German researchers aim to completely degrade breast cancer protein

Simply switching off a protein that helps breast cancer cells to grow? That is not enough for researchers at the University of Duisburg-Essen. They want to make it disappear completely. As part of the TaNGo research project, funded by German Cancer Aid to the tune of around 290,000 euros, molecular biologist Prof. Dr. Shirley Knauer and chemist Prof. Dr. Jens Voskuhl are working together to develop a strategy for removing the cancer-related protein Taspase1 from tumor cells.

Taspase1 influences key processes, such as cell division and growth, as well as the response to DNA damage. Increased activity of the protein can promote tumor growth in breast cancer cells. While the associated gene is not classified as an oncogene, i.e. a gene that directly causes cancer, some tumor cells are dependent on Taspase1. This dependence makes the protein a promising target.

Previous approaches have aimed to inhibit the function of Taspase1. With TaNGo, however, Knauer and Voskuhl are taking this a step further by aiming to make the tumor cell break down the protein itself. To achieve this, they are relying on nanobodies, which are small antibody fragments that bind specifically to Taspase1. The team has already developed nanobodies that bind to Taspase1 and inhibit its activity. These are now to be modified so that they simultaneously direct an endogenous enzyme to Taspase1. This enzyme attaches a tag to the protein that triggers its degradation. Such dual-action molecules are known as PROTACs. The tagged Taspase1 protein is then broken down by the cell's degradation system, the proteasome. "With this approach, we are taking a decisive step beyond conventional inhibitors," says Knauer.

The project name, TaNGo, says it all: the team is combining the high specificity of biological nanobodies with the capabilities of synthetic chemistry. Two PhD students specialising in molecular biology and chemistry, respectively, are working closely together on this project. Voskuhl's research group is developing chemically engineered nanobody-PROTACs. A bespoke linker couples the Taspase1-binding nanobody to a ligand that binds to a so-called E3 ligase. This enzyme marks Taspase1 for degradation by the proteasome, the cell's degradation system. The team is testing various linkers and E3 ligases to determine the most effective combination for degrading Taspase1.

"With TaNGo, biology and chemistry truly dance together," says Voskuhl. " We combine the precision of nanobodies with bespoke chemistry, while also seeking to visualize whether and how targeted protein degradation works within the cell."

To this end, the researchers are using fluorescent linkers to connect the individual components and reveal whether the systems they have developed reach their target and whether the desired protein degradation takes place. Meanwhile, Knauer's team is investigating the molecular and cellular effects of the newly developed compounds.