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Summary

Background and Scientific Aim: Malignant tumor diseases are the second most frequent cause of death. Their huge socio-economic impact will further increase given the present demographic situation of an increasingly aging population. Still less than half of the patients can be submitted to a potential curative therapy. Therefore a great need exists for innovative strategies in tumor prevention, diagnosis, and therapy. These goals require a comprehensive, efficiently coordinated, and multidisciplinary translational research concept in oncology. 'Translational Oncology' comprises all efforts to efficiently and rapidly transfer the results from basic tumor research to clinical applications ('bench-to-bedside'). Thus discoveries and novel technologies achieved in biomedical and medical physics research are validated in clinical trials with the aim to rapidly reach the patient or the person at risk of cancer.
 


To meet this challenge a specifically designed new translational oncology concept is proposed for our Cluster that incorporates the existing local cancer research expertise, defines research areas and workflows to promote the most promising research topics, enforces the interaction between basic and clinical oncology, and provides a dedicated resource and technology platform. The concept to link the expertise in basic research with the clinical units (lead entities/clinical paradigms) provides the backbone of translational oncology. To further promote the Cluster project structurally we will install a common Translational Oncology Research Unit (TORU) under one roof within the Heidelberg Technology Park. The building for TORU which will host the new Research Departments and Junior Groups has already been completed, and is provided free of charge to the Translational Oncology Cluster by a commitment of the Cluster partners.

The stategy that is inherent to translational oncology research promotes basic cancer research, especially those that identify molecular and cellular events that drive tumor development, and aims at interrupting or reverting the process at all stages from predisposition via initiation to tumor progression. At the same time, novel medical physics technologies unveil, with high accuracy, the morphological and functional status of the tumor and its micro-environment, and thus provide the basis for individualized intervention. Target identification and detection are the first procedural steps and, at the same time, a core of the translational process. On this basis innovative, evidence-based intervention strategies are designed and evaluated in preclinical settings. With regard to the translational oncology strategy, the Cluster identified five core research areas that are center around the ultimate goals of tumor prevention, early diagnosis, and treatment. The research areas share translational research intent, comparable methodological approaches, and clinical model systems (clinical paradigms/lead entities) including gastrointestinal, gynecological, and, hematological malignancies, as well as brain and lung tumors. This ensures a high level of synergy and cooperation between the different research groups.

Background in Heidelberg: The University of Heidelberg (Medical Faculties of Heidelberg and Mannheim, Bioscience Faculty) and its cooperating extra-university institutions German Cancer Research Center (DKFZ), including the Clinical Cooperation Units, and European Molecular Biology Laboratory (EMBL) already occupy an outstanding position in basic cancer research and clinical oncology. Their scientific achievements in terms of publications and funding place them among the top-ranking oncology research institutions in Europe, according to a recent independent and international review. The Cluster of Excellence 'Translational Oncology' will be embedded within the strategic alliance recently formed by Heidelberg University and the DKFZ in order to focus their common efforts in applied cancer research. As the main result the National Center of Tumor Diseases (NCT), the nationwide first Comprehensive Cancer Center, has been founded to provide lead structures and resources in interdisciplinary oncology. Translational tumor research by the University of Heidelberg and its cooperating partners resulted in several center grant programs coordinated by leading scientists of the Cluster: Tumor Immunology (DFG SFB 405), Apoptosis (Deutsche Krebshilfe), Tumor Angiogenesis (DFG Transregio-SFB 23), National Genome Research Network (NGFN: Cranial Cancer Network and Systems Biology of Embryonal Tumors (Neuroblastoma), SMPs/Core-Facilities for DNA, RNA, Proteomics, Epigenetics, and Bioinformatics), and Hereditary Tumor Diseases (Deutsche Krebshilfe). Additionally, research is funded since many years by one of the largest tumor centers nationwide: the Tumorzentrum (TZ) Heidelberg/Mannheim. The European Leukemia Net coordinates research of 133 clinical research centers in 24 countries and has installed central communication and management structures and also the BMBF-funded competence network 'Acute and Chronic Leukemias' is coordinated at Heidelberg University. Tumor research is also backed by well over 150 individual competitive national or international research grants including more than 60 EU grants. New venture concepts worked out together with large medical technology companies made it possible to establish the Heidelberg Ion Therapy facility (HIT), a 100 M' project that is unique worldwide with its highly sophisticated radiation delivery and monitoring methods. HIT will provide an entirely new platform for biomedical radiation research.

