Taking the next step in cancer treatment.
The OutMARCH approach
Many cancers are driven by proteins located at the surface of cancer cells. These proteins help cells grow, communicate, resist treatment, and evade the immune system. Although some of them can be blocked with existing therapies, many remain difficult to target effectively.
OutMARCH explores a different approach: instead of only blocking disease-driving surface proteins, we aim to remove them from the cell surface. By guiding selected proteins into the cell’s own degradation pathway, the project works towards new ways of targeting proteins that have long been considered difficult to drug.
Going beyond blocking strategies
Most current therapeutic strategies for cell surface proteins are designed to inhibit or block their activity. These approaches have led to major advances in cancer treatment, but they also have important limitations. Many require sustained target engagement to remain effective, and blocking a single interaction may not be enough to fully shut down complex signalling networks at the cell surface. Cancer cells can also adapt by activating compensatory pathways or developing resistance.
Targeted protein degradation offers a different way to think about therapy. Instead of only blocking a disease-driving protein, the goal is to remove that protein from the cell. This approach has opened new possibilities for targeting proteins that are difficult to inhibit with conventional drugs, especially proteins that lack a clear binding pocket or enzymatic activity.
Most established degrader technologies act inside the cell and use the proteasome, the cell’s protein disposal system for many intracellular proteins. However, many important therapeutic targets are located at the cell surface or move through membrane trafficking pathways. These proteins are more naturally handled by the cell’s endosomal and lysosomal system.
In addition, many clinically relevant surface proteins are difficult to inhibit directly. Their function may depend not on a single enzymatic activity, but on scaffolding, clustering, co-receptor interactions, or other non-enzymatic roles within larger signalling complexes. For these targets, simply blocking one binding site may be insufficient. This creates a need for therapeutic strategies that go beyond inhibition and instead remove disease-driving proteins from the cell surface.
Rethinking targeting
SureTACs: guiding proteins to removal
OutMARCH focuses on this opportunity. The project aims to develop SureTACs: antibody-based degraders designed to guide selected disease-driving surface proteins into the cell’s lysosomal degradation pathway. In simple terms, SureTACs are designed to bring a target protein together with a membrane-bound E3 ligase, triggering a process that can lead to internalisation and degradation of the target.
By removing surface proteins rather than only blocking them, OutMARCH explores a new strategy for targets that have been difficult to address with existing therapies. This could be especially valuable for proteins whose function depends on complex cell-surface interactions, unusual shapes, or signalling roles that are hard to inhibit directly.
News
30.06.2026
Website live!
12.02.2026
Interview with Madelon Maurice and Maureen Spit by Oncode Institute.
09.02.2026
News item on UMC Utrecht website about our novel precision strategy.