Methionine aminopeptidase 2 inhibition is an effective treatment strategy for neuroblastoma in preclinical models

Michael J. Morowitz, Rosalind Barr, Qun Wang, Rebecca King, Nicholas Rhodin, Bruce Pawel, Huaqing Zhao, Scott A. Erickson, George S. Sheppard, Jieyi Wang, John M. Maris, Suzanne Shusterman

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2680-2685
Number of pages6
JournalClinical Cancer Research
Volume11
Issue number7
DOIs
StatePublished - Apr 1 2005

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Morowitz, M. J., Barr, R., Wang, Q., King, R., Rhodin, N., Pawel, B., Zhao, H., Erickson, S. A., Sheppard, G. S., Wang, J., Maris, J. M., & Shusterman, S. (2005). Methionine aminopeptidase 2 inhibition is an effective treatment strategy for neuroblastoma in preclinical models. Clinical Cancer Research, 11(7), 2680-2685. https://doi.org/10.1158/1078-0432.CCR-04-1917