Scientific Program: On the basis of the existing research profile of the Heidelberg scientific community, five major Research Areas were identified that promise an excellent translational perspective: (A) Molecular Tumor Diagnostics and Therapy Monitoring, (B) Preventive Oncology, (C) Tumor Immunity and Tolerance, (D) Imaging and Radiooncology, and (E) Novel Therapeutics. These research areas are supported by a potent Resource and Technology Platform (clinical resources and research & development platforms), which provide ideal collectives, follow-up data for target evaluation, and high-level technology for data gathering and analysis as well as substance optimization.


The Research Areas closely interact and follow the same strategy of translating into application our understanding of tumor development  as a stagewise process which provides specific options for intervention at all stages. Research Area A will cover: (i) predictive signatures, target analysis, and marker definition, including molecular tissue/serum diagnostics, and assay design, (ii) minimal residual disease and tumor dormancy, and (iii) molecular in vivo monitoring of therapy response and resistance. Data bases as well as tissue and serum bank will be instrumental in developing new tools to predict the biological and/or clinical behavior of tumors by means of systems biology, and to establish tailored diagnostic tissue and serum assays needed to accompany novel targeted therapies (in cooperation with Research Area E). Strategies will be developed to detect those tumor cells that currently escape our diagnostic measures (tumor dormancy, minimal residual disease) and in close interaction with Research Area D, target molecules for molecular imaging will be optimized to aid innovative radiodiagnostic and -therapeutic approaches. Research Area B aims at integrating into clinical practice research on preventive measures that is based on the molecular analyses of pathways contributing to human carcinogenesis. It thus relies on the identification of (i) genetic markers that help to identify individuals with an increased inherited risk for cancer, (ii) markers expressed in emerging cancer cells as bases for novel early detection assays, and (iii) appropriate targets for chemical and/or immune prevention. In parallel, Research Area C uses immunological approaches ranging from the analysis of immunological evasion mechanisms and immunodiagnostics to therapeutic strategies such as tumor vaccination and breaking of immunotolerance, the use of anti-tumor antibodies, targeted guiding of T-cell response, and, in particular, the reverting of tumor therapy resistance by modulating apoptosis. Several major goals in the field of tumor immunity, tolerance, and cell death regulation, can be envisaged: (i) a better understanding of tumor-host interactions, (ii) overcoming tumor-induced tolerance, (iii) necessary improvement of immune intervention strategies, (iv) improved understanding of signaling pathways in apoptosis, caspase-independent cell death, and checkpoints that determine apoptosis sensitivity/resistance, (v) strategies to resensitize human tumor cells towards apoptosis, (vi) identification of new prognostic markers based on apoptosis signaling pathways by high throughput screening, and evaluation of new diagnostic methods by detecting apoptosis in therapeutic response monitoring, and (vii) preclinical and clinical evaluation of apoptosis modulators in connection with Research Areas D and E. The aim of Research Area D is to integrate the most advanced imaging modalities in the processes of radiation oncology by hard and software solutions and clinical developments. A close cooperation with Research Area A will facilitate and accelerate the clinical testing of new diagnostic tools in carefully designed clinical trials. The concept is to exploit the information available by 'biological imaging' for treatment planning and follow-up. The molecular mechanisms of ion radiotherapy on tumor cells, and, together with Research Area C, the role of apoptosis will be examined. Moreover, the rationale is to closely cooperate with Research Area E in order to lay the scientific basis for the combination of precision radiotherapy with novel therapeutic approaches, such as anti-angiogenesis. Novel therapeutics against cancer will be developed and studied by Research Area E, using three major strategies: (i) target identification, (ii) molecular intervention, and (iii) in vivo application. Target identification projects will closely interact with Research Areas A and B to guide the search for gene expression patterns that might reveal clues towards the identification of new molecular target structures, such as those involved in signal transduction or DNA damage response (with Research Area D), and in tumor and blood vessel interactions, or of structures that are potentially amenable to immunotherapeutic approaches (with Research Area C). In this regard, it will be indispensable to involve a recently established collaboration between EMBL and DKFZ, where novel approaches for a rationalized substance screening based on targeted drug design will be upgraded by the Translational Oncology Cluster resources.

