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. 2013 Dec 4;16(1):9–20. doi: 10.1093/neuonc/not147

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

3537,40
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.