Table 1.

Preclinical evidence for inhibition of key signaling pathways implicated in medulloblastoma

Signaling Pathway	Neoplastic Effects in MB	Inhibitor (target)	Preclinical Effects of Signaling Inhibition in MB	References
Hedgehog/SMO	Maintenance of MB tumor growth in vitro Overexpressed in group 2 MB tumors	HhAntag (SMO); GDC-0449 (SMO); LDE225 (SMO); IPI-926 (SMO); PF-5274857 (SMO)	Significant tumor growth reduction and increased survival in MB mouse models	5,24-29
WNT/β-catenin/PARP	Wnt/β-catenin expression associated with classical MB and favorable prognosis Increased PARP in MB is associated with poor prognosis Role in tumor growth and survival in vitro	Rucaparib (PARP)	Enhanced TMZ-induced tumor growth delay in MB xenografts	35–37,40
PI3K/AKT/mTOR	Involved in functions such as cell growth, motility, survival, and angiogenesis Several isoforms (including p110α and p110γ) are overexpressed in MB cell lines and in tumors from patients with MB Increased PI3K/mTOR signaling in a mouse model of MB displaying resistance to SMO inhibitors	LY294002 (PI3K);	Significantly reduced growth of MB cell lines	46
		YM024 (PI3K p110α); PIK-75 (PI3K p110α);	Reduced cell proliferation and sensitized MB cells to chemotherapy	43
		AS-252424 (PI3K p110γ)	Slowed proliferation of several MB cell lines and enhanced cisplatin cytotoxicity	44
mTOR	ERK- and PI3K-dependent mTOR activity upregulated in MB	BEZ235 (PI3K-mTOR); BKM120 (PI3K); RAD001 (mTOR);	Inhibited MB cell proliferation, clonogenicity, and tumor growth in vitro Significantly delayed SMO-mediated resistance in vivo	27,51,54
		Sorafenib (multitargeted inhibitor of mTOR) + valproate or vorinostat (HDAC inhibitors);	Induced MB cell apoptosis and enhanced radiation-induced apoptosis	107
		Rapamycin (mTOR); PP242 (mTORC1/2);	Suppressed MB cell proliferation and fibronectin-stimulated MB cell migration	108
		OSU-03012 (PDK1) alone or in combination with temsirolimus (mTOR);	OSU-03012 alone induced apoptosis and enhanced chemotherapy-induced cytotoxicity OSU-03012 + temsirolimus slowed growth of MB tumors	109
		OSU-03012 (PDK1) ± LY294002 (PI3K)	Reduced c-MYC and CCND1 in a β-catenin–dependent manner	109
RAS/MEK/ERK	Upregulated in patient MBs ERK upregulation associated with favorable prognosis	U0126 (MEK)	Inhibited PDGFA/MEK-induced cell migration Reduced PAK1 activation and MB cell migration	60, 61
PDGFR	Upregulated in tumors from patients with metastatic MB	Imatinib (PDGFR);	Inhibited ERK and AKT signaling, cell proliferation, survival, migration and invasion, and blocked EGFR transactivation by PDGF-BB	110
		Sunitinib (PDGFR);	Inhibited PDGF/PDGFR-mediated MB cell migration Sunitinib pretreatment reduced cell migration but not cell survival	111
		Tandutinib (PDGFRA)	Induced MB cell apoptosis in vitro and slowed Shh-dependent tumor growth in vivo	112
IGF-1R	Upregulated in tumors resistant to SMO antagonists	NVP-ADW742 (IGF-1R) + TMZ	Induced apoptosis and cell-cycle arrest	113
EGFR/HER2	HER2/neu overexpression in human MBs correlates with poor patient survival	AEE788 (HER1/2 and VEGFR1/2);	Inhibited MB cell proliferation in vitro and MB tumor growth in vitro (in both chemosensitive and chemoresistant models of MB)	114
		Gefitinib (EGFR)	Induced cell-cycle arrest of MB cell lines and primary MB cells in vitro and inhibited MB tumor growth in vivo	115
VEGF/VEGFR	Overexpressed in MB cell lines and in human MBs	Commercially available inhibitor VEGF V1 (VEGF-dependent angiogenesis via NRP-1 inhibition)	Treatment with a VEGFR2 inhibitor reduced VEGF-dependent MB cell proliferation in vitro	116
p53/PPM1D/HDM2	PPM1D is overexpressed in human MBs PPM1D expression enhances proliferation and decreases survival in MB xenograft models HDM2 promotes PPM1D-mediated growth of MB cells	Nutlin-3a (HDM2); CCT007093 (PPM1D)	Nutlin-3a treatment inhibits growth of MB cells with increased PPM1D expression CCT007093 treatment reduces HDM2 expression and growth of MB cells with high expression of PPM1D Combined inhibition of HDM2 and PPM1D more effectively blocks growth of MB cells	71
Notch	Overexpressed in human MBs	γ-secretase inhibitor (Notch)	Stimulated cell-cycle exit, apoptosis of stem-like cells, and neuronal differentiation of MB cells in vitro	74,75
COX-2	Expression is elevated in CD133-positive versus CD133-negative MB cells	Celecoxib (COX-2)	Inhibited CD133-positive MB cellular proliferation and colony formation; enhanced ionizing radiotherapy-induced apoptosis Reduced expression of angiogenesis- and stemness-related genes in vivo	82,83

Abbreviations: CCND1, cyclin D1; COX-2, cyclooxygenase-2; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; HDAC, histone deacetylase; HDM2/4, p53 E3 ubiquitin protein ligase (human homologue of MDM2/4); HER2, human epidermal growth factor receptor 2; IGF-1R, insulin-like growth factor 1 receptor; MB, medulloblastoma; MEK, mitogen-activated protein kinase kinase; mTOR, mammalian target of rapamycin; NRP-1, neuropilin-1; PAK1, p21-activated kinase 1; PARP, poly(ADP-ribose) polymerase; PDGFR, platelet-derived growth factor receptor; PDK1, phosphoinositide-dependent kinase 1; PI3K, phosphoinositide 3-kinase; PPM1D, p53-induced protein phosphatase, Mg2+/Mn2+ dependent, 1D; SMO, smoothened; TMZ, temozolomide; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.