Medulloblastoma growth inhibition by hedgehog pathway blockade.
Constitutive Hedgehog (Hh) pathway activity is associated with initiation of neoplasia, but its role in the continued growth of established tumors is unclear. Here, we investigate the therapeutic efficacy of the Hh pathway antagonist cyclopamine in preclinical models of medulloblastoma, the most common malignant brain tumor in children. Cyclopamine treatment of murine medulloblastoma cells blocked proliferation in vitro and induced changes in gene expression consistent with initiation of neuronal differentiation and loss of neuronal stem cell-like character. This compound also caused regression of murine tumor allografts in vivo and induced rapid death of cells from freshly resected human medulloblastomas, but not from other brain tumors, thus establishing a specific role for Hh pathway activity in medulloblastoma growth.
Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
David M
DM
Berman
Sunil S
SS
Karhadkar
Andrew R
AR
Hallahan
Joel I
JI
Pritchard
Charles G
CG
Eberhart
D Neil
DN
Watkins
James K
JK
Chen
Michael K
MK
Cooper
Jussi
J
Taipale
James M
JM
Olson
Philip A
PA
Beachy
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001640:Bicuculline / Q000627:therapeutic use*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002528:Cerebellar Neoplasms / Q000188:drug therapy*; D004195:Disease Models, Animal; D053823:Hedgehog Proteins; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy*; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D000072079:Patched Receptors; D011956:Receptors, Cell Surface; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D053823:Hedgehog Proteins; D008565:Membrane Proteins; D000072079:Patched Receptors; D011956:Receptors, Cell Surface; D015534:Trans-Activators; D001640:Bicuculline