Table 1.

Preclinical evidence supporting the role of hedgehog pathway targets in medulloblastoma tumorigenesis

Hh Pathway Target	Effects of Activated Hh Signaling	Suspected Role in MB Tumorigenesis	Effects of Targeted Inhibition
MYCN60,61	Increased expression in CGNPs	Induces miR-17/92 expression in CGNPs, promoting their proliferation	Anti–miR-17 and -19 reduced growth of MB tumor allografts (flank and brain) and prolonged survival in mice with intracranial transplants113
Snail162	Increased expression in GCPs, mouse MB models, and human MB-derived cell lines	Induces cell proliferation and transformation through induction of MYCN transcription
CXCR453,72	Induces cell surface localization and effector signaling in MB cells	Causes progrowth transcriptional response (increased expression of Math1/Atoh1 and cyclin D1) and increased tumor growth	CXCR4-specific antagonists, AMD3100 and AMD3465, inhibited growth of MB tumor xenografts
Sox264	Increased expression in CGNPs and Sox2-positive MB in mouse models	Overexpression leads to proliferation	Deletion of Sox2 in primary CGNP cultures with constitutive SHH signaling led to decreased proliferation
Sox965	Increased expression in SHH MB	Activation during embryogenesis leads to SHH-dependent MB; suppression during postnatal development promotes SHH-independent MB
ASPM66	Increased expression in CGNPs	Sustains the progenitor phenotype of CGNPs	ASPM knock-out led to decreased proliferative capacity and self-renewal
Bmi169–71	Drives expression in BTICs	Contributes to SHH-mediated expansion of GCPs through direct regulation of the cyclin-dependent kinase inhibitor p21 Waf1/Cip1 and modulation of other cell cycle inhibitors and TGFβ pathway targets; positive feedback loop between Bmi1 and SHH in BTICs; may regulate the SHH pathway through transcriptional silencing of the E3 ubiquitin ligase Cullin3
Bcl267,68	Increased expression	Increases proliferation and decreases apoptosis of SHH-induced MB
Lipids73	Lipid accumulation, increased lipogenic enzyme expression, and suppression of fatty acid oxidation		Fatty acid synthase-specific inhibitor C75 inhibited MB cell proliferation, promoted MB cell death, and prolonged survival in MB-bearing mice
PPARγ74	Increased expression in MB cells	Induces glycolysis	PPARγ-specific inhibitor, GW9662, blocked CGNP proliferation, drove MB cell death, and prolonged survival of mice with MBs (NeuroD2-SmoA1)

Abbreviations: ASPM, abnormal spindle-like microencephaly-associated; Atoh1, atonal homolog 1; BTIC, brain tumor initiating cell; CGNP, cerebellar granule neuron progenitor; GCP, granule cell progenitor; MB, medulloblastoma; MYCN, v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog; PPARγ, peroxisome proliferator-activated receptor gamma; SHH, sonic hedgehog; Sox, sex determining region Y; TFGβ, transforming growth factor beta.