title: Downregulation of MYCN through PI3K Inhibition in Mouse Models of Pediatric Neural Cancer.
abstract: The MYCN proto-oncogene is associated with poor outcome across a broad range of pediatric tumors. While amplification of MYCN drives subsets of high-risk neuroblastoma and medulloblastoma, dysregulation of MYCN in medulloblastoma (in the absence of amplification) also contributes to pathogenesis. Since PI3K stabilizes MYCN, we have used inhibitors of PI3K to drive degradation. In this study, we show PI3K inhibitors by themselves induce cell cycle arrest, with modest induction of apoptosis. In screening inhibitors of PI3K against MYCN, we identified PIK-75 and its derivative, PW-12, inhibitors of both PI3K and of protein kinases, to be highly effective in destabilizing MYCN. To determine the effects of PW-12 treatment in vivo, we analyzed a genetically engineered mouse model for MYCN-driven neuroblastoma and a model of MYCN-driven medulloblastoma. PW-12 showed significant activity in both models, inducing vascular collapse and regression of medulloblastoma with prominent apoptosis in both models. These results demonstrate that inhibitors of lipid and protein kinases can drive apoptosis in MYCN-driven cancers and support the importance of MYCN as a therapeutic target.
authors.affiliation: Department of Neurological Surgery, Brain Tumor Research Center, University of California San Francisco , San Francisco, CA , USA.
authors.forename: Tene Aneka
authors.initials: TA
authors.lastname: Cage
authors.affiliation: Department of Neurology, University of California San Francisco , San Francisco, CA , USA ; Department of Bioengineering, Santa Clara University , Santa Clara, CA , USA.
authors.forename: Yvan
authors.initials: Y
authors.lastname: Chanthery
authors.affiliation: Division of Paediatric Solid Tumour Biology and Therapeutics, The Institute of Cancer Research , London , UK.
authors.forename: Louis
authors.initials: L
authors.lastname: Chesler
authors.affiliation: Department of Neurological Surgery, Brain Tumor Research Center, University of California San Francisco , San Francisco, CA , USA ; Department of Neurology, University of California San Francisco , San Francisco, CA , USA ; Department of Biochemistry, University of Southern California , Los Angeles, CA , USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Grimmer
authors.affiliation: Department of Physiology, University of California San Francisco , San Francisco, CA , USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Knight
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California San Francisco , San Francisco, CA , USA.
authors.forename: Kevan
authors.initials: K
authors.lastname: Shokat
authors.affiliation: Department of Neurological Surgery, Brain Tumor Research Center, University of California San Francisco , San Francisco, CA , USA ; Department of Neurology, University of California San Francisco , San Francisco, CA , USA ; Department of Pediatrics, University of California San Francisco , San Francisco, CA , USA ; Department of Pediatric Hematology and Oncology, University of California San Francisco , San Francisco, CA , USA ; Hellen Diller Family Comprehensive Cancer Center, University of California San Francisco , San Francisco, CA , USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Weiss
authors.affiliation: Department of Pediatrics, University of California San Francisco , San Francisco, CA , USA ; Department of Pediatric Hematology and Oncology, University of California San Francisco , San Francisco, CA , USA ; Hellen Diller Family Comprehensive Cancer Center, University of California San Francisco , San Francisco, CA , USA.
authors.forename: W Clay
authors.initials: WC
authors.lastname: Gustafson
keywords: MYCN; PI3 kinase; cancer; cell signaling; mTOR; medulloblastoma; neuroblastoma; pediatric