Stopping tumor growth
The abbreviation EpCAM stands for “Epithelial Cell Adhesion Molecule”, a membrane protein that is present on the surface of many types of tumor cells, is produced in large amounts by tumor-initiating cells, and promotes tumor growth. EpCAM therefore presents an attractive point of attack for the development of novel approaches to cancer therapy. Its potential will be explored in a new study to be led by Professor Olivier Gires of the Munich University Hospital and Dr. Dierk Niessing, who is at the Helmholtz Center Munich.
“We are working on the identification and characterization of new and more specific inhibitors for the regulation of EpCAM function,” Gires explains. To find such agents, he and his team will first screen collections of small-molecule compounds of natural and synthetic origin using selected cellular test systems. The researchers hope that the work will help to pinpoint lead compounds for effective small-molecule inhibitors of EpCAM.
Finding and refining the best candidates
In parallel, structural biologist Niessing will determine the three-dimensional conformation of the binding sites recognized by proteins known to interact with EpCAM in the cell. In cooperation with bioinformatics specialists, computer simulations will be utilized to determine how well each potential small-molecule inhibitor fits a given binding site, and guide efforts to optimize binding affinity for EpCAM by structural modification. The most promising candidates will then be tested for their biological efficacy in the laboratory.
Gires und Niessing will focus particularly on the binding site for one of the central interacting partners of EpCAM, which is required for its activation. Hence, the primary aim of the project is to discover a molecule whose shape is complementary to that of the binding site for this activator. By blocking the site, or actively displacing the endogenous factor, such a molecule could ensure that EpCAM remains permanently inactive.
In their quest for novel inhibitors, the researchers will not lose sight of agents that recognize EpCAM and are already available. Indeed, they hope to come up with a “two-hit” therapy, in which conventional antibodies directed against EpCAM are combined with a chemical inhibitor that specifically blocks the activation of EpCAM. By targeting the molecule from different directions at once, so to speak, they expect to achieve a more potent and prolonged effect.
The project is supported by a grant of some 200,000 euros awarded by the Wilhelm Sander Foundation. The Foundation was set up to promote medical research, especially in the field of cancer therapy. Since its establishment, the Foundation has provided a total of more than 190 million euros in grant support to researchers in Germany and Switzerland. The Foundation’s capital stock derives from assets bequeathed by the industrialist Wilhelm Sander, who died in 1973.
For further information on the Foundation, see: www.wilhelm-sander-stiftung.de