Project Summary/Abstract Medulloblastomas are the most prevalent malignant brain tumor affecting children, accounting for 20% of all childhood brain tumors. Current therapies include surgical resection followed by postoperative radiotherapy across the craniospinal axis, with an additional higher dose to the tumor bed. This treatment regimen, while effective in eliminating medulloblastomas, also exposes healthy tissue to harmful levels of radiation, causing the cells to undergo apoptosis, or programmed cell death. This loss of neural cells can lead to lifelong negative effects, such as neurocognitive deficits and neuroendocrine dysfunction. Currently, clinicians must weigh the benefits of radiation therapy against the permanent damage from these treatments, leading to a critical need for improved therapies. As such, proton radiotherapy is being increasingly used clinically, as it reduces the entrance and exit doses compared to more commonplace photon therapy while still allowing for adequate target coverage, eliminating approximately half of the unnecessary radiation administered to normal tissue. Today, approximately 50% of pediatric medulloblastoma patients in the United States receive post-surgery proton radiation therapy. Even so, there is substantial healthy tissue being exposed to radiation, as medulloblastoma patients receive radiation to the tumor bed as well as the entire craniospinal axis. Despite the clear importance of maximizing post-treatment quality of life for pediatric cancer survivors, our understanding of the mechanisms driving radiation induced neurotoxicity is limited, and no clinically-useful mitigators currently exist. Previous studies have shown that genetic inhibition of BAX, a protein necessary for apoptosis, protects neural cells from radiation induced apoptosis. While there are currently no well validated direct pharmacological BAX inhibitors, Myc has been shown to directly promote the expression of BAX in the developing brain. Importantly, Myc also has been shown to be a critical driver of medulloblastoma growth, and targeting this oncogene promotes stress- induced apoptosis in medulloblastoma cells. Numerous inhibitors of Myc signaling have been developed, including bromodomain and extra-terminal motif (BET) inhibitors that target the transcription of Myc itself, and are currently being evaluated in clinical trials. These recent discoveries and developments create a potential opportunity to modulate Myc to improve patient outcomes. We thus hypothesize that targeting Myc with BET inhibitors will protect healthy neural cells from radiation induced apoptosis while simultaneously sensitizing medulloblastomas to radiotherapy, thus widening the therapeutic window for radiotherapy. Our studies to date show that BET inhibitors protect primary murine neurons from radiation induced apoptosis while potently inducing apoptosis in medulloblastomas cells. As such, we propose to expand our studies to elucidate the optimal manner in ...