PDTM-05. SONIC HEDGEHOG SIGNALING PRIMES CEREBELLAR GRANULE NEURON PROGENITORS AND MEDULLOBLASTOMA CELLS FOR APOPTOSIS BY INDUCING PRO-APOPTOTIC BIM

Medulloblastomas, unlike other malignant brain tumors, are typically sensitive to radiation therapy (xRT). However, although xRT allows medulloblastoma patients to survive, it can also confer significant long term cognitive sequelae. Understanding the mechanisms of radiation sensitivity in medulloblastoma may identify ways to increase this sensitivity through targeted therapy. Cerebellar granule neuron progenitors (CGNPs), the cells of origin for SHH-subgroup medulloblastoma, are also sensitive to xRT. We have shown that SHH signaling, which induces CGN proliferation and in excess can cause medulloblastoma, induces the pro-apoptotic protein BIM, resulting in increased radiation sensitivity. SHH-stimulated CGNPs show robust BIM expression, which is blocked by the SMO inhibitor vismodegib. CGNPs in BIM null mice show normal SHH-driven proliferation, but are markedly less sensitive to radiation. Protein studies show that BIM binds to the anti-apoptotic proteins BCL-xL and MCL-1, suggesting a mechanism for increasing the sensitivity to radiation by lowering the apoptotic threshold. On-going studies will determine whether BIM is required for radiation sensitivity in SHH-driven medulloblastoma. If validated, the BIM interactions with BCL-xL and MCL-1 may be novel mechanisms to be targeted to improve medulloblastoma therapy.