Science at the frontier of the unknown

Kasper Rouschop: “All of our research is related to cells experiencing hypoxia (oxygen deficiency), which is characteristic of tumours. Tumour cells are very good at coping well with a lack of oxygen. However, a major disadvantage of cells with hypoxia is that they do not respond well to treatment; we see this with radiotherapy, but also with chemotherapy and immunotherapy. In our research, we investigate at what cells do to compensate for this lack of oxygen. If we can interfere with these mechanisms, we may be able to cause these cells to die, leaving only the cells that are sensitive to treatment”.

“Tumour cells can survive well without oxygen, but because tumours grow rapidly, cells end up too far away from blood vessels to receive sufficient oxygen and nutrition. As a mechanism to solve this, cells stimulate the formation of new blood vessels. Another mechanism is that cells ‘eat’ structures they no longer need (autophagy) by enclosing them in small vesicles. This releases new building materials that can be converted into energy. We want to try to block this process. To do this, we use the antimalarial drug chloroquine. This drug makes it impossible to carry out a certain fusion that is necessary for autophagy. If that fusion cannot take place, the contents cannot be broken down and the building materials cannot be released. That is our goal. We first investigated this in cell cultures, then in mice, and subsequently in a successful phase 1 clinical trial involving patients. We are now ready to move on to phase 2 to measure its effectiveness. We hope to find out what this really means for patients. Our research focuses on glioblastomas, the most aggressive type of brain tumour. Patients with these tumours have a poor prognosis. We hope that we can help these people live longer while maintaining their quality of life”. 

Kasper Rouschop: “Another study we are working on focuses on the communication of hypoxic cells. We see that vesicles are formed in these cells and are released from the cell. These vesicles then move between other cells and enter the bloodstream, allowing them to communicate with cells throughout the body.

They are sent ahead, as it were, to prepare areas of the body that are favourable to cancer for the arrival of cancer cells. In this way, they ensure that tumours can survive and grow and that cancer can spread, causing metastases. We are trying to understand what signals are sent out from these vesicles and how they ‘know’ which cells to communicate with”.

“We can detect the vesicles in the blood of cancer patients – we do not see them in healthy volunteers. When we remove them, we have investigated this in mice, we see that 85 to 90% fewer metastases are formed. We are also trying to find out how we can block the vesicles. We have achieved groundbreaking results in this area by developing antibodies: when applied to mice with tumours, we see a reduction in tumour growth. The research into the vesicles goes beyond glioblastomas; we also find these vesicles in colon cancer and breast cancer”.

“Then there is a third line of research. We have discovered that there is also a group of tumours that cannot activate autophagy at all. And that is very good, because patients who have no or hardly any therapy-resistant cells respond extremely well to therapy. This subgroup accounts for between 10 and 40 percent of all tumours. This subtype is not yet widely recognised and acknowledged throughout the field, but our group is fighting to ensure that it is, among other things by investigating how these tumours are able to develop. There must be something that compensates for the autophagy mechanism. If we can identify that mechanism, we may eventually be able to use it in the long term to kill the rest”.

“To do this, we obviously need to know which tumours are involved: you have to be able to identify them. We are focusing on this with Prof. Andre Dekker from Clinical Data Science, who has received an Open Competition 2024 Grant for this purpose. It is not yet possible to see whether someone has cells with autophagy, so everyone receives the same treatment. But if you don't have autophagy or hypoxic cells, you may be overtreated. It will be very useful for clinical practice and especially for the patient if unnecessary treatments are avoided. Ultimately, in about 20 years' time, we want every patient to receive treatment tailored specifically to their tumour”.

Kasper Rouschop: “Ultimately, what we do here is focused on patients – but especially those of the future. That is why the collaboration with Maastro, and the short lines of communication with the doctors there, are very useful to us as researchers. If we can prevent metastases thanks to the antibodies, then we will have a huge impact. We may not know the real impact of much of our research for another 10 or 20 years, but I am convinced that we are already having an impact now. For me and all my fellow researchers, the directions we are taking will lead to better cures for patients. Of course, it is very special to be one of the first to discover something, such as the oxygen-deprived cells that activate autophagy. The same applies to the vesicles produced and secreted by hypoxic cells. We are the only ones doing this and were also the first to demonstrate what these vesicles can do. This opens doors for other researchers that they had not seen before. I am also proud that we have gone from researching a fundamental mechanism in a dish of cells to testing it in patients to determine whether it works. But there is still plenty more to do”.

“I used to say, ‘If science doesn't work out, I'll become a gardener’. I now have quite a large garden and love doing things in it. I also enjoy doing all sorts of things around the house. Painting a wall is very rewarding: you paint it and it's done. That's a nice contrast to my research, which is never really finished. For every little piece you solve, ten new questions immediately arise. But doing research, especially as part of a team, is wonderful. I really enjoy that teamwork, as well as training young talent to become independent researchers. The direction we take is determined by our interaction with each other. In that respect, my voice carries just as much weight as anyone else's”.

¹This is the phenomenon where vesicles (small bubbles) perform essential functions inside the cell and also play a key role in communication with other cells, enabling them to influence tumor growth.

Text: Eline Dekker
Photo: Henry Peters © Maastro

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