Welcome to this second edition of the ACGT Newsletter!
The recognition that clinico-genomic trials are part of the critical path has turned the spotlight on this aspect of drug development which for ACGT means that a very important opportunity exists to make an impact in an area of significant unmet needs.
Some of these needs especially in the area of trials that target child populations are addressed by the development of a European register of clinical trials in children. As reported in the Clinical Trials News section, the goal of these initiatives is treatment optimization and ultimately better therapies in Paediatrics. Still, this is only one aspect of the broader task of supporting clinico-genomic trials and ACGT is looking to create a host of tools that can be integrated in an easy to use environment. In the Grid News section we report on the latest features of Gridge Resource Management, an open source meta-scheduling system which allows developers to build and deploy resource management systems for large scale distributed computing infrastructures.
There is also some exciting news in terms of ACGT software deliverables. In the products section, the team at Fraunhofer presents the latest on GridR, an ACGT-grid enabled version of the well know statistical analysis package R. In the data protection area, we consider the question of whether patients want feedback of data from clinico-genomic research. The question of individual donor feedback (IDF) is certainly complex and the group at Hannover University will be analysing their findings in this and future editions.
The feature article of this edition discusses many of the challenges and requirements in the emerging field of Molecular Medicine and shows how many of these will eventually be served by the solutions methodologies and data exchange standards adopted by ACGT.
ACGT is certainly progressing and what better proof than a growing "ACGT member family"? EORTC (the European Organization Cancer) is our newest member and will be joining the consortium in order to contribute its experience in clinical trials needs and in the design of effective supporting infrastructures.
We hope that you will find this second issue of the ACGT newsletter interesting and look forward to welcoming you too as an active member of the growing ACGT community!
Latest developments in the world of clinical trials in cancer
It is by now recognized by all that clinical trials play a fundamental role in establishing new treatments for all kinds of diseases. For example, in Cancer, clinico-genomic trials as proposed by ACGT are critical in providing new insights on the molecular biology of the disease, leading to more personalized medicine with higher cure rates and fewer side effects. For child populations clinico-genomic trials help promote evidence based use of drugs, given that a lot of drugs used in children today are off-label.
In recognition of the importance of clinico-genomic trials the European Community has decided to support the development of a European register of clinical trials in children as part of its Fifth Framework Programme, Thematic Programme "Quality of Life" (contract QLG4-CT-2002-01054), in 2002. The project "The European register of clinical trials on medicines for children - Drug Evaluation in Children" (DEC-net), is co-ordinated by the Laboratory of Mother and Child Health of the "Mario Negri" Institute for Pharmacological Research in Milan and currently involves members from four countries: France, Italy, Spain, and the United Kingdom. It is unique in that it is the first population oriented clinical trial register.
The DEC-net register (www.dec-net.org) which was activated on July 1st 2004 is freely available to anyone interested in accessing information on paediatric drug therapy clinical trials. The register was set up by four groups (Italy, UK, France, Spain). A recent publication (Chiara Pandolfini et al.: The DEC-net European register of paediatric drug therapy trials: contents and context. Eur J Clin Pharmacol (2008) 64:611?617) updates the results for the years 2004 to 2006 of the registry.
New features of Gridge Resource Management System for ACGT
An important component of the ACGT Grid infrastructure is the Gridge Resource Management System (GRMS). GRMS is an open source meta-scheduling system, which allows developers to build and deploy resource management systems for large scale distributed computing infrastructures. GRMS is based on dynamic resource selection, mapping, advanced scheduling technologies and feedback control architecture I order to deal with dynamic Grid environments and resource management challenges such as load-balancing among clusters, remote job control or file staging support.
Therefore, the main goal of the GRMS is to manage the whole process of remote job submission to various batch queuing systems, clusters or resources. It has been designed as an independent core component for resource management processes which can take advantage of various low-level Core Services and existing technologies. GRMS can be considered as a robust system which provides abstraction of the complex grid infrastructure as well as a toolbox which helps to adapt to distributing computing environments.
One of the primary goals of ACGT is the support of standards in all possible grid-related areas. A good example of such a standard is JSDL which will be used for describing "jobs" for GRMS.
JSDL (Job Submission Description Language) is an extensible XML specification developed by the Global Grid Forum for the description of the structure of the tasks that can be submitted to local scheduling and queuing systems.
