Sometimes it is not enough for researchers to be in the right place at the right time, they also have to prepare the right project proposal. That is the experience of a group of Tübingen cancer researchers when they were considering setting up a new SFB about three years ago. Rather than dealing with the causes of cancer development (oncogenesis), the researchers planned to focus on the question as to why radio- and chemotherapy often had a negative outcome, and this has turned out to be the right decision.

At around the same time, a board of experts at the German Federal Ministry of Education and Research (BMBF) were debating the future direction of medical research in Germany. ”They decided that there was an urgent need to look into tumours’ resistance to therapy,” recalls Professor Dr. Sebastian Wesselborg from the Department of Internal Medicine I at the University Hospital of Tübingen (UKT). ”We did not know this when we submitted our application in 2006, but the reviewers reacted very positively to our proposal,” said the biologist who is also the spokesman for the new SFB.

The fact that the Tübingen researchers succeeded with their proposal was not only based on the excellent idea, but also on the number of people involved. “In Germany, there are currently only a few universities with such a high number of excellent research groups dealing with cancer research, and we are one of them,” said Wesselborg, adding that Tübingen University also had an excellent network of partners on its doorstep. This is clearly evident in the way the projects are distributed. The SFB integrates the faculties of medicine, biology as well as the chemical-pharmaceutical faculty.

Last but not least, the long-term concept finally convinced the DFG reviewers. “We not only want to examine the basic mechanisms of the tumours’ resistance to radio- and chemotherapy, we also want to develop new strategies for overcoming the tumours’ resistance to therapy,” said Wesselborg whose major aim is to turn their research results into new therapies.

Wesselborg explains that resistance to therapy has become of increasing importance over the last few years: “The cancer cells become resistant to chemo- and radiotherapy in order to survive, thus destroying entire organisms. That is why patients who die from cancer are actually victims of a tumour that is resistant to therapy.” And such tumours, for example breast or brain tumours, are nowadays still associated with a high mortality rate. And this is another reason why the Tübingen researchers are concentrating on such tumours.

There are different ways in which tumour cells become resistant to therapy. Six basic mechanisms have so far been identified and will now be examined in detail as part of the new SFB. Several projects are looking into the molecular mechanisms of programmed cell death (apoptosis). The activation of this cellular suicide programme represents a central action mechanism in radio- and chemotherapy. However, tumour cells are able to inactivate this cell-death programme and save their lives. “We have now identified a new apoptosis signalling pathway and found that the inhibition of several kinases in this signalling pathway also leads to the elimination of resistant tumour cells. If we succeed in finding substances that specifically attack these kinases, this will give us access to a new generation of highly active chemotherapeutics,” said Wesselborg describing the research activities of his own group of researchers.

Other projects concentrate on the function and properties of tumour stem cells. This cell population, which was only discovered five years ago, is different from other malignant cells because they have a much lower proliferation. “Since tumour stem cells only divide very slowly, they are insensitive to traditional radiotherapy, which affects the division rate of cells,” said Wesselborg. The surviving tumour stem cells are then able to generate new therapy-resistant tumour cells, which will then lead to the recurrence of the tumour. “This selective destruction of tumour stem cells might therefore be a new, promising anti-cancer strategy,” assumes Wesselborg.

Further SFB projects deal with protective autophagy, a metabolic programme that saves tumour cells from apoptosis when experiencing a lack of nutrients, epigenetic alterations and special survival signalling pathways in the tumours. “The reviewers were very enthusiastic about the fact that our research activities considered all aspects of resistance development,” said Wesselborg who is convinced that the broad interdisciplinary research will be successful.

It will not be possible to find a single drug to treat a therapy-resistant tumour in future. “The treatment will most likely be similar to the treatment of HIV infections. We assume that only the combination of different substances and therapies will lead to a positive outcome,” said Wesselborg. His model of success looks like this: “We need to attack the different Achilles’ heels of a tumour, i.e. cell division, apoptosis mechanisms and the population of tumour stem cells. Then there might be a realistic chance in about ten to 20 years’ time of being able to treat a lot more cancers than previously possible.”

sb - 9th July 2008 © BIOPRO Baden-Württemberg GmbH

Further information:
University Hospital Tübingen
Medical Hospital, Department of Internal Medicine I
Section of Molecular Hepatology and Gastroenterology
Prof. Dr. rer. nat. Sebastian Wesselborg
Otfried-Müller-Str. 10
72076 Tübingen
Tel.: +49 (0)7071 29-84113
Fax: +49 (0)7071 29-5865
E-mail: sebastian.wesselborg@uni-tuebingen.de