MBRS-58. VISMODEGIB NANOPARTICLE ENHANCES TUMOR TARGETING IN AN IN VIVO MEDULLOBLASTOMA MODEL

Medulloblastoma, the most common pediatric malignant brain tumor, is divided into at least four molecular subtypes. The Sonic Hedgehog (SHH) subtype, accounts for approximately 30% of all cases and has an intermediate prognosis (5-year overall survival of 60%). Current treatments involve surgery, adjuvant radiotherapy for older children, and chemotherapy, however, lead to devastating morbidity, including decline in cognition and intellect, endocrine deficiencies, and secondary malignancies. More recently, targeted treatment options that inhibit the Hedgehog pathway have demonstrated clinical efficacy, including the Smoothened inhibitor, Vismodegib, however result studies have also shown secondary toxicities including effects on bone development. Here we investigated the efficacy of Vismodegib packaged in a fucoidan-based nanoparticle (Fi-Vis) that targets P-selectin, a protein overexpressed on vascular endothelial cells and is induced by 2Gy ionizing radiation (XRT) in a time- and dose-dependent manner. This p-selectin targeting nanoparticle drug delivery system shows selectivity toward tumor vasculature and not normal brain vasculature in a genetically relevant SHH-driven medulloblastoma mouse model as assessed by ex vivo infrared imaging. Quantitative RT-PCR analysis on SHH medulloblastoma tumor tissue following 2Gy XRT and Fi-Vis single dose treatment (as low as 10mg/kg) showed a synergistic inhibition of Gli1 expression (up to ~90% target inhibition). Furthermore, we demonstrate that lower single fraction XRT doses as low as 1Gy also induce P-selectin expression within medulloblastoma tumor vasculature. These data suggest applicability of combined XRT and tumor vasculature-targeted nanotherapeutic dose de-escalation strategies for medulloblastoma and potentially other pediatric brain tumors.