title: ODC1 is a critical determinant of MYCN oncogenesis and a therapeutic target in neuroblastoma.
abstract: Neuroblastoma is a frequently lethal childhood tumor in which MYC gene deregulation, commonly as MYCN amplification, portends poor outcome. Identifying the requisite biopathways downstream of MYC may provide therapeutic opportunities. We used transcriptome analyses to show that MYCN-amplified neuroblastomas have coordinately deregulated myriad polyamine enzymes (including ODC1, SRM, SMS, AMD1, OAZ2, and SMOX) to enhance polyamine biosynthesis. High-risk tumors without MYCN amplification also overexpress ODC1, the rate-limiting enzyme in polyamine biosynthesis, when compared with lower-risk tumors, suggesting that this pathway may be pivotal. Indeed, elevated ODC1 (independent of MYCN amplification) was associated with reduced survival in a large independent neuroblastoma cohort. As polyamines are essential for cell survival and linked to cancer progression, we studied polyamine antagonism to test for metabolic dependence on this pathway in neuroblastoma. The Odc inhibitor alpha-difluoromethylornithine (DFMO) inhibited neuroblast proliferation in vitro and suppressed oncogenesis in vivo. DFMO treatment of neuroblastoma-prone genetically engineered mice (TH-MYCN) extended tumor latency and survival in homozygous mice and prevented oncogenesis in hemizygous mice. In the latter, transient Odc ablation permanently prevented tumor onset consistent with a time-limited window for embryonal tumor initiation. Importantly, we show that DFMO augments antitumor efficacy of conventional cytotoxics in vivo. This work implicates polyamine biosynthesis as an arbiter of MYCN oncogenesis and shows initial efficacy for polyamine depletion strategies in neuroblastoma, a strategy that may have utility for this and other MYC-driven embryonal tumors.
authors.affiliation: Division of Oncology, The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-4318, USA. hogartym@email.chop.edu
authors.forename: Michael D
authors.initials: MD
authors.lastname: Hogarty
authors.forename: Murray D
authors.initials: MD
authors.lastname: Norris
authors.forename: Kimberly
authors.initials: K
authors.lastname: Davis
authors.forename: Xueyuan
authors.initials: X
authors.lastname: Liu
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Evageliou
authors.forename: Candace S
authors.initials: CS
authors.lastname: Hayes
authors.forename: Bruce
authors.initials: B
authors.lastname: Pawel
authors.forename: Rong
authors.initials: R
authors.lastname: Guo
authors.forename: Huaqing
authors.initials: H
authors.lastname: Zhao
authors.forename: Eric
authors.initials: E
authors.lastname: Sekyere
authors.forename: Joanna
authors.initials: J
authors.lastname: Keating
authors.forename: Wayne
authors.initials: W
authors.lastname: Thomas
authors.forename: Ngan Ching
authors.initials: NC
authors.lastname: Cheng
authors.forename: Jayne
authors.initials: J
authors.lastname: Murray
authors.forename: Janice
authors.initials: J
authors.lastname: Smith
authors.forename: Rosemary
authors.initials: R
authors.lastname: Sutton
authors.forename: Nicola
authors.initials: N
authors.lastname: Venn
authors.forename: Wendy B
authors.initials: WB
authors.lastname: London
authors.forename: Allen
authors.initials: A
authors.lastname: Buxton
authors.forename: Susan K
authors.initials: SK
authors.lastname: Gilmour
authors.forename: Glenn M
authors.initials: GM
authors.lastname: Marshall
authors.forename: Michelle
authors.initials: M
authors.lastname: Haber
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D015317:Biogenic Polyamines / Q000096:biosynthesis; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002648:Child; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D055028:Comparative Genomic Hybridization; D004357:Drug Synergism; D000518:Eflornithine / Q000008:administration & dosage / Q000494:pharmacology; D005784:Gene Amplification; D020869:Gene Expression Profiling; D016259:Genes, myc; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics*; D009955:Ornithine Decarboxylase / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D015317:Biogenic Polyamines; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D009955:Ornithine Decarboxylase; D002945:Cisplatin; D000518:Eflornithine