The OutMARCH project was recently selected for funding via the EIC Pathfinder programme* - one of the most competitive European grants for high-risk, high-gain research. More than 1000 proposals were submitted, of which only 44 received funding. Within the OutMARCH project, Oncode Institute acts as co-ordinating partner - supporting the project strategically and organisationally, and helping shape the collaboration between academic and industrial partners.

Background

The OutMARCH project explores a new approach to cancer treatment based on the targeted degradation of disease-driving proteins at the surface of cancer cells. Many of these proteins cannot be effectively addressed with existing drugs, contributing to therapy resistance and limited treatment options. Rather than blocking such proteins, the OutMARCH project investigates whether selectively removing them could offer a more precise and durable way to intervene.

More specifically, the OutMARCH project focuses on a therapeutically promising, but technically challenging subset of so-called MARCH E3 ligases. These enzymes are present at elevated levels in certain types of cancer and have already been shown to be capable of degrading a wide range of disease-driving proteins. Their potential makes them highly attractive targets, but also difficult to access.

Madelon leads the project from her laboratory at UMC Utrecht, where her research focuses on understanding the molecular mechanisms that drive cancer progression and on identifying new vulnerabilities when established therapeutic strategies fall short.

Maureen contributes a complementary perspective grounded in stem cell biology and early translational development. At Laigo Bio - a spin-off company founded to develop innovative treatments for cancers and immune diseases - she works at the interface of academic discovery and translating these ideas into clinical applications. This reflects Oncode Institute’s mission to connect fundamental science with real-world impact.

From the outset, the OutMARCH project has been designed as an international collaboration, bringing together expertise in cancer biology, antibody engineering, clinical research and AI-based protein design. This interdisciplinary approach is essential for addressing a challenge of this complexity.

Support from the EIC Pathfinder programme has been critical in enabling this work. The grant provides room to pursue a high-risk, early-stage idea that sits between fundamental research and future application, and to build the scientific foundation needed to take the next steps.

What drives you as a cancer researcher?

What appears to be a straightforward question gives both Madelon and Maureen pause. Their motivation feels self-evident to them, yet difficult to summarise.

Madelon: ‘I’m a scientist through and through. What drives me is the environment: a group of passionate people working together, guided by curiosity and intuition. That moment of unexpected discovery. There is a certain freedom in science that allows you to follow an idea and see where it leads - and that excites me.’

Her interest in biology began early, but it was during an internship at the Sanquin institute that something clicked. ‘I loved the exchange of ideas. It felt dynamic and open. People were encouraged to dig deeper, to explore further, and to make complicated problems understandable. That culture and atmosphere stayed with me.’

Maureen nods in recognition. ‘For me, it was curiosity as well - specifically about how cells communicate. Not just how this communication alters their functions, but how these processes work at the molecular level. Proteins are the functional units of the cell. They build structures, transmit signals and act as enzymes. Understanding that machinery in detail was fascinating to me.’ 

She continues: ‘I’m intrigued by the question of whether we can use these molecular systems differently - more precisely, more intelligently - than they evolved to be used. Being able to explore that feels like a privilege.

Fundamental discoveries are pieces of a larger puzzle - and also small puzzles on their own - but making them meaningful for patients, by translating them into something that can genuinely improve cancer treatment, is what really motivates us.’

Madelon adds: ‘For me, it is also about the process. You get an idea, you bat it back and forth to see whether it sticks - and when it does, you dig deeper and try to make it real. That environment, that spark is what drive us.’

From SureTACs technology to the OutMARCH project

The conversation naturally turns to the origins of the OutMARCH project.

Madelon starts: ‘Prior to the OutMARCH project, we developed a tool that can bring two proteins together: a disease-driving surface protein and a natural “recycling” enzyme known as an E3 ligase. This enzyme labels proteins for degradation by the cell. The idea is to selectively guide harmful proteins to the cell’s own disposal system. The team designed a new class of bispecific molecules, known as SureTACs, which connect these two components.These SureTACs form the technological foundation of the work. The OutMARCH project builds on this earlier discovery.

We identified a specific group of E3 ligases that are present at the surface of certain cells, including stem cells. Stem cells act as the body’s primary repair and renewal system. Surface localisation is essential for our approach, because we need to access these enzymes for the SureTACs to work effectively.’

Cells communicate through surface proteins that transmit signals into the cell, regulating processes such as growth and division.

