Tumors in the brain stem, also called diffuse intrinsic pontine gliomas (DIPG), are intertwined with the healthy brain tissue of children in an area that regulated vital functions, such as breathing and heartbeat. ‘Surgical removal is not possible and the area is difficult to target with chemotherapy, since the blood brain barrier is not permeable for these chemicals. Moreover, tumor cells regularly develop resistance against chemotherapy’, says Hulleman. Currently, treatment encompasses radiotherapy, which is life-extending, but not curative.
By combining several treatment strategies, Hulleman is convinced to have found an effective therapy. With financial support from Stichting Semmy, she analyzed a combination therapy consisting of three parts. ‘The first compound inhibits a protein that is located on the exterior of the tumor cells’, explain Hulleman. ‘Inhibition of this protein, which is called AXL, has no effect on its own. However, the protein is responsible for the development of resistance against chemotherapy.’
Hulleman tested the AXL-inhibiting compound on tumor cells together with Panobinostat. ‘In the US there is a clinical trial with Panobinostat’, says Hulleman. ‘At first the results are very good, however, the tumor cells adapt rapidly and develop resistance. In combination with the AXL-inhibitor the resistance is not developed.’
‘The combination of these two compounds kills the existing tumor cells, but clones of the cancer cells will grow back’, says Hulleman. ‘A third therapy is needed to kill all cells. Radiotherapy, as we are using it now, is very suitable for this.’
The first results were found in tumor cells from patients, which were cultured in the laboratory where the developed into mini-tumors. These mini-tumors, also called organoids, represent the tumors in the brain. ‘It is a valuable first model, but ultimately you have to test a new therapy on effectiveness and safety in living organisms’, explains Hulleman.
The next step was to test the combination therapy in mice. The good news was that both the AXL-inhibitor and Panobinostat cross the blood brain barrier and reach the tumor cells. Less desirable was the finding that mice appeared not to be a good model for this experiment. Hulleman: ‘The dose in which Panobinostat had to be administered, was toxic for the animals. However, that does not mean that it will be dangerous for children. The metabolism that degrades the compounds is different between mice and men. The trial in the US shows that children do experience side effects, but not comparable in severity with the toxicity we found in mice.’
From bench to bed side
Together with colleagues in the Máxima, Hulleman pleads for a clinical trial. ‘To a certain extent, we will have to accept that there will be side effects’, says Hulleman. ‘The alternative is that all children with a pontine glioma die, and that is unacceptable.’