Game Changer Grant Awarded to Richard Lu

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 resistanttumors, but it is likely that a combination of therapies including radiation and drugs specifically targeted to these cells will be needed for cure. Development of such combinations represents an urgent unmet need in the pediatric brain tumor community. We discovered that chaetocin, a substance produced naturally by a fungus, shows an impressive killing effect on DMG/DIPG cells, which was increased when combined with radiation. Chaetocin works, in part by magnifying the effect of a natural “self-destruct” signal in brain tumor cells called TRAIL. Our collaborating partner, Dr. Carl Koschmann, has been studying another new drug called ONC201, which stops DMG/DIPG growth in lab models partly by increasing the production of TRAIL inside tumor cells. Clinical trials show that ONC201 improves survival for some DMG/DIPG patients. Since the ONC201 and chaetocin work in complementary ways by increasing the amount of TRAIL and magnifying its cancer-killing effect, we saw an opportunity to use them together, in combination with 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. The state-of-the-art proton research facility at Cincinnati Children’s Hospital Medical Center will also allow us to apply a new promising form of radiation (FLASH therapy) to our models as well. FLASH proton therapy delivers radiation at ultra-high speeds and causes less damage to surrounding healthy tissues than typical radiation. Initial experiments in 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 studies should help to design novel combined treatment strategies for DMG/DIPG in future clinical trials and improve therapy efficacy and patient survival.