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This professor designs molecules to combat cancer metastasis

In the Innovation Maestros series, we discuss innovations from the Netherlands.

Published on June 6, 2025

Hermen Overkleeft

Our DATA+ expert, Elcke Vels, explores AI, cyber security, and Dutch innovation. Her "What if..." column imagines bold scenarios beyond the norm.

The number of Dutch people diagnosed with cancer currently stands at over 900,000. According to KWF Kankerbestrijding (Dutch Cancer Society), this number will rise to 1.4 million over the next seven years. What makes cancer particularly deadly is metastasis. Hermen Overkleeft, professor of bio-organic synthesis at Leiden University, has designed a molecule that strengthens the tissue structure around a tumor, making it less likely to spread. Together with colleagues, he founded a start-up called AVIGI Therapeutics. “We have patented our knowledge and are currently busy with testing.”

Metastasis makes cancer more difficult to treat and greatly increases the risk of death. When a tumor metastasizes, tumor cells break away and travel through tissues and blood vessels to other parts of the body. They can only do this if they can find their way through the intercellular space in tissues. This space is normally solid, partly thanks to long chains of sugar molecules, such as heparan sulfate.

Tumor cells produce large amounts of an enzyme called heparanase, which breaks down heparan sulfate, making the tissue softer and more permeable. This makes it easier for cancer cells to metastasize. By blocking heparanase, this process can be slowed down. Overkleeft designs molecules that do just that.

Decades of experience lead to innovation

Let's take a moment to go back in time. The professor laid the foundations for his work decades ago. After high school, he quickly decided what he wanted to study — it had to be something scientific. Overkleef chose chemistry and immersed himself in the world of molecules. Thirty years ago, he obtained his PhD from the University of Amsterdam.

Not long after, he left for the prestigious Harvard Medical School, where he worked in a leading research group in the field of immunology, cell biology, and biochemistry. “That's where I began to understand what really happens in a cell at the molecular level.” He has been a professor of bioorganic chemistry in Leiden since 2001.

Catching enzymes with ‘fake molecules’

For years, the professor has focused on designing biologically active molecules. Together with colleagues from Leiden and structural biologists from York, Overkleeft developed a molecule in 2020 that is designed to inhibit metastasis. He explains: “It is a ‘lookalike’ of the natural substrate. Heparanase, the enzyme that plays a role in detaching tumor cells, appears to be able to break down this molecule. But as soon as heparanase bites, it gets stuck and stops working.”

The researchers also attach a so-called ‘molecular light’ to the synthetic molecule, which fluoresces and thus makes the heparanase enzyme visible when it binds to it. “This allows us to see exactly where the enzyme breaks down the sugar chains. That helps us to better understand how heparanase works.”

Potentially fewer side effects

The major advantage of the ‘lookalike’ is that it does not interfere with other processes in the body. Overkleef explains: "Heparan sulfate is a natural sugar chain in our body that has important functions, such as regulating blood clotting. Heparanase breaks down these sugar chains. Because heparan sulfate is so important in the body, you cannot simply mimic it. Traditional substances resemble it and block heparanase, but they also mimic other functions of heparan sulfate, precisely at moments when that is not desirable. That is why we created a small, synthetic molecule that resembles only a small part of heparan sulfate, but is structured slightly differently."

Taking the plunge: founding a startup

Overkleeft and colleagues Vincent Lit and Gijs Ruijgrok decided to take the plunge in 2024. They founded AVIGI Therapeutics. “We have patented our knowledge, which has been licensed to Avigi by Leiden University, and are now conducting various studies.”

In addition to substantive challenges, there is another major obstacle. “The funding gap is perhaps the biggest one at the moment.” The professor is referring to the gap between university research and venture capital, which must be bridged with subsidies and investments.

This is a well-known problem in drug research because medical research is so expensive. “The market is also relatively risk-averse—who is going to put a few million on the table at an early stage when there is a chance that a candidate drug will be rejected because, for example, it has too many side effects?” Overkleeft knows all too well how costly such a research process can be.

Biotech company Azafaros recently completed a successful €132 million financing round to further develop its innovative therapies for rare lysosomal storage disorders. The company is building on the research conducted by Overkleeft himself and his colleagues at Leiden University and the Academic Medical Center in Amsterdam.

AVIGI has already received an initial investment from UNIIQ, an investment fund based in South Holland.

A busy, promising future

Investors aside, Overkleeft himself sees great potential in the small synthetic molecule. "What we know now is that our inhibitor is more selective than other clinically tested heparanase inhibitors. Published mouse models with metastatic cancers also show that our inhibitor blocks tumor growth just as effectively as another, much broader compound that has already been tested in phase 2 clinical trials but had more side effects."

In addition, the researchers know that the molecule works synergistically with existing cancer drugs, such as those used to treat Kahler disease, a form of blood cancer. In mouse models, the combination of the new inhibitor with a proteasome inhibitor — a drug already in clinical use — was found to be more effective than either drug alone.

“So that's promising. What we still need to find out is whether our compound is non-toxic and whether it is stable in the blood. And if not, can we improve that? That's the whole process ahead of us now,” concludes the professor.

This professor designs molecules to combat cancer metastasis