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Survivin as a therapeutic target in Sonic hedgehog-driven medulloblastoma

Oncogene volume 34, pages 3770–3779 (2015)Cite this article

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Abstract

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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Acknowledgements

We appreciate the support of the Sanford-Burnham Shared Resources, including Amy Cortez, Jonna Hurtado and Yoav Altman (Flow Cytometry); Robbin Newlin (Histopathology); Danielle McAnally, Michael Vicchiarelli and Arianna Mangravita-Novo (Chemical Genomics); Lili Lacarra, Adriana Charbono and Kenny Venegas (Animal facility); and Anthony Pinkerton and members of the Medicinal Chemistry Resource for generation of S12 and LLP3. We are also grateful to Ana Miletic-Sedy and Robert Rickert for sharing Survivinfl/fl mice; and to Robert Margolis for helpful discussions. We thank the Flanders Institute for Biotechnology (VIB), Belgium, for allowing us to use the Survivinfl/fl mice. EMC is supported by grants from the Canadian Institutes for Health Research (CIHR), the Natural Sciences and Engineering Research Council of Canada (NSERC). He holds a Tier 1 Canada Research Chair (CRC) in Endothelial Cell Biology. MIG is supported by Grant 5R01CA08948. This work was supported by NCI award number 5P30CA030199 and R01 CA122759 and by the Cedars-Sinai/Sanford-Burnham Grant Program for Cancer Research. RWR is the recipient of a Research Leadership Award from the California Institute for Regenerative Medicine (CIRM LA1-01747).

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Authors and Affiliations

  1. Tumor Initiation and Maintenance Program, National Cancer Institute (NCI)–Designated Cancer Center, Sanford-Burnham Medical Research Institute (SBMRI), La Jolla, CA, USA

    S N Brun, S L Markant, L A Esparza & R J Wechsler-Reya

  2. Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA

    S N Brun, S L Markant, L A Esparza & R J Wechsler-Reya

  3. Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA

    S N Brun, S L Markant & R J Wechsler-Reya

  4. Histopathology Core SBMRI, La Jolla, CA, USA

    G Garcia

  5. Conrad Prebys Center for Chemical Genomics, SBMRI, Lake Nona, FL, USA

    D Terry & L H Smith

  6. Cedars-Sinai Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA

    J-M Huang & Q Wang

  7. Department of Neurological Surgery, The Ohio State University, Columbus, OH, USA

    M S Pavlyukov & I Nakano

  8. James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA

    M S Pavlyukov & I Nakano

  9. and Department of Pediatrics, Brain Tumor Program, Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX, USA

    X-N Li

  10. Department of Neurosurgery, Stanford University/Lucile Packard Children's Hospital, Stanford, CA, USA

    G A Grant

  11. Department of Pediatrics, University of California San Diego, San Diego, CA, USA

    J R Crawford

  12. Departments of Neurosciences, University of California San Diego, San Diego, CA, USA

    J R Crawford

  13. Rady Children's Hospital, San Diego, CA, USA

    J R Crawford & M L Levy

  14. Department of Neurosurgery, University of California San Diego, La Jolla, CA, USA

    M L Levy

  15. Division of Hematology, Department of Medicine, Centre for Blood Research, University of British Columbia (UBC), Vancouver, BC, Canada

    E M Conway

  16. Cardiopathobiology Program, Sanford Burnham Medical Research Institute, Lake Nona, FL, USA

    L H Smith

  17. Department of Biomedical Sciences at Cedars-Sinai Medical Center, Los Angeles, CA, USA

    A Berezov

  18. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA

    M I Greene

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Brun, S., Markant, S., Esparza, L. et al. Survivin as a therapeutic target in Sonic hedgehog-driven medulloblastoma. Oncogene 34, 3770–3779 (2015). https://doi.org/10.1038/onc.2014.304

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