Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1(+/-)p53(-/-) mice

Cancer Cell. 2004 Sep;6(3):229-40. doi: 10.1016/j.ccr.2004.08.019.


Medulloblastoma is the most common malignant pediatric brain tumor. Current treatment is associated with major long-term side effects; therefore, new nontoxic therapies, targeting specific molecular defects in this cancer, need to be developed. We use a mouse model of medulloblastoma to show that inhibition of the Sonic Hedgehog (Shh) pathway provides a novel therapy for medulloblastoma. A small molecule inhibitor of the Shh pathway, HhAntag, blocked the function of Smoothened in mice with medulloblastoma. This resulted in suppression of several genes highly expressed in medulloblastoma, inhibition of cell proliferation, increase in cell death and, at the highest dose, complete eradication of tumors. Long-term treatment with HhAntag prolonged medulloblastoma-free survival. These findings support the development of Shh antagonists for the treatment of medulloblastoma.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / pathology
  • Cell Division
  • Disease-Free Survival
  • Dose-Response Relationship, Drug
  • Hedgehog Proteins
  • Kruppel-Like Transcription Factors
  • Medulloblastoma / drug therapy
  • Medulloblastoma / metabolism*
  • Medulloblastoma / pathology
  • Mice
  • Mice, Transgenic
  • Receptors, G-Protein-Coupled / metabolism
  • Signal Transduction
  • Smoothened Receptor
  • Trans-Activators / antagonists & inhibitors*
  • Transcription Factors / metabolism
  • Tumor Cells, Cultured
  • Zinc Finger Protein GLI1


  • Gli1 protein, mouse
  • Hedgehog Proteins
  • Kruppel-Like Transcription Factors
  • Receptors, G-Protein-Coupled
  • Shh protein, mouse
  • Smo protein, mouse
  • Smoothened Receptor
  • Trans-Activators
  • Transcription Factors
  • Zinc Finger Protein GLI1