| Title: |
Survivin as a therapeutic target in Sonic hedgehog-driven medulloblastoma |
| Authors: |
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 |
| Source: |
Oncogene, vol 34, iss 29 |
| Publisher Information: |
eScholarship, University of California |
| Publication Year: |
2015 |
| Collection: |
University of California: eScholarship |
| Subject Terms: |
3101 Biochemistry and Cell Biology (for-2020); 32 Biomedical and Clinical Sciences (for-2020); 31 Biological Sciences (for-2020); 3202 Clinical Sciences (for-2020); 3211 Oncology and Carcinogenesis (for-2020); Neurosciences (rcdc); Brain Disorders (rcdc); Rare Diseases (rcdc); Genetics (rcdc); Orphan Drug (rcdc); Pediatric Cancer (rcdc); Pediatric (rcdc); Brain Cancer (rcdc); Cancer (rcdc); 5.1 Pharmaceuticals (hrcs-rac); 2.1 Biological and endogenous factors (hrcs-rac); Cancer (hrcs-hc); Animals (mesh); Apoptosis (mesh); Biphenyl Compounds (mesh); Blotting; Western (mesh); Cell Cycle (mesh); Cell Proliferation (mesh); Cerebellar Neoplasms (mesh); Chemoradiotherapy (mesh); Child (mesh); Hedgehog Proteins (mesh); Humans (mesh); Imidazoles (mesh) |
| Time: |
3770 - 3779 |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
unknown |
| Relation: |
qt2hk5k8x3; https://escholarship.org/uc/item/2hk5k8x3; https://escholarship.org/content/qt2hk5k8x3/qt2hk5k8x3.pdf |
| DOI: |
10.1038/onc.2014.304 |
| Availability: |
https://escholarship.org/uc/item/2hk5k8x3; https://escholarship.org/content/qt2hk5k8x3/qt2hk5k8x3.pdf; https://doi.org/10.1038/onc.2014.304 |
| Rights: |
public |
| Accession Number: |
edsbas.C8DCAECC |
| Database: |
BASE |