SC-03: NEURAL STEM CELL-MEDIATED ENZYME/PRODRUG THERAPY FOR MEDULLOBLASTOMA

Medulloblastoma is the most common malignant brain tumor in children. Despite recent advances in treatment, these tumors continue to be associated with high morbidity and mortality, and new strategies for treatment of medulloblastoma are urgently needed. Major obstacles to successful treatment of pediatric brain tumors include the blood-brain-barrier (BBB), which prevents many systemically administered anti-cancer agents from entering the central nervous system. Neural stem cells (NSCs) will effectively cross the BBB and preferentially migrate to tumor cells throughout the brain. We modified human NSCs to express and deliver the enzyme carboxylesterase (CE), which activates irinotecan (IRN; CPT-11) to the potent topoisomerase-1 inhibitor SN-38. In vitro cytotoxicity experiments demonstrate a 2000-fold increase in sensitivity of medulloblastoma cells to IRN in the presence of CE secreting NSCs (CE-NSCs). We have quantitatively assessed NSC tumor distributions in MP (c-myc, DNp53) and Daoy tumor models, and demonstrated that intranasally administrated NSCs migrate to medulloblastoma in the cerebellum. This suggests that intranasal delivery of CE-NSCs combined with systemic IRN may be a non-invasive strategy for treating pediatric brain tumors. We also found that NSCs do not distribute to non-cancerous areas of the brain, or to other peripheral tissues, suggesting that this approach could selectively target SN-38 production to pediatric tumor sites while sparing normal tissues. Pharmacokinetic and therapeutic efficacy studies are currently in progress. NSC-mediated enzyme/prodrug therapy can potentially limit the severe cognitive and functional deficits associated with currently available therapies, improving clinical outcome and quality of life for patients with medulloblastoma.