic stress, a process implicated in stroke and neurodegenerative diseases. Systems analysis identified a key network motif (known as a coherent feed-forward loop) that prevents apoptosis during physiological or short-term stress, but translates pathological long-term stress into robust apoptosis activation. This molecular framework thus provides a mechanism for cell fate decision making.

Double Strike for Theoretical Systems Biology @CSM !

heinhuber — Wed, 18 Jan 2012 15:57:22 +0000

The year 2012 started well for the Centre of Systems Medicine by providing two new studies that extend the Centre of Systems Medicine’s competency in methodological approaches and address, for the first time in the history of the centre and the department, two respected journals in the field of Theoretical and Systems Biology.

A study by Heinrich Huber (corresponding author), Niamh Connolly, Heiko Dussmann and Jochen H. M. Prehn was released online in the journal Molecular BioSystems on January 5^th. The paper provided a novel approach that addresses the gap between mechanistically detailed ODE models (which are often impractical for studying large systems because of their highly detailed nature) and models using top-down control analysis (which allow to identify abstract regulation principles, but are not mechanistically justified and often only practicable for systems close to steady state). The new approach will come handy when larger systems are studied that combine metabolic processes (often quasi-steady state processes) with oncogenic signalling (heavily dynamic).

A second paper by Fernando Lopez-Caamal, Miriam Garcia, Rick Middleton and Heinrich Huber was accepted in the Journal of Theoretical Biology on January 13^th. The paper is a result of a collaboration between the National University of Maynooth and the Centre of Systems Medicine, RCSI, within the mathematical modelling core of the National Biophotonics Platform (NBIP). Using a pure mathematical treatment, the authors investigated how growth signals in skeletal muscle cells are propagating in space and time. Since such partial differential equations are often hard or impossible to solve, the authors came up with two biologically justified approximations that allow mathematically exact solutions. Using Fourier Analysis, they demonstrated that a signal auto-feedback and diffusion act as a low-pass filter to eliminate fluctuations in signal input. The theoretically predicted filter may be a prototypical motif for signal propagation in larger cells.