RADT-03. Enhancing therapeutic sensitivity in medulloblastoma using an alternating day radiation dosing scheme

Craniospinal irradiation (CSI) is currently a mainstay of upfront therapy for medulloblastoma (MB) in children greater than 4 years old. Although effective for MB and other neuroembryonal tumors, the long-term neurocognitive sequelae preclude its use in younger children. Despite improved 5-year survival rates that approach ∼70-80% for all MB subtypes as a group and the reduced neurocognitive toxicity advantages of proton-based irradiation over x-ray irradiation, nearly one-third of children still relapse with very poor outcomes. Notably, re-irradiation of recurrent MB has been advanced as an effective therapeutic modality, however the durability of treatment response is short lasting with dosing limited by prior radiation exposure. Using a physiologically relevant GEM model of SHH subtype MB (Ptf1acre/+;Ptch1fl/fl), we found that a standard single 2Gy ionizing radiation dose resulted in tumor cell cycle exit by 4 hours measured by Ki67 and pH3 immunostaining, and widespread tumor cell death measured by cleaved caspase-3 between 6-24 hours following treatment. However, we observed that surviving Atoh1-GFP+ lineage traced MB cells following treatment did not re-enter the cell cycle until on average 48-72 hours later, suggesting that daily radiation dosing schemes might be targeting non-cycling tumor cells on most irradiation days. Interestingly during this 24-72hr post-radiation period, surviving GFP+ MB cells sequentially expressed primitive stem cell-like markers (CD34+ at 24hr and Nestin+ at 72hr). The radiation sensitivity of advanced stage SHH MB was dose-dependent between 0.25Gy to 2Gy and a radiation dosing schedule of 0.25Gy every other day for a total of 8 doses resulted in significant mouse survival (median 21 days) compared to equivalent daily dosing. We are now implementing a clinical trial for re-irradiation of relapsed MB utilizing an alternating day vertebral-sparing proton CSI schedule and propose that re-irradiation presents an opportunity to test novel and reduced dosing schemes to improve therapeutic index and patient outcomes.