Therapeutic Targeting of Developmental Signaling Pathways in Medulloblastoma: Hedgehog, Notch, Wnt and Myc

Abstract

During development of the cerebellum, a large number of molecular factors interact to produce an intricate brain structure. Many of these developmentally significant genes are members of signaling cascades implicated in the formation and growth of the embryonal brain tumor medulloblastoma. Genes controlling critical developmental pathways such as Hedgehog, Notch, Wnt, and Myc are known to be overexpressed and/or genetically altered in subsets of medulloblastoma. These pathways are also linked by their ability to induce or maintain stem-cell phenotypes in normal development. Their over-activation in tumors can lead to proliferation, invasion, altered metabolism, and evasion of treatment-induced cell death. The importance of these signaling cascades in medulloblastoma cells makes them attractive targets for therapeutic intervention. The development of therapeutic agents targeting these pathways may lead to improvement in patient survival and a reduction in the intensity of highly morbid radiation and chemotherapy that patients currently receive. In this review, we discuss a number of approaches to targeting these pathways in medulloblastoma. Keywords: Non-genotoxic therapy, primitive neuroectodermal tumor, gamma secretase, tankyrase, glutamine, cyclopamine, itraconazole