MODL-03. Establishment of intraventricular Shh inhibition as a therapeutic option for young patients with medulloblastoma

The prognosis of pediatric medulloblastoma is still dissatisfying today and tumor survivors often suffer from severe treatment-related morbidities. This poses an urgent need for more efficient therapies. Shh medulloblastoma is characterized by mutations in the Sonic Hedgehog (Shh) pathway, providing an elegant way of targeted therapy. The small molecule Vismodegib allosterically inhibits Smoothened (SMO), an upstream activator of Shh, and shows promising anti-tumor effects against Shh medulloblastoma. Unfortunately, Vismodegib caused severe bone deformities in preclinical studies and clinical trials, preventing its systemic application in children. In a mouse model, we established an intraventricular therapy with Vismodegib combining the benefits of targeted drug delivery and minimal systemic side effects. We compare intraventricular, oral, and placebo treatment regarding effects on survival, tumor biology, and bone morphology.Math1-cre::Ptch(1Fl/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=14) received intraventricular placebo, B (n=12) received 200 mg/kd/d oral Vismodegib, C (n=16) received 0.2 mg/kg/d intraventricular Vismodegib, and D (n=9) received 1.6 mg/kg/d intraventricular Vismodegib. Kaplan-Meier survival curves show a significant survival benefit of 1.6 mg/kg/d intraventricular Vismodegib over placebo (p=0.003). While all intraventricular treated animals develop proliferative tumors at end of observation, investigations at an early time point after completed treatment show promising anti-tumor effects with reduced or absent proliferation in the cerebellum compared to placebo. Bone histology and X-ray analysis of intraventricular treated mice show intact femoral and tibial growth plates, in contrast to orally treated mice that develop severe skeletal malformations. Based on these preliminary experimental results, we conclude that intraventricular application of a SMO-inhibitor might evolve as a promising new way of targeted treatment of Shh medulloblastoma in children.