Research And Grants

Combining innovative proton radiotherapy with targeted and immune therapies to treat DMG/DIPG

Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), are devastating childhood brain tumors that occur in the central portions of the brain. Traditional chemotherapies don’t work on them, and because of their location they cannot be removed by surgery. Radiation therapy slows tumor growth, but progression is inevitable. DMG/DIPG resistance to treatment is due to a genetic mutation called H3K27M which is found in the tumor cells. Currently, it is not totally clear why the H3K27M mutation leads to such resistant tumors, but it is likely that a combination of therapies including radiation and immunotherapy specifically targeted to the tumor cells and their surrounding support cells will be needed for a cure. Development of effective therapies represents an urgent unmet need in the pediatric brain tumor community. The state-of-the-art proton research facility at Cincinnati Children’s Hospital Medical Center will also allow us to apply a promising new form of radiation (FLASH therapy) to our pre-clinical brain tumor models. FLASH proton therapy delivers radiation at ultra-high speeds and causes less damage to surrounding healthy tissues than typical radiation. Initial experiments using FLASH indicate that it effectively kills DMG/DIPG tumor cells in lab models. For these reasons, FLASH may hold great promise for DMG/DIPG patients by allowing for higher safe doses of radiation and faster treatment. Our collaborator, Dr. Carl Koschmann, has been studying another new anti-tumor drug called ONC201, which stops DMG/DIPG growth in lab models and in patients. In addition, therapies combining immunotherapy targeting immune cells have proven more effective than traditional therapies, and with yield better outcomes. We see an opportunity to combine proton therapy with this targeted new drug along with immunotherapy, in comparison with standard x-ray radiation therapy, the only treatment that consistently slows DMG/DIPG growth. Our project is to test this powerful combination against a full range of experimental models and use cutting-edge molecular analyses to understand why they work and what may be needed to make them even more effective in the future. Our studies should help to design novel combined treatment strategies for DMG/DIPG in future clinical trials and improve therapy efficacy and patient survival.