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Methionine Aminopeptidase 2 Inhibition Is an Effective Treatment Strategy for Neuroblastoma in Preclinical Models

Authors' Affiliations:Divisions of ¹ Oncology and ² Biostatistics and Departments of³ Pathology, The Children's Hospital of Philadelphia; ⁴ Surgery, ⁵ Pediatrics and ⁶ Pathology & Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; and ⁷ Cancer Research, Global Pharmaceutical R&D, Abbott Laboratories, Abbott Park, Illinois

Requests for reprints: Suzanne Shusterman, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Room 350C, Shields Warren Building, 44 Binney Street, Boston, MA 02118. Phone: 617-632-4901; Fax: 617-632-5710; E-mail: suzanne_shusterman{at}dfci.harvard.edu.

Tumor vascularity is correlated with an aggressive disease phenotype in neuroblastoma, suggesting that angiogenesis inhibitors may be a useful addition to current therapeutic strategies. We previously showed that the antiangiogenic compound TNP-470, an irreversible methionine aminopeptidase 2 (MetAP2) inhibitor, suppressed local and disseminated human neuroblastoma growth rates in murine models but had significant associated toxicity at the effective dose. We have recently shown that a novel, reversible MetAP2 inhibitor, A-357300, significantly inhibits CHP-134–derived neuroblastoma s.c. xenograft growth rate with a treatment-to-control (T/C) ratio at day 24 of 0.19 (P < 0.001) without toxicity. We now show that the combination of A-357300 with cyclophosphamide at the maximal tolerated dose sustained tumor regression with a T/C at day 48 of 0.16 (P < 0.001) in the CHP-134 xenograft model. A-357300 also significantly inhibited establishment and growth rate of hematogenous metastatic deposits following tail vein inoculation of CHP-134 cells and increased overall survival (P = 0.021). Lastly, A-357300 caused regression of established tumors in a genetically engineered murine model with progression-free survival in five of eight mice (P < 0.0001). There was no evidence of toxicity. These data show that MetAP2 may be an important molecular target for high-risk human neuroblastomas. We speculate that the growth inhibition may be through both tumor cell intrinsic and extrinsic (antiangiogenic) mechanisms. The potential for a wide therapeutic index may allow for treatment strategies that integrate MetAP2 inhibition with conventional cytotoxic compounds.

Key Words: Pediatric cancers • Angiogenesis inhibitors: endogenous and synthetic • Small molecules and other therapeutic agents • Xenograft models

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