MEDU-32. ADVANCING PRECLINICAL MODELING OF HIGH RISK MEDULLOBLASTOMA BY PERFORMING CLINICALLY-RELEVANT RADIOTHERAPY ON PATIENT-DERIVED XENOGRAFTS

Medulloblastoma (MB) is the most common malignant pediatric brain tumor that comprises four major subgroups. Group 3 (MBGrp3) that overexpress MYC and Sonic hedgehog (MBSHH) with MYCN amplification and TP53 loss of function have a particularly poor prognosis. MBs are treated with surgical resection, craniospinal irradiation (CSI), and chemotherapy with or without targeted agents. Radiation therapy is a core component of the current MB treatment regimen. Despite this aggressive approach, a significant number of patients, particularly in the high-risk groups, will ultimately fail primary therapy. To improve preclinical trials that more faithfully recapitulate aspects of the disease and therapeutic interventions, we established and molecularly characterized patient-derived xenografts (PDXs) of the high-risk MB Grp3 and MBSHH subgroups. Initial preclinical delivery of two dimensional whole brain radiotherapy significantly increased overall survival of mice bearing MB Grp3 or MBSHH PDX tumors. However, control and radiation-treated mice developed metastases in the spine and brain regions shielded from the radiation. Therefore, we developed a more sophisticated protocol that accurately and reproducibly delivers CSI to mice using the image-guided Small Animal Radiation Research Platform. We have successfully treated mice orthotopically implanted with high-risk MBGrp3 tumors up to 36 Gy (2Gy per day, 5 days on 2 days off) and have observed significantly improved survival. We are now poised to deliver fully fractionated irradiation to the complete neuraxis of PDX-bearing mice and are beginning to systematically test CSI in combination with targeted pharmacologic agents to identify potential synergy that results in a therapeutic advantage.