Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449

N Engl J Med. 2009 Sep 17;361(12):1173-8. doi: 10.1056/NEJMoa0902903. Epub 2009 Sep 2.

Abstract

Medulloblastoma is the most common malignant brain tumor in children. Aberrant activation of the hedgehog signaling pathway is strongly implicated in the development of some cases of medulloblastoma. A 26-year-old man with metastatic medulloblastoma that was refractory to multiple therapies was treated with a novel hedgehog pathway inhibitor, GDC-0449; treatment resulted in rapid (although transient) regression of the tumor and reduction of symptoms. Molecular analyses of tumor specimens obtained before treatment suggested that there was activation of the hedgehog pathway, with loss of heterozygosity and somatic mutation of the gene encoding patched homologue 1 (PTCH1), a key negative regulator of hedgehog signaling.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anilides
  • Antineoplastic Agents / therapeutic use*
  • Benzimidazoles / therapeutic use*
  • Cerebellar Neoplasms / drug therapy*
  • Cerebellar Neoplasms / metabolism
  • Cerebellar Neoplasms / pathology
  • Gene Expression
  • Hedgehog Proteins / antagonists & inhibitors*
  • Humans
  • Male
  • Medulloblastoma / drug therapy*
  • Medulloblastoma / metabolism
  • Medulloblastoma / secondary
  • Patched Receptors
  • Patched-1 Receptor
  • Polymerase Chain Reaction
  • Pyridines
  • RNA, Messenger / metabolism
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism
  • Signal Transduction / drug effects
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Zinc Finger Protein GLI1

Substances

  • Anilides
  • Antineoplastic Agents
  • Benzimidazoles
  • GLI1 protein, human
  • Hedgehog Proteins
  • HhAntag691
  • PTCH protein, human
  • Patched Receptors
  • Patched-1 Receptor
  • Pyridines
  • RNA, Messenger
  • Receptors, Cell Surface
  • Transcription Factors
  • Zinc Finger Protein GLI1