Products and Services
GridR is an analysis tool based on the statistical environment R
(http://www.r-project.org/). GridR supports the use of the collection of methodologies available as R packages, in a grid environment. Within the ACGT project the aim of GridR is to provide a powerful framework for the analysis of clinico-genomic trials involving large amount of data (e.g. multilevel data from microarray-based clinical trials).
The R environment provides a broad range of state-of the-art statistical, graphical techniques and advanced data mining methods including comprehensive packages for linear and non-linear modelling, cluster analysis, prediction, hypothesis tests, resampling, survival analysis and time-series analysis. It is easily extensible and has turned out to be the de facto standard for statistical research and many applied statistics projects, especially in the biomedical field. The associated project BioConductor addresses the needs of the biomedical and biostatisticians community for genomic data-analysis oriented R packages. Numerous methods available as R/BioConductor packages that were considered experimental a few years ago are now accepted as standard in the analysis of high throughput genomic data.
Challenges in post genomic molecular medicine and clinical trials
Medical doctors have long known that people differ in susceptibility to disease and response to medicines. But, with little understanding on what causes these differences and little guidance on how to best account for them, treatments have been optimised for the many, not for the few.
However, this classical approach to medicine has been changing, and the genomic and post-genomic "revolution" is providing scientific bases for individualising treatments. Nowadays, we know that human DNA codes for more than 20,000 genes. Each person's overall "blueprint" is basically similar, made up of about 3 billion "letters" of code, each letter corresponding to a chemical subunit of the DNA molecule. But subtle variation in the DNA gives humans their individual identities.
Beyond physical appearance, genes determine the distinct and complex way our bodies interact and respond to the environment. The chemistry and biology taking place in our bodies at various levels (what we can call the "molecular signatures" of individuals) sometimes predispose people to particular diseases, and it can affect the way a person responds to therapies. These concepts form the basis of a relatively new scientific field called Molecular Medicine (MM). MM's final aim is to be able to "personalise" medical treatments by using genomic (gene), proteomic (proteins) and eventually metabolomic (biochemical reactions) information to understand how a patient would react to a therapy and select the correct therapy for him or her. Already, there are applications of MM. For example, for breast cancers variants of a gene linked to it can be the index of susceptibility to developing or surviving the disease, whereas the production of a particular protein signals that it might be controlled with the drug Herceptin. In this vein, several molecular signatures have been developed to predict prognosis and drug response in the context of breast cancer (reviewed in ).
Two pillars of MM are embedded in the name itself of this research field: medical science and molecular biology. All those interested in MM know its popular and effective motto: "From the bench to the bedside", however only a small fraction of them ask themselves: "How is the knowledge moved from the former to the latter"?. And this is by no means a minor question.
Although there exist some real practical examples where this is really happening , there remain difficulties in bridging the gap between the two. However, we argue here that this process could be immensely helped by a greater understanding and deployment of a third, and equally important, pillar: Computational Biosciences. In this term are included topics such as Medical Computer Science, Bio-informatics, Systems Biology and literature mining that together will contribute to organizing, understanding, standardizing and translating the knowledge accumulated in the laboratories to the clinic.
The case for expanding the ACGT family
Any large undertaking such as ACGT that aims to develop an infrastructure to support a wide range of target users, must constantly seek input from these users to ensure that it addresses true rather than imagined needs and that the solutions it puts together fit in well with current practices and deliver true value.
To date the guiding role of end user has been assumed by 2 partner organizations active in clinical trials and 2 biology research institutes, both groups representing the major target users of ACGT. Acquiring patient data and thoroughly testing standards and IT systems in use however is a demanding task that can only benefit from the involvement of as many end users as possible. With this in mind the European Organization for Research and Treatment of Cancer (EORTC) has been invited and will be actively joining ACGT in the next few months.
Legal and Ethical aspect
Do patients want feedback of data from clinico-genomic research?
ACGT-Poster presentation at the international conference "Genomics & Society"
In clinico-genomic cancer trials tumor tissue is analyzed to identify genetic components which are involved in cancer development, reaction to treatment and prognosis. Though genetic factors may influence these processes, they do not cause them in the narrow sense of the term. Therefore, the clinical relevance of research findings is difficult to evaluate - and so are the ethical and social implications regarding the feedback of such findings to patients.
