Research And Grants

Targeted Protein Degradation for DIPG Therapy

Childhood brain tumors are the second most common type of pediatric cancer, with overall survival and treatment related long-term side effects far worse compared to other children with solid tumors and haematological malignancies. The prognosis of brain tumors in children has improved over the past decades; however, one third of these patients cannot be cured. For high-grade gliomas such as diffuse intrinsic pontine gliomas, the most aggressive brain tumors in children, the prognosis is in fact even worse. Despite intensive multimodality treatment (surgery, chemo, and radiotherapy), refractory disease and relapse are frequent events. Thus, there is a clear need for improved therapy. One of the most exciting and emerging therapeutic strategy is to use the cells own “disposal” system to remove unwanted proteins, known as drivers for tumor development.  Recently, we identified the natural compound Obtusaquinone (OBT) to kill cancer cells, including DIPG, by inducing an overall stress response, while inhibiting DIPG growth in mouse models. Based on OBT, we developed a novel chimera for targeted protein degradation to remove one of the main drivers of DIPG, BRD4, leading to efficient killing of DIPG cells and inhibiting DIPG growth in mouse models. If successful, this proposal could provide a novel and improved therapeutic strategy for our young patients with DIPG, and other brain tumors, leading to an increase in their overall survival and improved quality of life.