‘In cancer, these signalling pathways are often dysregulated,’ Madelon explains. ‘Proteins can be overproduced or overactive. These become drivers of disease. Our aim is to remove those drivers selectively in cancer cells.’

Existing therapies often work by blocking such proteins, but this can also affect healthy tissue.

‘Our approach is fundamentally different,’ she says. ‘By degrading the target protein, rather than blocking it everywhere, we aim for a more precise effect and potentially fewer side effects.’

Maureen adds: ‘There is also the potential that treatment would be needed less frequently, because you are removing the disease-causing protein rather than continuously suppressing its activity.’

Madelon continues: ‘To turn this into a real-world treatment for patients, we need investors and a business environment. My lab and my team at the UMC Utrecht are incredibly skilled and driven, but we are not natural entrepreneurs, and we do not have the expertise needed to bring a medicine to market. That’s why we started working with an investor, and together we set up a spin-off company called Laigo Bio - fostered by Oncode Institute - to further develop this research. Maureen has been involved from a very early stage, and several members of the current Laigo Bio team previously worked at UMC Utrecht.’

Maureen elaborates: ‘Close collaboration is essential, because academic research has the freedom to explore and a company has to work within defined frameworks. Together, that allows discoveries to be translated into something that could eventually be tested and developed further.’

Eureka! The OutMARCH project.

Madelon explains how the project began.

‘When the concept emerged, I discussed it with Oncode Institute’s business development team to examine its potential for valorisation. That step is crucial - not only scientifically, but also to protect the intellectual property.

My lab - in collaboration with the Laigo team - discovered a subset of these E3 ligases with strong therapeutic potential - known as MARCH ligases. These enzymes show great capability to remove target proteins and, moreover, display increased levels in cancer tissues. This makes them attractive candidates for directing our therapeutic strategy to the diseased area while sparing healthy tissues.

A huge challenge is that these MARCH E3 ligases only expose very small parts of their structure at the outside of the cell. This makes it extremely difficult to develop molecules that can bind to them. Developing such binders that can connect with these tiny regions is essential for SureTACs to function, and it is the central objective of the OutMARCH project.

By focusing on this particular sub-family in the lab, we aim to study how these ligases function in detail. It gives us the opportunity to explore how we can create protein connectors that bind to these very small protein surfaces of the E3 ligases. This is where our work becomes truly distinctive.’

She continues: ‘And that is exactly where the EIC Pathfinder funding comes in. To take these next steps in development and implementation, we need multiple disciplines to come together. Through Pathfinder, we can collaborate with partners across Europe, including Professor Florian Schmidt at the University of Bonn, Danny Sahtoe at the Hubrecht Institute, and hemato-oncologist and researcher Thorsten Zenz at the University Hospital Zurich.

Danny is an expert in protein structure and mechanism, and a pioneer in AI-based protein design. That means he can design proteins that do not exist in nature and model a vast range of possible interactions. We aim to use his expertise in generating the most effective SureTACs by designing protein connectors to this difficult class of E3 enzymes.

In addition, the project involves the laboratory of Thorsten Zenz: together, we aim to develop new SureTAC-based strategies for hard-to-treat B-cell leukaemias - helping to connect the molecular work to clinically relevant disease settings.’

She adds: ‘This is high-risk research, but the potential gain is also high. The reason we applied for this grant is to create the conditions needed to translate these discoveries into real-world applications.’

Madelon and Maureen are careful and quick to emphasise that the work is still at an early stage.

Looking ahead

Together with their teams and international collaborators, Madelon Maurice and Maureen Spit are contributing to a new direction in targeted cancer research. The OutMARCH project operates at the frontier of what is currently possible, combining fundamental biology, advanced protein design and early translational development.

While the work is still at an early stage, its ambition is clear: to expand the range of cancer-driving proteins that can be addressed therapeutically, and to do so with a precise and patient-focused approach - positively impacting the lives of cancer patients. Supported by the EIC Pathfinder programme and embedded within the wider Oncode Institute ecosystem, the OutMARCH project is designed to bridge the gap between fundamental discovery and clinical application - ‘from bench to bedside’. 

With five core partners across Europe - UMC Utrecht, Laigo Bio, University of Bonn, Hubrecht Institute, University Hospital Zurich and Oncode Institute itself - the project creates the conditions to explore new technical directions. These range from advanced protein engineering to the development of next-generation antibody tools, while keeping the long-term goal in sight: creating new treatment strategies.

Together they are on their way to OutMARCHing cancer.