TY - JOUR
T1 - Polyamine antagonist therapies inhibit neuroblastoma initiation and progression
AU - Evageliou, Nicholas F.
AU - Haber, Michelle
AU - Vu, Annette
AU - Laetsch, Theodore W.
AU - Murray, Jayne
AU - Gamble, Laura D.
AU - Cheng, Ngan Ching
AU - Liu, Kangning
AU - Reese, Megan
AU - Corrigan, Kelly A.
AU - Ziegler, David S.
AU - Webber, Hannah
AU - Hayes, Candice S.
AU - Pawel, Bruce
AU - Marshall, Glenn M.
AU - Zhao, Huaqing
AU - Gilmour, Susan K.
AU - Norris, Murray D.
AU - Hogarty, Michael D.
N1 - Funding Information:
The authors thank Pat Woster (Medical University of South Carolina) for DFMO, Robert Cozens (Novartis, Basil, Switzerland) for SAM486, William Weiss (UCSF) for TH-MYCN mice, Naomi Balamuth and John Maris (University of Pennsylvania) for TH-MYCN model transcriptome datasets, Ashleigh Clark and Michelle Ruhle for expert technical assistance, and Andre Bachmann (Michigan State University) for helpful discussions. This work was financially supported by grants from the US Department of Defense W81XWH-10-1-0145 (to M.D. Hogarty and S.K. Gilmour), and the Richard and Sheila Sanford Chair in Pediatric Oncology (to M.D. Hogarty), the Children's Neuroblastoma Cancer Foundation (to N.F. Evageliou), The National Health and Medical Research Council (Australia) and Cancer Institute New South Wales (to M. Haber, G.M. Marshall, and M.D. Norris). Children's Cancer Institute Australia for Medical Research is affiliated with the University of New South Wales and Sydney Children's Hospital Randwick, Sydney, Australia and is a member of the Kid's Cancer Alliance.
Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2016/9/1
Y1 - 2016/9/1
N2 - Purpose: 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. Experimental Design: 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 ratelimiting 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 suchapproachesinneuroblastoma and potentially other MYC-driven tumors is warranted.
AB - Purpose: 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. Experimental Design: 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 ratelimiting 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 suchapproachesinneuroblastoma and potentially other MYC-driven tumors is warranted.
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U2 - 10.1158/1078-0432.CCR-15-2539
DO - 10.1158/1078-0432.CCR-15-2539
M3 - Article
C2 - 27012811
AN - SCOPUS:84982240848
SN - 1078-0432
VL - 22
SP - 4391
EP - 4404
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 17
ER -