Share your Science (III)

Share your Science is the section where CENL-SWNL members disseminate the research that they do in the Netherlands. Today, Hans Meel from Princess Maxima Center for Pediatric Oncology talks about his research to find new therapeutic strategies for DIPG, a pediatric brain tumor with very bad prognosis.

My name is Hans Meel, and I’m a medical doctor and scientist in the field of pediatric oncology. For the past six years I have dedicated myself to studying aggressive pediatric brain tumors in the research group of dr. Esther Hulleman at the VU University Medical Center and Princess Máxima Center for Pediatric Oncology. My research mainly focused on the preclinical development of therapeutic strategies for diffuse intrinsic pontine glioma (DIPG).

DIPG is a tumor of the brainstem occurring in children of all ages, with a peak incidence in kids between six and nine years old. These tumors carry the worst prognosis of all pediatric brain tumors, with patients rarely surviving more than a year after diagnosis. Currently, there is no effective treatment available to cure the disease, and we can only offer radiotherapy to relieve the symptoms and extend the lifespan of the children by a couple of months.

You may be wondering why this disease is so difficult to treat and study. First of all; as these tumors are located in the brainstem, the part of the brain responsible for our vital functions such as breathing and blood pressure, surgery is not possible and even biopsies are rarely performed due to the risks involved. As such, there is almost no tissue available to study these tumors. Additionally, the blood vessels in the brain, and thus around the tumor, are highly impermeable. Normally, this functions to protect the brain from toxic substances. However, in the case of DIPG, this so-called blood-brain barrier (BBB) prevents most drugs from reaching the tumor cells, rendering chemotherapy ineffective.

To be able to develop a treatment for DIPG, we first needed to obtain tumor tissue and laboratory models to study the disease. To do so, we set up research protocols to obtain tumor tissue from DIPG patients. From these tissues, we extract cancer cells to grow in the laboratory in the shape of micro-tumors, called spheroids. To be able to study the tumor cells in the presence of normal brain cells and blood vessels, we also inject these cells in mice, where they grow tumors resembling DIPG.

We then use these models to study the disease on a molecular level, aiming to identify particular “weaknesses” in the cancer cells that are not present in normal cells. We then target these weaknesses using drugs and evaluate whether these drugs are specifically toxic to DIPG cells. As we aim to develop a treatment as soon as possible, we choose to focus on drugs that are already tested in humans. This ensures that we can rapidly test a potential therapy in patients, when we identify a promising drug treatment. We also determine if promising drugs can reach the brain, as current treatments often fail because of the blood-brain barrier mentioned before. Finally, we use our mouse models to confirm that these drugs actually prolong the life of mice with DIPG – the final stage of preclinical research.

Our most recent study focused on understanding why DIPG is so resistant to radio- and chemotherapy. The mesenchymal transition is a molecular process that allows cancer cells to become resistant to radio- and chemotherapy, and to invade healthy tissues surrounding the tumor. (1) In our most recent study we identified AXL, a protein present on the cell surface, to be responsible for initiating and maintaining this process in DIPG cells.(2) Inhibiting AXL with a known anti-cancer drug, bemcentinib, reverses this mesenchymal phenotype of DIPG cells. This effect is especially prominent when bemcentinib is combined with panobinostat, a drug already under investigation for the treatment of DIPG. We show that the combination of these drugs selectively kills DIPG cells and renders them more sensitive to radiotherapy. We also demonstrate that both bemcentinib and panobinostat are capable of crossing the blood-brain barrier, and result in improved survival of mice with DIPG. As such, this combination of drugs forms a potential future treatment strategy for these deadly brain tumors.

Currently, the research group of dr. Hulleman is continuing to study this therapeutic strategy for the treatment of DIPG. Together with our international collaborators, we hope that the development of disease-representative models and the knowledge about DIPG that we gained through them will contribute to the development of an effective treatment to combat this disease.

References:

  1.       Meel MH, Schaper SA, Kaspers GJL, Hulleman E. Signaling pathways and mesenchymal transition in pediatric high-grade glioma. Cell Mol Life Sci. 2018;75(5):871-87. https://link.springer.com/article/10.1007/s00018-017-2714-7
  2.       Meel MH, de Gooijer MC, Metselaar DS, Sewing ACP, Zwaan K, Waranecki P, et al. Combined Therapy of AXL and HDAC Inhibition Reverses Mesenchymal Transition in Diffuse Intrinsic Pontine Glioma. Clin Cancer Res. 2020. https://clincancerres.aacrjournals.org/content/26/13/3319

Foundations to support DIPG research: 

In Spain : http://fondoaliciapueyo.org/

In The Netherlands: http://www.stichtingsemmy.nl/

Human DIPG cells (green) forming a typical DIPG-like tumor in a mouse brain (blue)

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