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: 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, Ngan Ching Cheng, Jayne Murray, Janice Smith, Rosemary Sutton, Nicola Venn, Wendy B London, Allen Buxton, Susan K Gilmour, Glenn M Marshall, Michelle Haber
• Journal: Cancer research (Cancer Res) Vol. 68 Issue 23 Pg. 9735-45 (Dec 01 2008) ISSN: 1538-7445 [Electronic] United States
• PMID: 19047152 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biogenic Polyamines
• MYCN protein, human
• N-Myc Proto-Oncogene Protein
• Nuclear Proteins
• Oncogene Proteins
• Ornithine Decarboxylase
• Cisplatin
• Eflornithine

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Biogenic Polyamines (biosynthesis)
• Cell Growth Processes (physiology)
• Cell Line, Tumor
• Child
• Cisplatin (administration & dosage, pharmacology)
• Comparative Genomic Hybridization
• Drug Synergism
• Eflornithine (administration & dosage, pharmacology)
• Gene Amplification
• Gene Expression Profiling
• Genes, myc
• Humans
• Mice
• Mice, Transgenic
• N-Myc Proto-Oncogene Protein
• Neuroblastoma (drug therapy, enzymology, genetics, metabolism)
• Nuclear Proteins (genetics)
• Oncogene Proteins (genetics)
• Ornithine Decarboxylase (biosynthesis, genetics)