title: Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449.
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.
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21231, USA. rudin@jhmi.edu
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rudin
authors.forename: Christine L
authors.initials: CL
authors.lastname: Hann
authors.forename: John
authors.initials: J
authors.lastname: Laterra
authors.forename: Robert L
authors.initials: RL
authors.lastname: Yauch
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Callahan
authors.forename: Ling
authors.initials: L
authors.lastname: Fu
authors.forename: Thomas
authors.initials: T
authors.lastname: Holcomb
authors.forename: Jeremy
authors.initials: J
authors.lastname: Stinson
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Gould
authors.forename: Barbara
authors.initials: B
authors.lastname: Coleman
authors.forename: Patricia M
authors.initials: PM
authors.lastname: LoRusso
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Von Hoff
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: de Sauvage
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Low
mesh_terms: D000328:Adult; D000813:Anilides; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000627:therapeutic use*; D002528:Cerebellar Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D008527:Medulloblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D016133:Polymerase Chain Reaction; D011725:Pyridines; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000071676:Zinc Finger Protein GLI1
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D001562:Benzimidazoles; C400551:GLI1 protein, human; D053823:Hedgehog Proteins; C538724:HhAntag691; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011725:Pyridines; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1