In search of a tumour’s Achilles’ heel
Celia Berkers studies the metabolic processes of cancer cells.
As a child, Celia Berkers thought it would be amazing to discover a new drug against cancer. And as an adult, she still dreams of finding ways to improve the lives of cancer patients. Over time, cancer cells tend to become desensitised to specific drugs or chemotherapy – a phenomenon that claims the lives of many patients each year. Berkers is engaging with tumours and looking for the weak link in their metabolism.
Celia Berkers speaks quickly and enthusiastically as she talks about her research. She speaks both English and Dutch with the same flawless intonation, sowing a moment of doubt as to where she is from. ‘I attended university here, but spent two years as a postdoc in Glasgow,’ the Professor of Metabolomics explains, which is a relatively new field of study that Berkers and her colleagues around the world are working to establish. ‘Everything I’m doing now, I learned there.’
Even as a child, you were fascinated by cancer. Why?
‘I have always had a fascination with cancer. It’s important to me that my research contributes to tackling a societal problem. I was aware that cancer was a problem when I was young, and as a kid, you want to find a solution. Beyond that, I really like complex issues – I love solving puzzles. This is a huge challenge to try to achieve. I started out as a chemistry student, but quickly switched to the biochemistry programme.’
Would you rather study life processes than non-living ones?
‘Yes, life processes fascinate me to no end. In secondary school, I was incredibly interested in biology. Metabolic processes are so complex, and cells regulate them all by themselves! I feel a certain admiration when I see that. It’s absolutely fascinating to be able to use chemical techniques to study how all that works.’
How does the metabolism of a cancer cell work?
‘Cancer cells have a different kind of metabolism than healthy cells. We’ve known that for quite some time, actually – since the 1930s and 40s. That’s when researchers were figuring out all the biochemical processes in the body, and they noted that cancer cells absorbed much more glucose than healthy cells. Cancer cells also excrete more lactic acid than their healthy counterparts.’
Has that affected the cancer therapies being used?
‘For quite some time now, we’ve been using the same drugs as the standard chemotherapy to treat cancer. Cells are constantly absorbing nutrients, which they need in order to generate energy or building blocks. To do that effectively, cancer cells modify their internal metabolic processes. My research explores how all that works.’
As a child, I thought it would be amazing to discover a new drug to cure cancer. I never lost sight of that idea.
How exactly are you and your colleagues doing that?
‘Our primary focus is how cancer cells adjust their metabolism in order to survive chemotherapy. They can develop a tolerance for specific medicines, for example, which is known as “drug resistance”. In such cases, the patient’s body stops responding to chemotherapy and the tumour starts to grow again. That is a big problem. We think it might account for 90 per cent of cancer fatalities – a huge number, really. By modifying the metabolism of cancer cells, it might be possible to interrupt the process by which they become resistant, for instance by combining metabolic drugs with existing cancer therapies. Then you can hit the cancer cells harder and it will take longer for them to develop a resistance.’
Does reducing a cancer cell’s access to glucose help?
‘It’s funny you should say that: it does stand to reason that it would, and the first studies in that area are now emerging. These involve having people fast during chemotherapy, for instance, or eat a low-carb diet for the purpose of facilitating the healing process. But this idea is still in its infancy. What’s more, modifications in diet are extremely difficult to study, especially in humans. How can you track exactly what a person eats? This aspect is easier to study in animals, because you can switch their feed or combine a prescribed diet with a certain medicine. I’m currently consulting on this with Alain de Bruin, Professor of Pathobiology at the Faculty of Veterinary Medicine. It is a great topic for further research, including in the field of veterinary medicine.’
Does metabolism have to do with the citric acid cycle, a famously difficult chapter in biology class?
‘You’re exactly right! Glycolysis, the citric acid cycle: we can monitor all those kinds of metabolic reactions. By using glucose that we’ve chemically “tagged”, for example, we can observe exactly where the glucose goes and how quickly. That gives you a lot of information about such a system. After that, we test possible ways for us to intervene in those processes.’
To do so, you use mass spectrometry. What is that, exactly?
‘We use a mass spectrometer to measure the molecules released during the metabolic processes, both by cancer cells and by cancer cells that have become resistant to chemotherapy. Next, we develop models that better simulate the natural environment, such as lab-grown mini-organs (organoids). Then we measure what happens when we introduce certain medications. Metabolism is an unbelievably dynamic system. We have special techniques that allow us to precisely map out those dynamics.’
Are you and your colleagues doing that alone?
‘Our expertise in metabolomics is fairly unique within the Netherlands, especially in the context of cancer research. People from all over Europe visit us to conduct this type of measurement – we have quite the reputation in our field. We frequently collaborate with the Hubrecht Institute, the Princess Máxima Centre, UMC Utrecht, the Netherlands Cancer Institute, Sanguin and nearly all of the university medical centres, such as in Groningen and Leiden. But we also work with partners in north-western Europe such as in Germany, England, France, Belgium and Switzerland, as well as Bulgaria and Spain.
Do you feel you are any closer to finding the Achilles’ heel of cancer cells?
‘Yes; we are currently studying a type of bone-marrow tumour known as multiple myeloma or Kahler’s disease. We’ve observed that when cancer cells build up a tolerance to chemotherapy, they also become strongly dependent on a particular step in cholesterol synthesis. By blocking that step in the metabolic process, we can greatly increase the effectiveness of the cancer medicine, as we’ve demonstrated in mice. Half of the people in the world are taking cholesterol blockers. When you combine cholesterol blockers with this chemotherapy, you get a better response to the therapy. The tumour shrinks faster. While we have yet to publish these results, they’re certainly wonderful.’
Do you think cancer will one day be a chronic illness?
‘Cancer is not a single disease, but I think that day is fast approaching for many types of tumours. Immunotherapy is such a major development! But certain forms of cancer will remain difficult to treat, like pancreatic cancer, for instance. There are still many people who pass away within weeks of hearing a diagnosis. That diagnosis is incredibly grave.’