Pre-doctoral Fellowship Grant Awarded to Aimee du Chatinier

After decades of intense research it has become clear that DIPGs are highly treatment resistant tumors that unlikely will be cured by monotherapy. To effectively eliminate DIPG cells, a combination of different treatment modalities, such as radio-, chemo- and immunotherapy, is likely needed to reach clinical effect. In this project we propose to study a combination therapy in which we incorporate both radiotherapy and two drugs, Paxalisib and Givinostat, which are currently in clinical trials for DIPG (Paxalisib) or for children with Duchenne muscle dystrophy (Givinostat). We recently identified that very low doses of Givinostat can kill DIPG cells growing in a dish and that this drug can enhance the tumor-killing effect of radiotherapy and Paxalisib. Furthermore, preliminary data suggest that Givinostat treatment results in local inflammation in DIPG-bearing mice, a sign that the immune system is fighting the tumor cells, and reprogramming of immune cells that support DIPG growth. However, although promising, Givinostat by itself was insufficiently potent to cure mice from DIPG, suggesting that it should be used in combination with other treatment modalities. It is the aim of this project to test different treatment regimens incorporating Givinostat, Paxalisib and radiotherapy in DIPG mouse models to identify the most optimal combination therapy and dosing scheme. Besides looking at survival benefit of these treatments, we will study the impact on the immune cells within the tumor and its surrounding healthy brain tissue. By obtaining a better understanding of the biological effect of this drug combination we can prepare for the inclusion of Givinostat on a backbone of Paxalisib in future clinical trials, either as a radio/chemotherapy combination or as a backbone for immunotherapy. As such, the results from this study open the door for therapeutic combinations that ultimately may lead to an increased progression free- and overall survival of DIPG patients.