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Science 297 (5586): 1559-1561

Copyright © 2002 by the American Association for the Advancement of Science

Medulloblastoma Growth Inhibition by Hedgehog Pathway Blockade

David M. Berman,125* Sunil S. Karhadkar,125* Andrew R. Hallahan,67 Joel I. Pritchard,7 Charles G. Eberhart,2 D. Neil Watkins,4 James K. Chen,15 Michael K. Cooper,135 Jussi Taipale,15 James M. Olson,67dagger Philip A. Beachy15dagger

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.

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.

dagger    To whom correspondence should be addressed. E-mail: jolson{at} (J.M.O.) and pbeachy{at} (P.A.B.)

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The SmoA1 Mouse Model Reveals That Notch Signaling Is Critical for the Growth and Survival of Sonic Hedgehog-Induced Medulloblastomas.
A. R. Hallahan, J. I. Pritchard, S. Hansen, M. Benson, J. Stoeck, B. A. Hatton, T. L. Russell, R. G. Ellenbogen, I. D. Bernstein, P. A. Beachy, et al. (2004)
Cancer Res. 64, 7794-7800
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Inhibition of Smoothened Signaling Prevents Ultraviolet B-Induced Basal Cell Carcinomas through Regulation of Fas Expression and Apoptosis.
M. Athar, C. Li, X. Tang, S. Chi, X. Zhang, A. L. Kim, S. K. Tyring, L. Kopelovich, J. Hebert, E. H. Epstein Jr., et al. (2004)
Cancer Res. 64, 7545-7552
   Abstract »    Full Text »    PDF »
The Upregulated Expression of Sonic Hedgehog in Motor Neurons after Rat Facial Nerve Axotomy.
C. Akazawa, H. Tsuzuki, Y. Nakamura, Y. Sasaki, K. Ohsaki, S. Nakamura, Y. Arakawa, and S. Kohsaka (2004)
J. Neurosci. 24, 7923-7930
   Abstract »    Full Text »    PDF »
Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling.
P. Sanchez, A. M. Hernandez, B. Stecca, A. J. Kahler, A. M. DeGueme, A. Barrett, M. Beyna, M. W. Datta, S. Datta, and A. Ruiz i Altaba (2004)
PNAS 101, 12561-12566
   Abstract »    Full Text »    PDF »
Indian hedgehog gene transfer augments hematopoietic support of human stromal cells including NOD/SCID-{beta}2m-/- repopulating cells..
M. Kobune, Y. Ito, Y. Kawano, K. Sasaki, H. Uchida, K. Nakamura, H. Dehari, H. Chiba, R. Takimoto, T. Matsunaga, et al. (2004)
Blood 104, 1002-1009
   Abstract »    Full Text »    PDF »
RENKCTD11 is a suppressor of Hedgehog signaling and is deleted in human medulloblastoma.
L. Di Marcotullio, E. Ferretti, E. De Smaele, B. Argenti, C. Mincione, F. Zazzeroni, R. Gallo, L. Masuelli, M. Napolitano, M. Maroder, et al. (2004)
PNAS 101, 10833-10838
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Molecular Profiles of Neurofibromatosis Type 1-Associated Plexiform Neurofibromas: Identification of a Gene Expression Signature of Poor Prognosis.
P. Levy, I. Bieche, K. Leroy, B. Parfait, J. Wechsler, I. Laurendeau, P. Wolkenstein, M. Vidaud, and D. Vidaud (2004)
Clin. Cancer Res. 10, 3763-3771
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Abnormalities of the vitreoretinal interface caused by dysregulated Hedgehog signaling during retinal development.
G. C.M. Black, C. J. Mazerolle, Y. Wang, K. D. Campsall, D. Petrin, B. C. Leonard, K. F. Damji, D. G. Evans, D. McLeod, and V. A. Wallace (2003)
Hum. Mol. Genet. 12, 3269-3276
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Hemangiosarcomas, Medulloblastomas, and Other Tumors in Ink4c/p53-null Mice.
F. Zindy, L. M. Nilsson, L. Nguyen, C. Meunier, R. J. Smeyne, J. E. Rehg, C. Eberhart, C. J. Sherr, and M. F. Roussel (2003)
Cancer Res. 63, 5420-5427
   Abstract »    Full Text »    PDF »
Smoothened translates Hedgehog levels into distinct responses.
J. E. Hooper (2003)
Development 130, 3951-3963
   Abstract »    Full Text »    PDF »
DEVELOPMENT: Longing for Ligand: Hedgehog, Patched, and Cell Death.
I. Guerrero and A. Ruiz i Altaba (2003)
Science 301, 774-776
   Abstract »    Full Text »    PDF »
Sonic hedgehog.
H S Heussler and M Suri (2003)
Mol. Pathol. 56, 129-131
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Inhibition of Epithelial Ductal Branching in the Prostate by Sonic Hedgehog Is Indirectly Mediated by Stromal Cells.
B.-e. Wang, J. Shou, S. Ross, H. Koeppen, F. J. de Sauvage, and W.-Q. Gao (2003)
J. Biol. Chem. 278, 18506-18513
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Identification of a small molecule inhibitor of the hedgehog signaling pathway: Effects on basal cell carcinoma-like lesions.
J. A. Williams, O. M. Guicherit, B. I. Zaharian, Y. Xu, L. Chai, H. Wichterle, C. Kon, C. Gatchalian, J. A. Porter, L. L. Rubin, et al. (2003)
PNAS 100, 4616-4621
   Abstract »    Full Text »    PDF »
How a Hedgehog might see holoprosencephaly.
E. Roessler and M. Muenke (2003)
Hum. Mol. Genet. 12, R15-25
   Abstract »    Full Text »    PDF »

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