Abstract
Medulloblastoma (MB), a primitive neuroectomal tumor of the cerebellum, is the most common malignant pediatric brain tumor. The cause of MB is largely unknown, but aberrant activation of Hedgehog (Hh) pathway is responsible for ~30% of MB. Despite aggressive treatment with surgical resection, radiation and chemotherapy, 70%–80% of pediatric medulloblastoma cases can be controlled, but most treated patients suffer devastating side effects. Therefore, developing a new effective treatment strategy is urgently needed. Hh signaling controls transcription of target genes by regulating activities of the three Glioma-associated oncogene (Gli1-3) transcription factors. In this review, we will focus on current clinical treatment options of MB and discuss mechanisms of drug resistance. In addition, we will describe current known molecular pathways which crosstalk with the Hedgehog pathway both in the context of medulloblastoma and non-medulloblastoma cancer development. Finally, we will introduce post-translational modifications that modulate Gli1 activity and summarize the positive and negative regulations of the Hh/Gli1 pathway. Towards developing novel combination therapies for medulloblastoma treatment, current information on interacting pathways and direct regulation of Hh signaling should prove critical.
Highlights
Medulloblastoma (MB) is a rapidly-growing, highly invasive tumor arising from embryonal cells in the cerebellum
Towards exploring new venues of drug development for Sonic hedgehog (SHH) signaling, this review will describe limitations with current therapies, pathways interacting with SHH signaling in MB, as well as pathways interacting with SHH in other cancer types
At the activation of Hh signaling, Hh morphogens bind to the 12 pass-transmembrane receptor, PATCH (PTCH1) which is localized to the base of primary cilium, releasing its inhibition of Smoothened (SMO), a protein responsible for activating the downstream Hh pathway
Summary
Medulloblastoma (MB) is a rapidly-growing, highly invasive tumor arising from embryonal cells in the cerebellum It is the most common malignant brain tumor in pediatric patients, accounting for about 20% of all brain tumors in children [1,2]. WNT-MBs demonstrate the best survival outcome, with 95% 5- and 10-year overall survival in children and 100% five-year in adults, while Group 3 and Group 4 demonstrate the worst survival outcome, and this may be correlated with the higher frequency of 17p chromosome loss in these groups [10,11] Out of these four, SHH-MBs are most common in infants and in adults, and small molecular inhibitors have been developed targeting SHH signaling [12]. The review will discuss points of direct regulation of SHH signaling by different kinases and provide critical insight for drug-resistant in MB treatments
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