Abstract
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. 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. 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. 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.
Highlights
MYC genes coordinate transcriptional programs to promote cell proliferation, biomass production, self-renewal, and numer-Note: Supplementary data for this article are available at Clinical Cancer Research Online.N.F
Polyamine homeostasis is faithfully recapitulated in the THMYCN neuroblastoma model Human neuroblastomas with MYC activation coordinately deregulate polyamine enzymes to promote polyamine sufficiency and support Myc functions [18]
Catabolic SAT1 and spermine oxidase, SMOX, were downregulated, whereas polyamine oxidase, PAOX, which cleaves acetylated polyamines to restore spermidine and/or putrescine was elevated. This pattern closely recapitulates the transcriptional changes found in human neuroblastomas and credentials the TH-MYCN model for preclinical polyamine antagonist studies (Supplementary Table S1)
Summary
Polyamine homeostasis is faithfully recapitulated in the THMYCN neuroblastoma model Human neuroblastomas with MYC activation coordinately deregulate polyamine enzymes to promote polyamine sufficiency and support Myc functions [18]. Catabolic SAT1 and spermine oxidase, SMOX, were downregulated, whereas polyamine oxidase, PAOX, which cleaves acetylated polyamines to restore spermidine and/or putrescine was elevated This pattern closely recapitulates the transcriptional changes found in human neuroblastomas and credentials the TH-MYCN model for preclinical polyamine antagonist studies (Supplementary Table S1). The combination of DFMO and SAM486 extended tumor latency (P < 0.001) and reduced penetrance to approximately 60% in homozygous mice (n 1⁄4 67; P < 0.01; Fig. 2A and B) and from 66% to 17% in hemizygous mice (n 1⁄4 213; P < 0.001; data not shown). On-target activity was supported by reduced putrescine in DFMO and SAM486þDFMO–treated tumors, while the addition of SAM486 to DFMO led further to reduced spermidine and spermine, biomarkers of Amd inhibition (Fig. 2E). Mice harboring BE2C tumor xenografts (MYCN amplified, TP53 mutant, multidrug resistant) were treated with cyclophosphamide and topotecan, a regimen often used after relapse, and again DFMOþSAM486 failed to improve survival (P 1⁄4 0.62; Fig. 3B)
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