2023-05-24 10:41:00
“Tobias was good when I left, bad when I got back.” It is the autumn holiday of 2017, when father Reitse is in the south of France and son Tobias and daughter Novalinde are traditionally on holiday with grandpa and grandma. During the video call, Reitse already sees that something is not right, Tobias also indicates it himself. His motor skills falter, he even drools a little. Reitse drives full throttle back to the hospital in Zwolle. His wife Evelien does not have to say anything to show that it is not good. The diagnosis: a tumor on the brain stem, a diffuse intrinsic pontine glioma — or DIPG — as doctors call it. The chance of recovery: 0 percent.
The inevitable
DIPG is a rare form of brain cancer. Ten children and ten adults in the Netherlands are diagnosed each year. Tobias Sybesma was one of them in 2017. The Sybesma family soon came into contact with pediatric oncologist Dannis van Vuurden, then working at the VUmc, who had a place in a treatment study. ‘In DIPG, the tumor is in the so-called pons, the bridge between the brain and spinal cord that controls heart rate, breathing and swallowing functions, among other things,’ he explains. ‘The tumor is diffuse and therefore intertwined with the brain stem in such a way that it is not operable at all. All we have is medication – radiation. This can temporarily halt the growth of the tumor cells until the inevitable finally happens.’
Because the treatment did not work at first, the Sybesma family feared that Tobias would not make it to his twelfth birthday. Father Reitse started since then bonus day to keep up. Until the inevitable happened. After 248 bonus days, Tobias Sybesma passed away on July 31, 2018. Two days after his death, father Reitse started the Tobias Sybesma Foundation. The dream: finding a treatment for brain stem cancer. Because Tobias wanted to become a professional volleyball player, a benefit match was held. The Twente ’05 coach drew Sybesma’s attention to UT professor Albert van den Berg, who might be able to help. He in turn hooked up with Loes Segerink, who brought in the expertise of colleagues Andries van der Meer and Kerensa Broersen.
Orange floors and a barrier
This is how a special triangular collaboration was created in November 2019: the father who lost his son to the disease, pediatric oncologist Van Vuurden who is at the hospital bed every day and the three scientists from Twente. Their common goal ever since: trying to make that untreatable disease treatable. They explain how difficult the road to get there is at the Princess Máxima Center in Utrecht, the largest pediatric cancer center in Europe and the place where Van Vuurden has been working for several years now. A bright place with bright orange floors, where you are surrounded by teddy bears and coloring pages. And a place where a smile and a tear are never far apart.
‘It’s not just how intertwined and spread the tumor is in relation to the brain stem’, Broersen explains the complexity of the disease. ‘What makes it even more difficult is that someone’s immune system does not respond to this variant. That does happen with other forms of cancer; like having a splinter in your finger, inflaming the tissue around it. In these tumor cells, however, the immune system comes to a standstill. We don’t really understand why yet.’ And then there is the blood-brain barrier, adds Van der Meer. ‘The blood vessels in the brain are unique and there is literally a barrier between the blood vessels in the brain and the other blood vessels in your body. The barrier actually prevents bad substances from reaching your brain, but they also prevent the substances from a pill or infusion from entering the brain.’
‘We can even extract stem cells from the patients’ urine’
Patient on a chip
The UT researchers are looking for the possible solution in the use of organ-on-a-chip-technology. ‘The previous method was that you had a plate with holes in it, containing tumor cells. By then adding a certain concentration of a drug, you could see whether the tumor cells would die,’ explains Broersen. How different it works with organs-on-chips. ‘The brain works much more dynamically than a plate with holes in it. We can mimic this effect in a microfluidic environment. For example, we use stem cells to build mini-brains and mini-tumors, which allow us to approach the actual situation as closely as possible. We can even extract those stem cells from the patients’ urine, so completely non-invasively.’ It is an approach that Van Vuurden applauds. ‘The old method, that plate with holes, has its value. But I also thought: there must be something better. There was too much of a gap between such a test set-up and a patient in bed a few doors away. With the organs-on-chips we can approach reality much better; a drug must not only be effective against a tumor, it must also keep the surrounding healthy cells out of harm’s way, the so-called therapeutic index. It helps tremendously that we now have a patient on a chip, so to speak.’
The researchers were assisted by PhD candidate Job Komen. ‘He developed so-called pharmacokinetic models to simulate in the chips how different types of medication can cross the blood-brain barrier and kill a tumor cell,’ explains Van der Meer. And the first results turned out to be promising. ‘Even the extremely low drug concentrations that can end up in the human brain were sometimes enough to kill certain DIPG tumor cells in the chips. That observation gives us confidence in the possible effectiveness of such a substance in the patient.’ Building on this initial success, the researchers now want to develop the technology further: ‘That is another advantage of this method with the microfluidic chips: you can scale up your testing capacity enormously. That way we can test a thousand different treatments at once.’
‘In this project everyone is on board to help, not for that publication in Nature’
Constant confrontation
The work of the PhD candidate has recently received a new impetus; Segerink and Van Vuurden received a subsidy from the Dutch Cancer Society. ‘To try to cross the blood-brain barrier using ultrasound during radiation treatment,’ explains Segerink. ‘We also receive help from UT spin-off Demcon. What once started with Reitse walking into our house will in any case continue for at least four years.’
It is an unorthodox partnership, especially compared to how most scientific consortia are formed. And that is precisely the strength, say those involved. ‘A lot of the credit definitely goes to Reitse, he is rightly our fire maker,’ says Broersen. ‘Moreover, the essence of being a scientist is that you have the freedom to pursue a certain curiosity,’ says Van der Meer. ‘The strong involvement of a parent ensures that we are constantly confronted with what we are doing it for’, adds Van Vuurden. ‘I always notice that here in this hospital, that one purpose to make sick children better. It is felt by everyone, from doorman to professor. In this project too, everyone is on board to help, not because of selfishness or that publication in Nature.’
“I can’t be saved anymore, but I hope no one comes after me”
Hoop
Even though a flame has been lit that won’t just die out, the road to a possible treatment method is still as long as it is complicated, they say. “I’m beyond saving, but I hope no one comes after me.” It is a quote from Tobias that is prominently featured on the foundation’s website. ‘Everyone understands, of course, that that didn’t work out,’ says Sybesma with a grimace. “But we have to start somewhere. And ideally you want someone to have the guts to put down a lot of money, so that we are not dependent on the subsidy circuit’, Segerink adds. ‘It should be manageable to find a treatment,’ says Van Vuurden. “As humanity, we have always been able to solve problems with our innovation and technology. Why shouldn’t that apply to brain stem cancer?’
What is needed even more than money is energy, knowledge and a critical mass of experts who want to contribute to a solution. Hope instead of a disguised death sentence. “Tobias had his own thoughts about that. About how a game could be made, in which everyone would puzzle together to find a cure.’ And there is always hope, Van Vuurden emphasizes. ‘I always assume hope, in every bad news conversation. It’s never: this is it and you die. You don’t know what tomorrow will bring.’ Sybesma recognizes that. “We lived from day to day, minute to minute. There have been plenty of moments after the diagnosis when we were intensely happy. In the little moments, for example when the cat crawled under his blanket. Ten minutes later we were on the line with the emergency number. We were king of living in the moment. And hope, we have never given up.’
#Making #untreatable #disease #treatable