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Targeting Ornithine Decarboxylase Impairs Development of MYCN-Amplified Neuroblastoma

Department of Cancer Biology, The Scripps Research Institute, Scripps Florida, Jupiter, Florida

Requests for reprints: John L. Cleveland, Department of Cancer Biology, The Scripps Research Institute, Scripps Florida, 5353 Parkside Drive, RE-1, Jupiter, FL 33458. Phone: 561-799-8775; Fax: 561-799-8957; E-mail: jcleve{at}scripps.edu.

Key Words: neuroblastoma • MYCN • ornithine decarboxylase • DFMO • p21^Cip1

Neuroblastoma is a pediatric malignancy that arises from the neural crest, and patients with high-risk neuroblastoma, which typically harbor amplifications of MYCN, have an extremely poor prognosis. The tyrosine hydroxylase (TH) promoter-driven TH-MYCN transgenic mouse model faithfully recapitulates many hallmarks of human MYCN-amplified neuroblastoma. A key downstream target of Myc oncoproteins in tumorigenesis is ornithine decarboxylase (Odc), the rate-limiting enzyme of polyamine biosynthesis. Indeed, sustained treatment with the Odc suicide inhibitor -difluoromethylornithine (DFMO) or Odc heterozygosity markedly impairs lymphoma development in Eµ-Myc transgenic mice, and these effects are linked to the induction of the cyclin-dependent kinase (Cdk) inhibitor p27^Kip1, which is normally repressed by Myc. Here, we report that DFMO treatment, but not Odc heterozygosity, impairs MYCN-induced neuroblastoma and that, in this malignancy, transient DFMO treatment is sufficient to confer protection. The selective anticancer effects of DFMO on mouse and human MYCN-amplified neuroblastoma also rely on its ability to disable the proliferative response of Myc, yet in this tumor context, DFMO targets the expression of the p21^Cip1 Cdk inhibitor, which is also suppressed by Myc oncoproteins. These findings suggest that agents, such as DFMO, that target the polyamine pathway may show efficacy in high-risk, MYCN-amplified neuroblastoma. [Cancer Res 2009;15(4):547–53]

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