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Prostate Cancer – New Predictive & Therapeutic Options with TRAIL

(Vienna, 21 September 2010) One of the human body's protective mechanisms initiated by the TRAIL protein is massively altered in prostate cancer cells – yet the same protein seems to improve the survival prospects of patients. These outstanding results of a cooperative venture between the Clinical Program on Urological Tumours at the Medical University of Vienna and Harvard Medical School, USA, have just been published. They show that the TRAIL protein opens up the prospect to a more accurate prediction of the disease’s course, as well as the opportunity to identify a new intervention point for innovative therapies in advanced prostate cancer.

Even for cancer cells, life can be hard: The body fights them using many and varied mechanisms. The TRAIL protein (TNF-Related Apoptosis Inducing Ligand) stimulates a particularly complex mechanism that ends with the self-destruction, or apoptosis, of a tumour cell. Numerous other proteins are also involved in this protective mechanism, and the role of these proteins in prostate cancer has now been closely analysed in a joint project between the Clinical Program on Urological Tumours at the Medical University of Vienna, Harvard Medical School, Boston, and Mount Sinai School of Medicine, New York – with surprising results.

Survival through TRAIL
This comprehensive project involved the examination of protein patterns (that is the frequency of certain proteins) in 200 prostate tissue samples. Prostate carcinoma patterns were compared with those of healthy prostate tissue: the unequivocal nature of the differences found surprised even the director of the Clinical Program on Urological Tumours, Prof. Michael Krainer: "In 99.5 per cent of all cancerous tissue examined, the protein patterns showed reduced activity of the TRAIL reaction pathway." In other words, the anti-tumour protection provided by TRAIL was compromised in these tissues. This alone shows that TRAIL plays an important role in the development of prostate cancer. However, the team found another result to be just as striking: an increased concentration of TRAIL proteins in the immediate vicinity of the tumour increases the recurrence-free survival of patients – an effect that revealed itself to be independent of other prognostic markers. "This may make it possible to predict the future course of the disease using TRAIL measurements", according to Prof. Krainer. "And this result is also an impressive confirmation of the protection that can be provided by the TRAIL protein."

It is that very protection that new TRAIL-based therapeutic interventions seek to exploit. Consequently, tests are currently ongoing on agents that seek to activate the body's TRAIL-dependent protective mechanism. In a well-received publication on ovarian cancer in 2005 Prof. Krainer showed the importance of a detailed understanding of the reaction pathway in order to achieve effective interventions. He identified two strategies used by cancer cells to evade the destructive effect of the TRAIL protein.

In order to gain a better understanding of the complex TRAIL reaction pathway in prostate cancer, the international team analysed the frequency of six TRAIL-relevant proteins in tumours and healthy tissue. TRAIL itself was studied, along with the two receptor proteins DR4 and DR5, which bind TRAIL and induce cell death. Receptors DcR1 and DcR2, which bind TRAIL but do not initiate cell death, were also included. These "decoy receptors", as they are known, effectively intercept TRAIL, protecting tumour cells from its action. This effect is shared by FLIPL, a protein that was also analysed by the team.

Prognosis and treatment
In point of fact, this detailed analysis revealed a differentiated image of the TRAIL reaction pathway. In 99.5 per cent of cancer tissue with reduced reaction pathway activity, the cause of reduced activity was not at all uniform. In some cases, less DR4 and DR5 were detected, and in other cases there was more FLIPL. In other cells, even both effects were found. Further results showed a correlation between the loss of DR4 and DR5 receptors and the Gleason score – a histological classification of the degree of change in prostate tissue. Another finding revealed that tissue samples from men over 60 had significantly fewer DR4 and DR5 receptors.

This collaboration between Austrian and American scientists clearly shows the importance of the TRAIL reaction pathway in prostate cancer – and that it may provide a basis for predicting the course of the disease as well as for designing new therapies.

Original article: Recurrence Free Survival in Prostate Cancer is Related to Increased Stromal TRAIL Expression. M. Anees, P. Horak, A. El-Gazzar, M. Susani, G. Heinze, P. Perco, M. Loda, R. Lis, M. Krainer, and W. K. Oh. CANCER, September 2010