EXTH-70. ESTABLISHMENT OF INTRAVENTRICULAR SHH INHIBITION AS A THERAPEUTIC OPTION IN YOUNG PATIENTS WITH MEDULLOBLASTOMA

Medulloblastoma is the most common malignant brain tumor in children. The embryonal tumor arises in the posterior fossa and disseminates via the cerebrospinal fluid. Medulloblastoma divides in four molecular subgroups, one of which is characterized by mutations in the sonic-hedgehog (SHH) -pathway. SHH inhibition provides an elegant way of targeted therapy. The small molecule Vismodegib allosterically inhibits Smoothened (SMO), an upstream activator of SHH. Unfortunately, Vismodegib has shown to cause irreversible premature epiphyseal growth plate fusions in preclinical studies and clinical trials, preventing its systemic application in children (Kimura et al. 2008; Robinson et al. 2017). We established an intraventricular therapy with Vismodegib, combining the benefits of targeted drug delivery and minimizing systemic side effects. In a mouse model for SHH medulloblastoma, we compare intraventricular, oral and placebo treatment regarding effects on survival, tumor biology, and bone morphology. Math1-cre::Ptch1 Fl/Fl mice show a homozygous loss of PTCH1 in Math1-positive cells, resulting in SHH-pathway overactivation and development of SHH medulloblastomas. At postnatal day 11-13, Math1-cre::Ptch1 Fl/Fl mice were randomized in four treatment arms: group A (n= 9) received placebo intrathecally, B (n= 9) received Vismodegib 200 mg/kd/d orally, C (n= 19) received Vismodegib 0.2 mg/kg/d intrathecally, and D (n= 8) received Vismodegib 1.6 mg/kg/d intrathecally. Kaplan-Meier survival analysis showed a significant survival benefit for 1.6 mg/kg/d intraventricular Vismodegib compared to placebo (p= 0.012). Bone histology and X-ray analysis of intraventricular treated mice showed intact femoral and tibial growth plates, in contrast to orally treated mice that developed skeletal malformations. Further analyses such as DNA sequencing, gene expression analysis, and histological evaluation are ongoing and will add to the picture of the anti-tumor effects of intraventricular SHH-inhibition. Based on the preliminary experimental results, we conclude that intrathecal application of a SMO-inhibitor might evolve as a promising new way of targeted treatment of SHH medulloblastomas.