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Medulloblastoma Growth Inhibition by Hedgehog Pathway Blockade
David M. Berman,125*Sunil S. Karhadkar,125*Andrew R. Hallahan,67Joel I. Pritchard,7Charles G. Eberhart,2D. Neil Watkins,4James K. Chen,15Michael K. Cooper,135Jussi Taipale,15James M. Olson,67Philip A. Beachy15
Constitutive Hedgehog (Hh) pathway activity is
associated with initiation of neoplasia, but its role in the continued
growthof established tumors is unclear. Here, we investigate the
therapeuticefficacy of the Hh pathway antagonist cyclopamine in
preclinicalmodels of medulloblastoma, the most common malignant brain
tumorin children. Cyclopamine treatment of murine medulloblastoma
cellsblocked proliferation in vitro and induced changes in gene
expressionconsistent with initiation of neuronal differentiation and
lossof neuronal stem cell-like character. This compound also causedregression of murine tumor allografts in vivo and induced rapiddeath
of cells from freshly resected human medulloblastomas, butnot from
other brain tumors, thus establishing a specific rolefor Hh pathway
activity in medulloblastoma growth.
Departments of 1 Molecular Biology and Genetics,
2 Pathology, 3 Neurology, 4 Oncology,
and 5 Howard Hughes Medical Institute, Johns Hopkins
University School of Medicine, Baltimore, MD 21205, USA.
6 Clinical Research Division, Fred Hutchinson Cancer
Research Center, and 7 Division of Pediatric Oncology,
University of Washington/Children's Hospital, Seattle WA 98105, USA.
*
These authors contributed equally to this work.
To whom correspondence should be addressed.
E-mail: jolson{at}fhcrc.org (J.M.O.) and
pbeachy{at}jhmi.edu (P.A.B.)
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