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ODC1 Is a Critical Determinant of MYCN Oncogenesis and a Therapeutic Target in Neuroblastoma

¹ Division of Oncology, The Children's Hospital of Philadelphia; Departments of ² Pediatrics, ³ Pathology, and ⁴ Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; ⁵ Children's Cancer Institute Australia for Medical Research; ⁶ Centre for Children's Cancer and Blood Disorders, Sydney Children's Hospital, Randwick, New South Wales, Australia; ⁷ Lankenau Institute for Medical Research, Wynnewood, Pennsylvania; and ⁸ Department of Statistics, University of Florida and Children's Oncology Group Statistics and Data Center Department, Gainesville, Florida

Requests for reprints: Michael D. Hogarty, Division of Oncology, The Children's Hospital of Philadelphia, 9 North ARC, Suite 902C, 3615 Civic Center Boulevard, Philadelphia, PA 19104-4318. Phone: 215-590-3931; Fax: 215-590-3770; E-mail: hogartym{at}email.chop.edu.

Key Words: Embryonal tumors • metabolomics • polyamines • oncogene • experimental therapeutics

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 -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. [Cancer Res 2008;68(23):9735–45]