ODC1 is a critical determinant of MYCN oncogenesis and a therapeutic target in neuroblastoma

Michael D. Hogarty, Murray D. Norris, Kimberly Davis, Xueyuan Liu, Nicholas F. Evageliou, Candace S. Hayes, Bruce Pawel, Rong Guo, Huaqing Zhao, Eric Sekyere, Joanna Keating, Wayne Thomas, Ching Cheng Ngan, Jayne Murray, Janice Smith, Rosemary Sutton, Nicola Venn, Wendy B. London, Allen Buxton, Susan K. GilmourGlenn M. Marshall, Michelle Haber

Research output: Contribution to journalArticle

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 α-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.

Original languageEnglish (US)
Pages (from-to)9735-9745
Number of pages11
JournalCancer Research
Volume68
Issue number23
DOIs
Publication statusPublished - Dec 1 2008
Externally publishedYes

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Hogarty, M. D., Norris, M. D., Davis, K., Liu, X., Evageliou, N. F., Hayes, C. S., ... Haber, M. (2008). ODC1 is a critical determinant of MYCN oncogenesis and a therapeutic target in neuroblastoma. Cancer Research, 68(23), 9735-9745. https://doi.org/10.1158/0008-5472.CAN-07-6866