Research And Grants

Assessing the potential of the HDAC inhibitor givinostat ± radiotherapy for the treatment of diffuse midline glioma.

Pediatric brain tumors are the most frequent childhood solid tumors, and the leading cause of cancer related death in children. Patients with a diffuse intrinsic pontine glioma (DIPG) or midline glioma (DMG) – located in the brainstem, thalamus, or spinal cord – have a particularly bad prognosis. These tumors often cannot be surgically removed and to date, treatment with several types of chemotherapy has not been effective. Radiotherapy, the other cornerstone of cancer treatment, only temporarily alleviates symptoms without leading to cure. Thus, to develop an effective treatment for this patient group we will need to combine different forms of treatment, such as radio- or immunotherapy, a treatment in which the patient’s own immune system is used to fight the tumor.

In this project, we will study the effect of givinostat, a drug used in the treatment of children suffering from Duchenne muscle dystrophy, in combination with radiotherapy on DIPG/DMG in specially developed mouse models. Besides looking at survival benefit of this treatment, we will also study the immunological changes in the tumor and its surrounding healthy brain tissue. By mapping these changes, we can identify additional therapeutic targets to be used in future treatment combinations that include chemo-, radio- and immunotherapy.

We think that such a combinational treatment may be needed to tackle hard-to-treat cancer types like DIPG/DMG. Previous experiments from our laboratory have shown that very low doses of givinostat can kill DIPG cells growing in a dish and that this drug can enhance the effect of radiotherapy. As such, we anticipate that givinostat + radiation will enhance survival when tested in DMG-bearing mice. Yet, this combination may still not be sufficient for cure, as DIPG cells have been shown to escape treatment by switching to alternative survival strategies. Previous experiments also showed, however, that givinostat treatment (on itself) induces an increase of immune cells in the tumor, which may allow for the use of immunotherapy as an additional therapeutic option. Together, these results open the door for immunochemotherapeutic combinations that ultimately may lead to an increased progression free- and overall survival of DIPG/DMG patients.