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Artificial evil put to therapeutic use

Simulated viral infection could help combating skin cancer

Munich, 07/21/2009

Dark skin cancer, malignant melanoma, is one of the worst types of tumor there is. It rapidly forms metastases that can spread to the lungs or live. Once metastasized therapeutic intervention is of limited success. A research group led by LMU Munich pharmaceutical scientist PD Dr. Robert Besch has now developed a method that drives cancer cells into apoptosis – programmed cell death. This is done by inserting artificial viral RNA that drives cancer cells to destroy themselves. As an additional arm, the treatment activates the immune system, which then detects and fights the cancer cells. Healthy cells are kept out of the battle in this approach because a protective mechanism will not allow them to suicide. In laboratory tests, the researchers have shown that the new method successfully reduces skin cancer metastases in the lungs – and could potentially be used as a basis for novel cancer therapies. (Journal of Clinical Investigation, 20 July 2009).

Skin cancer is on the advance all over the world: The most significant trigger is intense, sustained exposure to sunlight or artificial UV light in solariums. There are also genetic factors involved. Damaging of cells, for example by UV light, can lead to malignant cells. Normally the body has its own protective mechanisms that recognize damaged cells and repair them – or eliminate them. If these potentially malignant cells are not recognized and completely removed at an early stage, the danger of metastasis is very high. Also the tumors are largely resistant to radiotherapy or chemotherapy.

“When for example DNA is irreparably damaged, the cell in question is normally driven to programmed suicide,” says Robert Besch, head of the study and of the workgroup “Cell Adhesion” at the Department of Dermatology and Allergology of Ludwig-Maximilians-Universität (LMU) in Munich. “Apoptosis thus protects the body against potentially dangerous cells.” Cancer can develop when this cellular suicide program is deactivated.

The body is also able to recognize viruses, which insert only their naked genetic information into body cells, by specific traits. Once recognized, infected cells are also driven to apoptosis. “We wanted to put the mechanisms of virus defense to use on combating tumors,” reports Professor Gunther Hartmann of the University of Bonn. “To do this, we used artificially produced viral RNA as a drug.” This so-called triphosphate RNA possesses the characteristic chemical traits by which the body normally identifies and combats a viral infection. Unlike intact viruses, however, synthetic RNA has the advantage of being unable to propagate or spread throughout the body.

Yet it is still effective: it drives melanoma cells to programmed suicide – thus triggering a mass die-off of the cancer cells. Healthy cells remain unharmed. “We observed that, as a response to the artificial viral RNA, all cells produced elevated amounts of proteins that normally induce apoptosis,” Besch reports. “What is exciting is that a protein called Bcl-xL prevented this programmed cell death in healthy cells – and only in healthy cells.” In this study, which was funded by the Deutsche Krebshilfe (German Cancer Aid) and by the Deutsche Forschungsgemeinschaft DFG (German Research Foundation), the tumors shrank significantly in size and mass in animal tests.

This method of therapy is given an extra push from another important agent that the viral RNA calls into action: “Tumors are often effectively invisible in the body and are not attacked by the immune system,” says PD Dr. Simon Rothenfusser of the Medical Clinic Innenstadt of LMU Munich. “Our tests showed that treatment with viral RNA allowed the immune system to recognize melanoma cells. The body’s natural defenses could then identify the remaining tumor cells as foreign bodies and attack them," continues Dr. Hendrik Poeck, another significant contributor to the study.

“Thanks to its combined effect, this is a very promising approach for a new treatment of malignant melanoma and possibly even for other cancers,” Besch says. “There is still extensive research to be done, however, before the new method can be tested in patients or actually used in cancer therapy.” The study was performed as a close cooperation between the Department of Dermatology and Allergology and the Department of Clinical Pharmacology of LMU Munich and the Institute of Clinical Chemistry and Pharmacology of the University Clinic of Bonn, and was supported, among others, in the scope of DFG Graduate College 1202 “Oligonucleotides in Cell Biology and Therapy". (CA/suwe)

 

Publication:
“Proapoptotic signaling induced by RIG-I and MDA-5 results in type I interferon–independent apoptosis in human melanoma cells”;
Robert Besch, Hendrik Poeck, Tobias Hohenauer, Daniela Senft, Georg Häcker, Carola Berking, Veit Hornung, Stefan Endres, Thomas Ruzicka, Simon Rothenfusser, Gunther Hartmann;
The Journal of Clinical Investigation, 20. July 2009 (online);

Contact:
PD Dr. Robert Besch
Department of Dermatology and Allergology
Frauenlobstr. 9-11
80337 Munich
Phone: +49 (0) 89 / 5160 - 6365
E-Mail: robert.besch@med.uni-muenchen.de
Website of the Clinic for Dermatology: http://derma.klinikum.uni-muenchen.de

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