Every year, some 10 children in the Princess Máxima Center are diagnosed with a tumor in the brain stem called diffuse pontine glioma (DIPG). There is currently no treatment for these children. Immunotherapy, a new form of treatment that uses the body’s own immune system against cancer, has also been unsuccessful so far. Part of the reason is the small number of immune cells in the brain. With funding from the Koppie-Au charity, dr. Dennis Metselaar, postdoctoral researcher in the Hulleman group, hopes to offer a new perspective on a treatment.
Microglia
In a new study, Metselaar looks at so-called microglia, cells with various supporting tasks in the brain. He says: ‘Microglia clean up waste products in the brain and help shape it during development. During puberty, they help to form new nerve pathways and in the meantime they control the immune system in the brain. That makes microglia, sometimes called 'the conductors of the brain', a type of immune cell. For our research into better treatment for DIPG, it is important that they fulfil that immune cell role even better.’
Microglia make up half of the cells in a brain stem tumor, Metselaar discovered in earlier research. And in tumor tissue from children and mouse studies, he noticed that they had a very different shape than the microglia in healthy tissue. ‘Brainstem tumors manipulate the microglia to create a comfortable environment for themselves,’ he says. ‘They keep away other immune cells, make substances that enable cancer cell growth, and create pathways through which the cancer can spread.’
Fault
All cells in a brain stem tumor have a particular fault in the way their DNA is folded, the so-called H3K27M abnormality. There are early clues that the microglia in brain stem cancers also have this abnormality. Metselaar: ‘We think that this is the way in which the cancer cells 'hijack' the microglia, by folding the DNA differently. Our hope is that if you reverse that change, the microglia will go back to their normal selves. That should attract other immune cells to clean up the tumor cells.’
The scientists will first compare the microglia inside and outside the tumor. Abnormalities in the RNA – the translation of the DNA code – or proteins, which they find in both the tumor and microglia, are possible new targets for treatment. The researchers will also look at the differences between microglia in adults and children of different age groups. This work is a collaboration with dr. Marike Broekman, neurosurgeon at the Haaglanden MC and Leiden University Medical Center, and colleagues at Harvard University in the United States. Metselaar explains: ‘Microglia, for example, have a markedly different shape during embryonic development. We think that for young children with this type of microglia, a different treatment will ultimately be needed.’
Existing medicines
Metselaar hopes that the current phase of the research into microglia will provide clear jumping-off points for follow-up research. ‘First, we will map out the RNA and protein profile of the microglia in brain stem cancer. Once that is successful, we can start looking for existing drugs that specifically target the changes in these cells. For example, there are already drugs that target the H3K27M fault, and we hope to find a dozen more targets for existing drugs in this way.’
Metselaar and his colleagues are deliberately focusing on existing medicines, in order to bridge the gap between the lab and the clinic as quickly as possible. ‘In the search for a treatment, the focus has long been on the tumor cells themselves. Research into the interaction with microglia is relatively new. We’re tapping into a whole new field of research, and we can revisit medicines that previously didn't work. By manipulating the microglia, we may also be able to make existing immunotherapies, such as CAR T-cell therapy, effective for brain stem cancer.’
‘New hope’
The research is still in a very early stage, but offers new hope, says Metselaar. ‘I have been working for seven years on finding treatment methods to cure brain stem cancer. I have come to learn how difficult it is to treat this tumor. That is precisely why I am so enthusiastic about our research into microglia. The first results give me a lot of courage and confidence that new answers can be found here for children with this devastating disease.’