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Cancer Cell. 2016 Mar 14;29(3):311-23. doi: 10.1016/j.ccell.2016.02.011.

HDAC and PI3K Antagonists Cooperate to Inhibit Growth of MYC-Driven Medulloblastoma.

Author information

1
Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; Cancer and Immunology Department, Brain Tumor Institute, Children's National Medical Center, Washington, DC 20010, USA.
2
Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
3
Cancer and Immunology Department, Brain Tumor Institute, Children's National Medical Center, Washington, DC 20010, USA.
4
Department of Pediatrics, University of California San Diego - Rady Children's Hospital, San Diego, CA 92123, USA.
5
Program in Developmental and Stem Cell Biology, Division of Neurosurgery, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
6
Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; German Cancer Consortium, Core Center, 69120 Heidelberg, Germany.
7
Brain Tumor Program, Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
8
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
9
Fred Hutchinson Cancer Research Center, Seattle Children's Hospital, Seattle, WA 98109, USA.
10
Department of Pediatrics, University of California San Diego - Rady Children's Hospital, San Diego, CA 92123, USA; Department of Neurosciences, University of California San Diego - Rady Children's Hospital, San Diego, CA 92123, USA.
11
Department of Neurosurgery, University of California San Diego - Rady Children's Hospital, San Diego, CA 92123, USA.
12
Program in Developmental and Stem Cell Biology, Division of Neurosurgery, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Division of Neurosurgery, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
13
Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. Electronic address: rwreya@sbpdiscovery.org.

Abstract

Medulloblastoma (MB) is a highly malignant pediatric brain tumor. Despite aggressive therapy, many patients succumb to the disease, and survivors experience severe side effects from treatment. MYC-driven MB has a particularly poor prognosis and would greatly benefit from more effective therapies. We used an animal model of MYC-driven MB to screen for drugs that decrease viability of tumor cells. Among the most effective compounds were histone deacetylase inhibitors (HDACIs). HDACIs potently inhibit survival of MYC-driven MB cells in vitro, in part by inducing expression of the FOXO1 tumor suppressor gene. HDACIs also synergize with phosphatidylinositol 3-kinase inhibitors to inhibit tumor growth in vivo. These studies identify an effective combination therapy for the most aggressive form of MB.

PMID:
26977882
PMCID:
PMC4794752
DOI:
10.1016/j.ccell.2016.02.011
[Indexed for MEDLINE]
Free PMC Article
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