Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449.
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.
Rudin
Charles M
CM
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21231, USA. rudin@jhmi.edu
Hann
Christine L
CL
Laterra
John
J
Yauch
Robert L
RL
Callahan
Christopher A
CA
Fu
Ling
L
Holcomb
Thomas
T
Stinson
Jeremy
J
Gould
Stephen E
SE
Coleman
Barbara
B
LoRusso
Patricia M
PM
Von Hoff
Daniel D
DD
de Sauvage
Frederic J
FJ
Low
Jennifer A
JA
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
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