The interdisciplinary structure that is needed for the Translational Oncology endeavor has benefited enormously from the foundation of the National Center for Tumor Diseases (NCT). It serves as a common entry for all cancer patients and combines excellence in translational preclinical and clinical cancer research with clinical application. The Clinical Resource Platform, consisting of the tissue bank, IT, the study section, and the bioinformatics unit, represents a core element of the Cluster. Translational research will be fostered further by the Research and Development Platform, consisting of facilities for chemical biology screening, animals housing and small animal imaging, advanced microscopy, and genome analysis.
 


The scientific community of the Cluster 'Translational Oncology' already consists of over 100 research groups which cover a broad range of expertise and provide the solid basis of the project. These groups were selected from the Heidelberg research community according to their scientific quality and their contribution to the program objectives. Accordingly, there is potential for further development, and the cluster is conceived as an open and dynamic structure.

A major part of the Cluster's effort is devoted to a novel stringent, efficient, and coherent concept for education and promotion of the best scientists and physician scientists at all stages of their careers. The first column of the concept consists of the education and development program (curricula) which is expected to attract the most talented individuals, to train them, to give them guidance but also freedom to develop and, finally, to offer them attractive positions (including tenure options). The second column is the stipend and funding program, which takes a major share of the cluster funding and provides specific measures to support gifted individuals at all stages of their career by specific instruments and that is subjected to vigorous evaluation.

 


The Cluster will implement 6 new Research Departments and 7 new Junior Research Groups. The department heads will receive a W3 position. To underline the commitment of the University and its cooperation partner DKFZ to promote the Cluster, three of the Research Departments and two of the Junior Research Groups will be covered by budgets of the Cluster partners. The Research Department and Junior Research group leaders will be primarily selected on the basis of outstanding scientific performance. Recruitment to all positions will be performed by an expedited procedure as outlined in the application. It is planned to closely link the new Research Departments and Junior Research Groups with clinical units that are involved in the management of the different clinical lead entities. A decisive measure is the formal affiliation of the new professorships with these units (or with the NCT), which will be decided upon selection of the applicants and based on the congruency with the individual research background. This will strengthen the ties between translational researchers and the 'Clinical Research Partners' (Department Heads and clinicians coordinating trial management), and guarantee sustainability of translational oncology research at Heidelberg University Medical Faculties (tenure track).

One decisive measure to implement the new structural concept for Translational Oncology in the existing environment of cancer research is to install a Translational Oncology Research Unit (TORU) that will host the 6 new Research Departments and the 7 new Junior Research Groups. This Unit will be housed in a new, but already existing building on campus in the Heidelberg Technology Park with equipped laboratory space and administrative facilities, including the Cluster's management offices. TORU is available free of charge to the Translational Oncology Cluster based on the strong commitment of the participating institutions.


Organisation and Management of the Cluster 'Translational Oncology' exhibits a flat hierarchy. It consists of a general assembly that is responsible for the scientific program, a steering committee with a coordinator managing the Cluster and its intramural funding program, with the scientific guidance exerted by the international scientific advisory board, and with the administrative help from the project management office. The Cluster is conceived as an open and dynamic structure, and all interested and qualified scientists working in related research areas are welcome to apply for membership and funding. Membership is decided upon by the general assembly on the basis of scientific quality and contribution to the program objectives. The volume of the Cluster will be upgraded by commitments of the Cluster partners and industry to an annual volume of more than 10 M' not even counting the support needed for the establishment of TORU. More than 50% of the Cluster funding will be spent on education and training programs and career development in the area of translational oncology and a significant budget is devoted to promote gender aspects. A structured concept has been worked out to guarantee long term sustainability of all Cluster programs beyond the applied funding.

Taken together the concept of the Cluster is aimed to establish and further develop an internationally leading center in Translational Oncology and to provide a model for successful translation of biomedical research.