Short ribonucleic acid molecules only 21 nucleotides long are providing new impulses for lung cancer treatment. A team of doctors and biologists from the University of Tübingen have been awarded a prize by the German Society of Thoracic Surgery for their research on siRNA.
The team of researchers from the Department of Thoracic, Cardiac and Vascular Surgery (Medical Director: Prof. Dr. Christian Schlensak) at Tübingen University Hospital were particularly excited to attend the annual meeting of the German Society of Thoracic Surgery (DGT) held this year in Düsseldorf where the society awarded this year's prize for outstanding achievements in the field of basic thoracic surgery research on 24th September. Dr. Tobias Walker, a specialist in cardiac and thoracic surgery, heads up the eight-member team from Tübingen. "We submitted an abstract to the society; the reviewers assessed the abstracts and invited the best 14 teams, including ourselves, to come to Düsseldorf," said Walker. The researchers from Tübingen knew they were among the best, but did not know who the winner was prior to the award ceremony on 24th September.
Walker's team was surprised and pleased when they were declared this year's winners of the German Society of Thoracic Surgery prize. Prof. Dr. Bernward Passlick, President of the DGT, presented the prize which came with a purse of 2000 euros. Although the money will be useful, the award's real importance lies in the fact that it attests the researchers' excellence in this field. Walker and his team have been working on the use of RNA molecules for the treatment of lung cancer (non-small cell bronchial carcinoma to be more precise) for a number of years. The study, which the researchers have already submitted for publication in an expert journal, shows that siRNA is able to efficiently damage and destroy lung cancer cells.
"We have been able to show that siRNA is able to efficiently damage and destroy squamous epithelial carcinomas as well as adeno- and large cell bronchial carcinomas. We've used the same iRNA for all the cancers we have investigated and found that it had different effects on different cancer subtypes. We also found that even different cell lines responded differently to siRNA treatment. The target structures differed in their sensitivity to siRNA," explained Walker. The importance of the researchers' results lies, amongst other things, in the fact that up until now all tumours have been treated with the same chemotherapies. The researchers and doctors from Tübingen believe that RNA-based therapies will enable customised treatment for individual cancer patients. "Optimal treatment outcome depends on the profiling of individual tumours," said Walker.
In practice, the profiling of tumours requires cell cultures to be established with a patient's cancer cells. The cells are removed by minimally invasive surgery (bronchoscopy) and the optimal siRNA dosage is calculated from the results gained in the laboratory. The researchers are concentrating on known siRNA target structures, including three molecular transcription factors: SRF (serum response factor), E2F1 and survivin (tumour survival protein). Blocking these factors inhibits entire reaction cascades that would otherwise lead to the production of tumour-relevant proteins. Successful siRNA treatment leads to apoptosis, i.e. the death of the cancer cells.
So the question remains as to how get the RNA to its target – the bronchial carcinoma in human lungs. The group of researchers has already considered potential solutions to this challenge. “We are thinking about using a life support machine to perfuse the pulmonary lobe with RNA solution. In this way, we can achieve higher siRNA concentrations than with other methods. This also enables us to specifically treat the lungs, without interfering with other parts of the body. We are also planning to use a transfection medium to get siRNA into the cytoplasm of cancer cells,” said Walker, going on to add “transfection is usually done with viral vectors. However, viral vectors can only be used in laboratories with specific safety conditions and there are also concerns relating to the approval of the method. We are hoping to find a way round this and we are planning to use a cationic liposomal carrier molecule.”Besides evaluating the target structures, another particular challenge was developing a suitable transfection medium. “We have been looking for a commercially available medium that would be less aggressive. We did not want a medium that would kill the cells and we have now one that spares healthy cells,” said Walker. The researchers’ results are all based on research involving cell cultures. One of the next steps will be to test the method in animal models and optimise it for future human application. The researchers need to focus on the effect of siRNA in the destruction of tumours, and also on potential adverse affects in order to minimise or prevent them altogether. They also need to concentrate on tailoring the cell culture conditions to the needs of individual patients. At present, it still takes around two weeks for cell culture results to become available. “We are sure that we can cut down the time to result even further,” concluded Walker.
Further information:University Hospital TübingenDepartment of Thoracic, Cardiac and Vascular SurgeryDr. Tobias WalkerHoppe-Seyler-Straße 372076 TübingenTel.: +49 (0)7071/ 29 832 88E-mail: Tobias.Walker(at)med.uni-tuebingen.de