1. Survivin as a therapeutic target in Sonic hedgehog-driven medulloblastoma.
- Author
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Brun SN, Markant SL, Esparza LA, Garcia G, Terry D, Huang JM, Pavlyukov MS, Li XN, Grant GA, Crawford JR, Levy ML, Conway EM, Smith LH, Nakano I, Berezov A, Greene MI, Wang Q, and Wechsler-Reya RJ
- Subjects
- Animals, Apoptosis drug effects, Apoptosis radiation effects, Biphenyl Compounds pharmacology, Blotting, Western, Cell Cycle drug effects, Cell Cycle radiation effects, Cell Proliferation drug effects, Cell Proliferation radiation effects, Cerebellar Neoplasms drug therapy, Cerebellar Neoplasms genetics, Chemoradiotherapy, Child, Hedgehog Proteins antagonists & inhibitors, Humans, Imidazoles pharmacology, Inhibitor of Apoptosis Proteins antagonists & inhibitors, Inhibitor of Apoptosis Proteins genetics, Interleukin Receptor Common gamma Subunit deficiency, Interleukin Receptor Common gamma Subunit genetics, Ki-67 Antigen metabolism, Medulloblastoma drug therapy, Medulloblastoma genetics, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, Knockout, Mice, Nude, Mice, SCID, Microscopy, Confocal, Naphthoquinones pharmacology, Pyridines pharmacology, Repressor Proteins antagonists & inhibitors, Repressor Proteins genetics, Survivin, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Cerebellar Neoplasms metabolism, Hedgehog Proteins metabolism, Inhibitor of Apoptosis Proteins deficiency, Medulloblastoma metabolism, Repressor Proteins deficiency
- 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.
- Published
- 2015
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