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Survivin as a therapeutic target in Sonic hedgehog-driven medulloblastoma.

Publication ,  Journal Article
Brun, SN; Markant, SL; Esparza, LA; Garcia, G; Terry, D; Huang, J-M; Pavlyukov, MS; Li, X-N; Grant, GA; Crawford, JR; Levy, ML; Conway, EM ...
Published in: Oncogene
July 2015

Medulloblastoma (MB) is a highly malignant brain tumor that occurs primarily in children. Although surgery, radiation and high-dose chemotherapy have led to increased survival, many MB patients still die from their disease, and patients who survive suffer severe long-term side effects as a consequence of treatment. Thus, more effective and less toxic therapies for MB are critically important. Development of such therapies depends in part on identification of genes that are necessary for growth and survival of tumor cells. Survivin is an inhibitor of apoptosis protein that regulates cell cycle progression and resistance to apoptosis, is frequently expressed in human MB and when expressed at high levels predicts poor clinical outcome. Therefore, we hypothesized that Survivin may have a critical role in growth and survival of MB cells and that targeting it may enhance MB therapy. Here we show that Survivin is overexpressed in tumors from patched (Ptch) mutant mice, a model of Sonic hedgehog (SHH)-driven MB. Genetic deletion of survivin in Ptch mutant tumor cells significantly inhibits proliferation and causes cell cycle arrest. Treatment with small-molecule antagonists of Survivin impairs proliferation and survival of both murine and human MB cells. Finally, Survivin antagonists impede growth of MB cells in vivo. These studies highlight the importance of Survivin in SHH-driven MB, and suggest that it may represent a novel therapeutic target in patients with this disease.

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Published In

Oncogene

DOI

EISSN

1476-5594

Publication Date

July 2015

Volume

34

Issue

29

Start / End Page

3770 / 3779

Location

England

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Cells, Cultured
  • Survivin
  • Repressor Proteins
  • Pyridines
  • Oncology & Carcinogenesis
  • Naphthoquinones
  • Microscopy, Confocal
  • Mice, SCID
  • Mice, Nude
 

Citation

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Brun, S. N., Markant, S. L., Esparza, L. A., Garcia, G., Terry, D., Huang, J.-M., … Wechsler-Reya, R. J. (2015). Survivin as a therapeutic target in Sonic hedgehog-driven medulloblastoma. Oncogene, 34(29), 3770–3779. https://doi.org/10.1038/onc.2014.304
Brun, S. N., S. L. Markant, L. A. Esparza, G. Garcia, D. Terry, J. -. M. Huang, M. S. Pavlyukov, et al. “Survivin as a therapeutic target in Sonic hedgehog-driven medulloblastoma.Oncogene 34, no. 29 (July 2015): 3770–79. https://doi.org/10.1038/onc.2014.304.
Brun SN, Markant SL, Esparza LA, Garcia G, Terry D, Huang J-M, et al. Survivin as a therapeutic target in Sonic hedgehog-driven medulloblastoma. Oncogene. 2015 Jul;34(29):3770–9.
Brun, S. N., et al. “Survivin as a therapeutic target in Sonic hedgehog-driven medulloblastoma.Oncogene, vol. 34, no. 29, July 2015, pp. 3770–79. Pubmed, doi:10.1038/onc.2014.304.
Brun SN, Markant SL, Esparza LA, Garcia G, Terry D, Huang J-M, Pavlyukov MS, Li X-N, Grant GA, Crawford JR, Levy ML, Conway EM, Smith LH, Nakano I, Berezov A, Greene MI, Wang Q, Wechsler-Reya RJ. Survivin as a therapeutic target in Sonic hedgehog-driven medulloblastoma. Oncogene. 2015 Jul;34(29):3770–3779.

Published In

Oncogene

DOI

EISSN

1476-5594

Publication Date

July 2015

Volume

34

Issue

29

Start / End Page

3770 / 3779

Location

England

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Cells, Cultured
  • Survivin
  • Repressor Proteins
  • Pyridines
  • Oncology & Carcinogenesis
  • Naphthoquinones
  • Microscopy, Confocal
  • Mice, SCID
  • Mice, Nude