title: Polyamine Antagonist Therapies Inhibit Neuroblastoma Initiation and Progression.
abstract: OBJECTIVE
  Deregulated MYC drives oncogenesis in many tissues yet direct pharmacologic inhibition has proven difficult. MYC coordinately regulates polyamine homeostasis as these essential cations support MYC functions, and drugs that antagonize polyamine sufficiency have synthetic-lethal interactions with MYC Neuroblastoma is a lethal tumor in which the MYC homologue MYCN, and ODC1, the rate-limiting enzyme in polyamine synthesis, are frequently deregulated so we tested optimized polyamine depletion regimens for activity against neuroblastoma.
  
  
  METHODS
  We used complementary transgenic and xenograft-bearing neuroblastoma models to assess polyamine antagonists. We investigated difluoromethylornithine (DFMO; an inhibitor of Odc, the rate-limiting enzyme in polyamine synthesis), SAM486 (an inhibitor of Amd1, the second rate-limiting enzyme), and celecoxib (an inducer of Sat1 and polyamine catabolism) in both the preemptive setting and in the treatment of established tumors. In vitro assays were performed to identify mechanisms of activity.
  
  
  RESULTS
  An optimized polyamine antagonist regimen using DFMO and SAM486 to inhibit both rate-limiting enzymes in polyamine synthesis potently blocked neuroblastoma initiation in transgenic mice, underscoring the requirement for polyamines in MYC-driven oncogenesis. Furthermore, the combination of DFMO with celecoxib was found to be highly active, alone, and combined with numerous chemotherapy regimens, in regressing established tumors in both models, including tumors harboring highest risk genetic lesions such as MYCN amplification, ALK mutation, and TP53 mutation with multidrug resistance.
  
  
  CONCLUSIONS
  Given the broad preclinical activity demonstrated by polyamine antagonist regimens across diverse in vivo models, clinical investigation of such approaches in neuroblastoma and potentially other MYC-driven tumors is warranted. Clin Cancer Res; 22(17); 4391-404. ©2016 AACR.
authors.affiliation: Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. Center for Childhood Cancer Research, University of New South Wales, Sydney, Australia.
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Evageliou
authors.affiliation: Children's Cancer Institute Australia, Sydney, Australia.
authors.forename: Michelle
authors.initials: M
authors.lastname: Haber
authors.affiliation: Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Annette
authors.initials: A
authors.lastname: Vu
authors.affiliation: University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Theodore W
authors.initials: TW
authors.lastname: Laetsch
authors.affiliation: Children's Cancer Institute Australia, Sydney, Australia.
authors.forename: Jayne
authors.initials: J
authors.lastname: Murray
authors.affiliation: Children's Cancer Institute Australia, Sydney, Australia.
authors.forename: Laura D
authors.initials: LD
authors.lastname: Gamble
authors.affiliation: Children's Cancer Institute Australia, Sydney, Australia.
authors.forename: Ngan Ching
authors.initials: NC
authors.lastname: Cheng
authors.affiliation: Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Kangning
authors.initials: K
authors.lastname: Liu
authors.affiliation: Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Megan
authors.initials: M
authors.lastname: Reese
authors.affiliation: Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Corrigan
authors.affiliation: Children's Cancer Institute Australia, Sydney, Australia. Kids Cancer Centre, Sydney Children's Hospital, Sydney, Australia. School of Women's and Children's Health, Faculty of Medicine, University of New South Wales, Kensington, Sydney, Australia.
authors.forename: David S
authors.initials: DS
authors.lastname: Ziegler
authors.affiliation: Children's Cancer Institute Australia, Sydney, Australia.
authors.forename: Hannah
authors.initials: H
authors.lastname: Webber
authors.affiliation: Lankenau Institute for Medical Research, Wynnewood, Pennsylvania.
authors.forename: Candice S
authors.initials: CS
authors.lastname: Hayes
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Bruce
authors.initials: B
authors.lastname: Pawel
authors.affiliation: Children's Cancer Institute Australia, Sydney, Australia. Kids Cancer Centre, Sydney Children's Hospital, Sydney, Australia.
authors.forename: Glenn M
authors.initials: GM
authors.lastname: Marshall
authors.affiliation: Department of Biostatistics, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Huaqing
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Lankenau Institute for Medical Research, Wynnewood, Pennsylvania.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Gilmour
authors.affiliation: Children's Cancer Institute Australia, Sydney, Australia. Center for Childhood Cancer Research, University of New South Wales, Sydney, Australia.
authors.forename: Murray D
authors.initials: MD
authors.lastname: Norris
authors.affiliation: Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. hogartym@email.chop.edu.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Hogarty
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000068579:Celecoxib / Q000494:pharmacology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004195:Disease Models, Animal; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D000518:Eflornithine / Q000494:pharmacology; D016259:Genes, myc; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009447:Neuroblastoma / Q000188:drug therapy / Q000209:etiology* / Q000401:mortality / Q000473:pathology*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011073:Polyamines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D015513:Oncogene Proteins; D011073:Polyamines; D000068579:Celecoxib; D000518:Eflornithine