Separate research is needed in the case of children with cancer. Children differ from adults in the types of cancer they develop. Researchers at the recently opened Princess Máxima Centre for Pediatric Oncology are looking for medications that work more specific than chemotherapy. NEMO Kennislink visited them.

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Medications specifically for Children with Cancer

Oncode Institute

I can see it straight away from my bike: a brand new, white building with sleek lines in all colours of the rainbow. It stands in the middle of a meadow, at the very back of the Utrecht Science Park. Today I am visiting the Princess Máxima Centre for Pediatric Oncology, which opened officially this year.

All the care, research and teaching concerning child cancer in the Netherlands have come together at this spot, with the goal of improving the prospects of children with cancer. There are two sides to this mission: increasing the chances of survival and reducing the side effects of the therapy. At present, one child in four dies from the disease. I enter the building, which still has the scent of newness, by the main entrance. The orange floors give me a strange feeling of the Dutch King’s Day celebrations. You certainly cannot call the building gloomy.

Accumulated mutations

I have an appointment with Professor Monique den Boer. Her research group is concentrating on acute leukaemia (cancer of the blood) and is investigating the ways in which leukaemia cells differ from normal blood cells. She previously worked in Rotterdam’s Erasmus Medical Centre, where much of the research into leukaemia was being carried out. Now, all the scientists and doctors have come together under one roof. Handy, she thinks. Researchers can immediately carry out studies with patients’ tissue and blood, with their permission. Fragments of tissue left over from diagnoses find their way straight to the labs.

We walk to her office, in the wing where the research groups have their laboratories and also where the Diagnostics department and the pharmacy are to be found. In the other part of the Centre you find the Care department, which receives all children in the Netherlands suffering from cancer: about six hundred per year. Their disease does not compare well with cancer in adults. Cancer cells arise in different organs and the type of tumour is often different too. For instance, you see cancer of the intestines, lung and prostate in adults, but never in a child. Some forms, such as brain tumours and leukaemia, occur in both. Even so, often there are differences. Children, for example, suffer mostly from acute leukaemia, while it is the chronic variant that occurs more often in adults.

Not everything you discover in adults is applicable to children

“Not everything you discover in adults is applicable to children,” Den Boer explains. “A child is still actively growing, so very different physiological processes are at play.” The tumours’ origin is also different. “This is because with cancer in adults, such as that of the intestines, there is often an accumulation of abnormalities in the DNA (mutations – ed.). When there are enough DNA mutations, the cell in the intestine can become malignant and go off the rails.” Broadly speaking, the aging process lies at the core of this: over the years, or decades, the mutations pile up. This process over time is not, or hardly at all, a factor in young children.

Leukemia cells (purple) in the bone marrow. (Wikimedia Commons, VashiDonsk via CC BY-SA 3)

Genes stuck together

It is largely a mystery why children develop cancer, sometimes even before birth. “In the case of leukaemia, we see special abnormalities in the blood cells’ DNA,” Den Boer explains. “Sometimes genes from different chromosomes stick to each other.” These fusion genes do not necessarily give rise to leukaemia; usually there is no problem. This is why new-born babies are not screened for such ‘fusion genes.’ “Fusion genes are the cause of the disease, but a number of other mutations are necessary for leukaemia to develop.”

Treating leukaemia is a long haul. Patients receive chemotherapy with toxic substances that stop the cells dividing for as long as two or three years. Chemo causes a lot of damage, because healthy cells are also hit. The stuff ends up everywhere in the body via an infusion or a tablet. Especially the rapidly renewing tissues, such as mucous membranes in the intestines, are damaged.

It would make a huge difference to patients if the medications attacked just the cancer cells. This approach is called targeted therapy. That is why Den Boer and her colleagues are looking for DNA errors and abnormal proteins in the leukaemia cells. Once you know what makes such a cell differ from normal cells, you have a starting point for medication. As it happens, the characteristics of the leukaemia cell also vary from patient to patient. Den Boer: “It is our goal that eventually everyone will receive an appropriate therapy, tuned to the characteristics of the leukaemia cell. Oncode’s mission is essential for high-risk, high gain research leading to new out-of-the-box treatment concepts for cancer.”

Acute leukaemia

Leukaemia is cancer of the blood. There are stem cells in the bone marrow that develop into immature blood cells, and subsequently grow into full-fledged blood cells. But if those immature cells start to grow uncontrollably, they disturb the formation of the normally maturing blood cells (red and white blood cells and blood platelets).

If that stifling occurs in a short period of time, the disease is called ‘acute’ and it is highly dangerous. There are two forms of acute leukaemia, the lymphatic and myeloid variants. The difference lies in the type of immature cell that divides unrestrained (either a lymphoblast or a myeloblast). Acute lymphatic leukaemia occurs mostly in children up to 14 years of age and it is the most common child cancer. It is the acute myeloid form that is more common in adults.

Residual cancer cells

As well as finding out who benefits from which ‘targeted’ medication, they also want to discover why some patients are resistant to the current chemotherapy. One-fifth of children with acute lymphatic leukaemia reacts inadequately to such therapy. “Leukaemia cells invent ingenious escape routes. If we can discover these routes, we can make the cells sensitive again to those medications.”

A cancer cell can also go into hibernation to defend itself against each medication. They huddle up in their cocoon, and when the coast is clear they appear again: then the cancer is back. Traditionally, scientists have been concentrating on the cancer cell and medications to kill it. But in more recent years not only the cell itself but also its surroundings have become the target. Den Boer: “Leukaemia cells that remain behind after chemotherapy, attach themselves to other cells in the bone marrow and get fed by them.” At the same time they are shielded from a new round of chemotherapy. “We are trying to find a way of liberating those leukaemia cells from the bone marrow, so that the medications can gain access again. As long as they are stuck, they are resistant, also to specifically targeted medication.”

Den Boer has a clear idea where treatment is heading: a few weeks of general chemotherapy to kill the majority of the leukaemia cells, followed by specific medications that home in on a certain DNA mutation in order to kill the stragglers. This can happen once the stragglers have been extracted from the bone marrow. Targeted therapy can take less than two years, making the process gentler psychologically and less intense in terms of side effects.

Climbing in the hospital

After our conversation we go on a tour at the Research Department. Den Boer is looking at cells, but the Princess Máxima Centre’s research programme encompasses much more. From fundamental studies to clinical trials with patients. There are also research groups concentrating on the quality of life and the psychosocial problems associated with years of treatment. Furthermore, there is an ongoing programme in the Centre aiming at more physical activity. Children are allowed to climb on everything. “Moving supports the recovery process. In the case of chemotherapy, it helps to jump a lot to strengthen the bones.”

Each room we enter is full of modern lab technology. There are incubators for culturing cells under conditions that simulate those in our bodies, microscopes that observe living cells, machines that can separate the various kinds of cells and collect them in separate tubes, instruments to detect DNA mutations. Still expected is a robot that is able to pipette. Some extra robot power will serve well in fathoming the complex biology behind child cancer.

This article was originally published by NEMO Kennislink: https://www.nemokennislink.nl/publicaties/specifieke-medicijnen-voor-kinderen-met-kanker/

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