Survivin as a therapeutic target in Sonic hedgehog-driven medulloblastoma

S N Brun; S L Markant; L A Esparza; G Garcia; D Terry; J-M Huang; M S Pavlyukov; X-N Li; G A Grant; J R Crawford; M L Levy; E M Conway; L H Smith; I Nakano; A Berezov; M I Greene; Q Wang; R J Wechsler-Reya

doi:10.1038/onc.2014.304

Survivin as a therapeutic target in Sonic hedgehog-driven medulloblastoma

Oncogene. 2015 Jul;34(29):3770-9. doi: 10.1038/onc.2014.304. Epub 2014 Sep 22.

Authors

S N Brun¹, S L Markant¹, L A Esparza², G Garcia³, D Terry⁴, J-M Huang⁵, M S Pavlyukov⁶, X-N Li⁷, G A Grant⁸, J R Crawford⁹, M L Levy¹⁰, E M Conway¹¹, L H Smith¹², I Nakano⁶, A Berezov¹³, M I Greene¹⁴, Q Wang⁵, R J Wechsler-Reya¹

Affiliations

¹ 1] Tumor Initiation and Maintenance Program, National Cancer Institute (NCI)-Designated Cancer Center, Sanford-Burnham Medical Research Institute (SBMRI), La Jolla, CA, USA [2] Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA [3] Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA.
² 1] Tumor Initiation and Maintenance Program, National Cancer Institute (NCI)-Designated Cancer Center, Sanford-Burnham Medical Research Institute (SBMRI), La Jolla, CA, USA [2] Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA.
³ Histopathology Core SBMRI, La Jolla, CA, USA.
⁴ Conrad Prebys Center for Chemical Genomics, SBMRI, Lake Nona, FL, USA.
⁵ Cedars-Sinai Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA.
⁶ 1] Department of Neurological Surgery, The Ohio State University, Columbus, OH, USA [2] James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
⁷ Brain Tumor Program, Texas Children's Cancer Center, and Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
⁸ Department of Neurosurgery, Stanford University/Lucile Packard Children's Hospital, Stanford, CA, USA.
⁹ 1] Department of Pediatrics, University of California San Diego, San Diego, CA, USA [2] Departments of Neurosciences, University of California San Diego, San Diego, CA, USA [3] Rady Children's Hospital, San Diego, CA, USA.
¹⁰ 1] Rady Children's Hospital, San Diego, CA, USA [2] Department of Neurosurgery, University of California San Diego, La Jolla, CA, USA.
¹¹ Centre for Blood Research, Division of Hematology, Department of Medicine, University of British Columbia (UBC), Vancouver, BC, Canada.
¹² 1] Conrad Prebys Center for Chemical Genomics, SBMRI, Lake Nona, FL, USA [2] Cardiopathobiology Program, Sanford Burnham Medical Research Institute, Lake Nona, FL, USA.
¹³ Department of Biomedical Sciences at Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹⁴ Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

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
Cerebellar Neoplasms / metabolism*
Chemoradiotherapy
Child
Hedgehog Proteins / antagonists & inhibitors
Hedgehog Proteins / metabolism*
Humans
Imidazoles / pharmacology
Inhibitor of Apoptosis Proteins / antagonists & inhibitors
Inhibitor of Apoptosis Proteins / deficiency*
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
Medulloblastoma / metabolism*
Mice, Inbred C57BL
Mice, Inbred NOD
Mice, Knockout
Mice, Nude
Mice, SCID
Microscopy, Confocal
Naphthoquinones / pharmacology
Pyridines / pharmacology
Repressor Proteins / antagonists & inhibitors
Repressor Proteins / deficiency*
Repressor Proteins / genetics
Survivin
Tumor Cells, Cultured
Xenograft Model Antitumor Assays

Substances

Biphenyl Compounds
Birc5 protein, mouse
Hedgehog Proteins
Il2rg protein, mouse
Imidazoles
Inhibitor of Apoptosis Proteins
Interleukin Receptor Common gamma Subunit
Ki-67 Antigen
Naphthoquinones
Pyridines
Repressor Proteins
Survivin
sonidegib
sepantronium

Abstract

Publication types

MeSH terms

Substances

Grants and funding