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Max-Planck-Gesellschaft
Max-Planck-Institut für Experimentelle Medizin
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Since the discovery of ion channels, and even before the molecular mechanisms linking certain channels to diseases were known, it was observed that many (over 30%) of the drugs used in modern medicine have ion channels as targets. In some cases, there is a clear causal link between ion channel malfunction and disease, and in many others the activity of the channel can be modified in a way that interferes with the development of the disease in a more indirect way (take for example the effects of sulphonylureas in diabetes). Some advantages of ion channels as therapeutic targets are their accessibility (most ion channels are exposed to the outside of the cells), and the possibility of measuring their function with very high sensitivity (at the level of single molecules) and in real time. Researchers have therefore increasingly pursued the identification of ion channels that are implicated in disease. Cancer is not an exception, and a growing number of ion channels are being investigated as potential targets to influence the disease.

 

The work of the Department Molecular Biology of Neuronal Signals is directed to the understanding of the molecular actions of voltage-gated potassium channels in cancer cells. As a logical complement, novel diagnostic and therapeutic procedures are being investigated using these molecules as targets. In particular, most efforts are concentrated on a voltage-gated potassium channel termed Eag1, identified in the laboratory as the first case of a molecule in this class that is directly implicated in tumor biology. A pivotal feature of Eag1 is its restricted expression in the healthy central nervous system. But Eag1 appears in cancer patients in over 75% of solid tumors and therefore makes them distinguishable from the surrounding healthy tissues. This means that the normal protein is located behind the blood-brain barrier and therefore inaccessible for many drugs. In other words, a therapeutic agent directed against Eag1 that is excluded by the blood-brain barrier will attack only tumor cells.

 

The identification of the molecule allowed to design highly specific antibodies against the channel that were subsequently modified to generate diagnostic tools. Pathologists at the University Hospital Göttingen and the Brazilian INCA applied these tools to over 800 tumors. Three out of four tumors expressed significant amounts of the channel molecule. Antibodies suitable for imaging purposes in live animals were also generated. With them, it is possible to unequivocally identify tumors in laboratory mice.

 

Pharmacological and genetic manipulations directed against Eag1 reduce tumor cell proliferation in vitro and tumor progression in animal models. More specifically, reduction in tumor progression using Eag1 blockers in a breast cancer model was achieved with comparable efficacy as antitumor drugs currently used in clinics, but with significantly less toxicity. To overcome the lack of highly specific blockers, antibodies were produced that are able to bind Eag1 and inhibit its electrophysiological function in cells in culture. Currently validating the use of the antibody for therapeutic purposes in animal models is pursued.

 

Even if these results finally do not prove helpful immediately for cancer patients, the search for in-depth knowledge on the cellular processes behind the effects of Eag1 expression in tumor cells will still be an advance on the development of tumor therapies. The last years have witnessed a profound change in the strategies searching for anticancer therapies. Deeper knowledge of the molecular mechanisms of the disease has led to a number of targeted therapies, some of them remarkably effective. Knowing the exact pathways implicated in Eag1 actions should allow a multitarget approach to the treatment of tumors expressing Eag1, lead to synergistic actions of different agents and thereby to better efficacy with lower side effects.





Fig. 1: Tissue section of a human biopsy of a muscle affected with rhabdomyosarcoma. The dark staining is due to binding of a specific antibody against Eag1, which is tagged with alkaline phosphatase and induces the colour reaction. The labelled cells are limited to those affected by the tumour, whereas the adjacent healthy tissue is not labelled. The Eag1 antibody clearly marks the tumour.





Fig. 2: Images of a mouse carrying a human tumor on the right flank before (left) and 48 h after (right) injection of an anti-Eag1 antibody labeled with a fluorescent dye. The scale in the middle shows the color coding for the fluorescence intensity (red means high intensity). The dye signal clearly marks the tumor.


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Dr. Luis Pardo
Phone: +49 (551) 3899 - 643 



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