At least in the European context it is indisputable that everyone has the right to make inquiries about personal data which have been collected about him or her. Due to legal provisions, investigators are obliged to disclose such data on request. This is especially applicable if a research process yields information that helps to avoid sickness or adverse drug reactions. But what is about information on genetic polymorphisms and gene expression whose clinical significance has not been fully established yet? Should such information that has only the potential to be clinically relevant be returned to patients? And if yes, should researchers actively approach patients to return study findings that might be or become relevant for him or her?
UICC World Cancer Congress, August 2008 Geneva
ACGT will be participating at the next UICC World Cancer Congress planned August 27th to 31st in Geneva. ACGT will be present with its own stand during the whole duration of the event.
40th Annual SIOP Meeting
The SIOP (International Society of Paediatric Oncology) Annual Meetings are the most significant scientific and educational events for paediatric oncology worldwide. Physicians of all disciplines co-operating in the research and treatment of childhood cancer, but also scientists, psychologists, nurses, parents and former patients will meet and discuss novel developments at the 40th Annual Meeting in Berlin from the 1st to the 6th of October 2008.
Life in ACGT
The International Symposium on Grid Computing (ISGC) 2008 was held in Taipei, Taiwan from 7 to 11 April 2008. Organized by ASGC since 2002, ISGC is stepping into the 7th year of this grand event. ISGC is one of the most significant annual international events in the Asia Pacific region that brings together scientists and engineers to exchange ideas and to present on challenges, solutions and future development issues in the field of Grid Computing.
ACGT was represented by our partner Poznan Supercomputing Center. Juliusz Pukacki presented the Grid aspects of ACGT in the "Biomedicine and Life Sciences" session. The presentation included a general overview of ACGT goals, and the role of Grid technologies in cancer research.
ACGT Technical meeting, Milan
In February we had a nice and fruitful general consortium meeting in Milan, Italy, organized by our partner European Institute of Oncology (IEO). We thank our hosts IEO, the food (of course!) was excellent and to top it all up, ACGT members were introduced to our new guest star (the ACGT Magnetic piggy)!
EBCC-6, Berlin, April 15-16
In the recent European Breast Cancer Conference (EBCC-6) ACGT organized the workshop "Advancing Clinico Genomic Trials on cancer: open grid services for improving medical knowledge discovery". Attended by over 50 delegates from both industry and academia the workshop presented the rationale of the ACGT initiative together with latest results both on the clinical and technical aspects of the project.
People in ACGT
Christine Desmedt received her bio-engineer degree in Cells and Genes Biotechnology from the Catholic University of Leuven, Belgium, in 2000. Since then she is working at the Jules Bordet Institute, an autonomous comprehensive cancer centre devoted entirely to the fight against cancer. For two years she worked as a clinical monitor for the Breast European Adjuvant Studies Group (Br.E.A.S.T), co-coordinating the monitoring activities of external groups for the conduct of breast cancer trials. In 2002, she joined the Functional Genomics & Translational Research Unit of the Bordet Institute, where she is currently coordinating different research programs. In 2004 she earned a master in bio-medical sciences at the Free University of Brussels and her work is supported by a grant from the "Fonds National de la Recherche Scientifique".
Her current research projects, conducted in collaboration with different international institutions, involve the identification and validation of prognostic and predictive markers in breast cancer, as well as a better characterization of breast cancer development and metastasis.
Dr. Stefan Ruping
Dr. Stefan Ruping is the leader of the Integrated Data Mining group at Fraunhofer IAIS. He studied Computer Science at the University of Dortmund and worked as research assistant at the artificial intelligence chair at the University of Dortmund in the DFG Collaborative Research Center on Complexity Reduction in Multivariate Data (SFB 475), where he also finished his PhD thesis on Learning Interpretable Models in 2006.
His research interests are on the combination of statistical and machine learning algorithms, novel learning tasks, and on the interpretability and adaptability of machine learning models. He co-organized a workshop on Learning with Multiple Views at the International Conference on Machine Learning ICML?05. He served as a member of the program committee of several international conferences, e.g. the European Conference on Machine Learning (ECML) 2005-2008. His project experience includes leading the technical management committee of the EU integrated project ACGT, work package leadership in several other EU projects, and management of a wide range of commercial projects.