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Fighting gliobastoma brain tumours with two grants

Few researchers see potential in research on glioblastoma, an incurable brain tumour. Alexander Kros brought together colleagues who are up to the challenge. European research funder ERC recently made 10.6 million euros available, a year earlier NWO provided 3 million euros. ‘In six years, we certainly won’t have developed a therapy, but we will have learned a lot.’

Research millions based on a gut feeling. Sounds odd perhaps, but this is chemical intuition of Professor of Supramolecular Chemistry Alexander Kros, who bases that feeling on extensive knowledge and experience. In October, he was awarded a major European ERC Synergy grant with UvA colleague Joost Reek and NKI cancer biologist Leila Akkari. Kros compares this ERC Synergy Grant to an investment: ‘It is high risk, high gain research. That characterises this ERC grant, just like the NWO-XL grant Leila and I also received last year, with among others Leiden cell biologist Ewa Snaar.’

Glioblastoma research: hardly any progress for thirty years

For thirty years, there has been hardly any progress in finding successful therapies to treat glioblastoma. The disease affects some 600 people in the Netherlands every year and is incurable. Kros explains why this disease is unattractive to most pharmaceutical companies: ‘It is a very difficult disease to treat. Currently, patients are treated by surgery and radiation followed by chemotherapy. But surgery is difficult because the tumour has no sharp borders.’ In addition, most drugs cannot reach the tumour because the blood-brain barrier largely blocks them. ‘With chemotherapy, you then have to administer so much that the side effects make the treatment unbearable.’ Besides, the tumour very quickly develops resistance to the current generation of drugs. ‘Even immunotherapy, which works very well in many other tumours, does not work in glioblastoma.’

Chemotherapy only active near the tumour

In the NWO-XL project, the focus is on understanding tumour biology; in the ERC Synergy project, the scientists involved are looking for ways to get an inherently harmless, inactive ‘pro-medicine’ to the tumour. When it has arrived, the pro-medicine must be converted into an active drug. For that, supramolecular catalysts can provide: special molecules that are also brought to the tumour. This approach saves the rest of the body from the side-effects of such chemotherapy, which often lead to the abortion of treatment.

Strategy to cross the blood-brain barrier

Kros is working on two aspects within these projects. First, he ensures that one drug very selectively blocks the production of lipid around the tumour and another drug exclusively attacks the covering layer of endothelial cells around the tumour. He is also working on a strategy that allows the drugs to cross the blood-brain barrier. Blood flowing from the heart to the brain can only carry oxygen and other small molecules. Most drugs do not reach the brain. Packaged in newly developed lipid nanoparticles – very small fat molecules – they may succeed. 

Across the border of their field

According to Kros, it is extraordinary that all those involved go beyond the boundaries of their fields. ‘In the ERC project Cat4CanCenter, a total of 21 PhD students and postdocs are going to work on this, seven per institute. We make sure they don’t stay safely in their tumour biology, chemistry or supramolecular corner, but learn to speak all three languages. This is how we train a new generation of interdisciplinary researchers.’

Fundamental and practical

Another striking aspect is that the research is very fundamental, that is, focused on basic mechanisms and fundamentals, but at the same time aimed at a concrete disease. ‘Leila has direct contact with patients and treating doctors at the NKI and the Antoni van Leeuwenhoek Hospital. We feel the need. We look at fundamental principles, but take into account potentially practical applications. Such as that it is easier and cheaper to be able to administer a drug through an infusion than through surgery.’ Still, Kros does state: ‘In six years, we certainly won’t have developed a therapy, but we will have learned a lot and created a new field of research.’

Research as a calling

Kros brought the ERC project partners together. ‘Leila, Joost and I have the same research mentality. If you want to achieve something in research, it’s “all or nothing”. It is not a nine-to-five job but rather a calling.’ Kros is enormously grateful to the colleagues who helped in the preliminary process. ‘To get this grant, we held tough test interviews with colleagues in preparation. We could only answer the critical questions because of the excellent preparatory work done by the current PhD candidates and postdocs in our research groups.’

In particular, Kros wants to make a stand for foreign PhDs. ‘A kind of internationalisation phobia seems to have emerged,’ he says, referring to reports of knowledge theft or, on the contrary, exploitation. ‘Certain high-tech companies do indeed have knowledge that they need to protect, but at the university we actually want to make the knowledge public and share it with the world. And the PhD candidates in our groups are intrinsically highly motivated. For many of my (international) PhD candidates, it is a way forward. It’s an investment that brings them a lot, but also benefits the Netherlands!’

Text: Rianne Lindhout
Photo: Flickr - Jeff Mackintosh

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