Targeting Children’s Brain Tumors: Development of Hedgehog Pathway Inhibitors for Medulloblastoma

Abstract

Hedgehog (Hh) is a secreted protein family that controls proliferation, differentiation, cell fate specification, left-right asymmetry and morphogenesis during development. The Hh pathway is extremely complex and mutations in various components result in developmental abnormalities as well as increased tumor incidence, including medulloblastoma, in mice and humans. Loss of one copy of Patched 1 (Ptch1), a receptor for Hh, causes increased activity of Smoothened (Smo) and elevated expression of the transcription factor Gli1 in both familial and sporadic medulloblastoma. Fifteen years ago, we embarked on a long-term program to develop new therapeutic approaches for this devastating childhood brain tumor. Small molecule inhibitors of the Hh pathway, both naturally occurring and chemically synthesized, inhibit Smo activity and provide potential novel therapeutic agents. We generated a genetically engineered mouse meduloblastoma model, Ptch1(+/-)p53(-/-) mice, that exhibits a 100% incidence of medulloblastoma. Using these mice, we tested the effect of a Smo inhibitor (HhAntag), isolated by Curis Inc., on the growth of spontaneous medulloblastoma. We found that twice daily dosing, by oral gavage, effectively eliminated even large tumor masses in the cerebellum of mice 3 to 10 weeks of age. These findings led to Phase I clinical trials of a Smo inhibitor in pediatric and adult medulloblastoma.