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Czech Scientists are Working to Find the Achilles‘ Heel of Cancer Cells

Date: 19.2.2007 

Czech scientists are participating at unique European project focused on finding new methods of fighting cancer, methods both more effective and friendly to the patients. The Gate2Biotech.com portal was the first to present an interview with Assoc. Prof. Jiří Ehrmann, M.D., Ph.D., the leader of Apotherapy project. The contemporary medicine utilizes often quite aggressive treatments when fighting cancer, like chemotherapy. However, these therapies usually harm both healthy and diseased cells. The inflicted bone marrow damage results in a significant drop in the organism’s immunity and the patients are victims of undesirable complications. Therefore, the scientists are searching for new, more patient-friendly and less burdening treatments targeted exclusively at the diseased cells. One of these procedures is so-called apotherapy, the principle of which is to trigger the tumor cell destruction via means of programmed cell death – the apoptosis. The large international project Apotherapy has its representatives also in the Czech Republic – the scientists from Palacký University in Olomouc. #img_444#.<> The previous research has shown that via activation of certain proteins localized on the surface of tumor cells, it is possible to stimulate an immunity response in such a way that the tumor cell is destroyed without any negative effects on any other healthy cell in the organism. This fact serves as a basal idea for a new method, that – as the Chief Coordinator of the Apotherapy project, Prof. Aristides Eliopoulos of the University of Crete says – will attack the “Achilles’ heel” of cancer. The progress in the current anti-tumor therapy should be provided by the selectivity of the activators that ensures that the normal cells remain resistant against the tumor cell death activation. The research teams will focus on partial areas of the problem – some of them will focus on the isolating the substances capable of activating the desired protein, others will work on the activation process amplification and yet others will search for the best media capable of transporting the substance to the tumor cells. The three-year project Apotherapy was granted a financial support from the Sixth Framework Programme's 'Life sciences, genomics and health' priority. The partners of the Czech scientists can be found in Greece, Great Britain, Italy, Sweden, Finland and Germany. The task of the team of the Laboratory of Molecular Pathology at the Palacký University in Olomouc is to detect, monitor and verify the results of individual experiments. If the initial hypotheses are confirmed, a successful solution of the project’s objectives may lead to a clinical study of lung, ovarial and bladder carcinomas. “Combined with chemotherapy and new anti-tumor drugs, this strategy should achieve a maximum effectiveness of the treatment with minimum side-effects” says one of the Apotherapy Project leaders, Assoc. Prof. Jiří Ehrmann, M.D., Ph.D. of the Laboratory of Molecular Pathology at the Palacký University in Olomouc in the interview for Gate2Biotech.com. --- !!Interview Assoc. Prof. Jiří Ehrmann, M.D., Ph.D. of the Laboratory of Molecular Pathology at FM PU in Olomouc was kind to give an interview to Gate2Biotech. #img_443#.<> **Mr. Associate Professor, why is the project called Apotherapy?** The project is based on current knowledge about signaling pathways that lead to cell death, so-called apoptosis. The objective of the project is, in the widest sense, therapeutic induction of destruction of tumor cells just via means of programmed cell death – therefore, Apotherapy. **What was the basis of the project and how it was born?** The project was born primarily thanks to the scientists’ personal contacts during their study stays and the discussions during specialized conferences. The unifying research topic of all participating laboratories is an effort to improve the so far not quite satisfactory results of current anti-tumor therapy. The basic idea of the research is that on the surface of the various tumor cells, there is present the CD40 receptor, the activation of which (by a proper ligand) induces an immunity response and subsequent destruction of the tumor cell. As the Chief Coordinator of the project, prof. Aristides Eliopoulos of the Molecular and Cellular Biology Laboratory at the University of Crete Medical School, says, it is a direct hit to Achilles’ heel of the tumor cell. There are several partial objectives of the project. One of them is development of appropriate and specific enough ligands for the CD40 receptor, capable of inducing the immunity response. In accordance with the recent finding that the CD40 activation process can be amplified by simultaneous inhibition of the PI3 kinase, a parallel development of synthetic inhibitors of this kinase is going to be started, based primarily on inositolphosphates. These substances are going to be developed in cooperation of scientists of the University of Crete, the University College at London, the Instituto Mario Negri Laboratories at Milano and the Uppsala University. The third and no less important objective of the project is to ensure the transport of the drug to the tumor cell. The most interesting way appears to be a transport of the ligand in the form of liposome-based microparticle, or using recombinant adenoviruses. This research issue is going to be addressed by scientists of the University of Helsinki and a research team from German biotechnology company Novosom AG. For in vitro experiments, cell lines of various tumors (primarily ovarium, lung and bladder) are going to be used. Mice models of these tumors are going to be used as well. **Could you explain the structure, function and activation process of the CD40 protein a bit more closely?** The signalling pathway and the activation effect of the CD40 protein is illustrated by Figure 1. CD40 and its ligand CD40L/CD154 play an important role in the immunity system and homeostasis regulation. CD40 participates significantly in the proliferation and differentiation of B lymphocytes, the cells that play a crucial role in the antibody-mediated immunity response. Even in addition, CD40 participates in the activation of macrophages, cytotoxic T lymphocytes and dendritic cells. It was found that the proper function of CD40 is crucial for keeping anti-tumor and antiviral immunity. However, CD40 can be found not only on the immunity system cells – its expression has been proved also in other types of cells, including the tumor cells. The specificity of CD40 tumor activation is caused by the fact that the normal epithelial cells are resistant to the activity of CD40-ligand. It is apparent that the existence of the CD40-ligand’s selective ability to block the proliferation and survival of tumor cells can be used only for treatment of such tumors, where the presence of functional CD40 protein has been proved. As mentioned before, this is valid primarily for the lung, ovarium and bladder carcinoma. Confirmation of this hypothesis and successful solution of this project may lead to starting a clinical study regarding some of these tumors. **What is the role of the Laboratory of Molecular Pathology in this project?** The desired result of most of the experiments should be a therapeutically-induced destruction of the tumor cells via apoptosis and subsequent diminishment, or eventually even complete disappearance of the tumor. The scientific team of the LMP has a wide apoptosis-detection experience based on various methodical approaches ( Tunnel method, immunohistochemistry, caspase fragmentation method, DNA-ladder creation detection, etc. Moreover, we are able to determine simultaneously (from an histologic image) whether the experiment achieved a specific hit of the tumor cells or an undesirable global destruction of all cells including the non-tumor ones. Therefore, the main task of the LMP is going to be the detection of programmed cell death of tumor cells in the experiments performed at mice models, as well as the verification of the efficiency of the monitored therapeutic approaches. To a certain extent, we are going to be the “check-out control” for all the experiments across the whole project. Eight research workers of the LMP are participating in the grant project – four university students (including two postgraduates) and four laboratory technicians. The administrative part is covered by the Project Service of Palacký University with an excellent performance. Thanks for the interview. Gate2Biotech

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