title: Methionine aminopeptidase 2 inhibition is an effective treatment strategy for neuroblastoma in preclinical models.
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.
authors.affiliation: Division of Oncology, Department of Pathology, The Children's Hospital of Philadelphia, PA, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Morowitz
authors.forename: Rosalind
authors.initials: R
authors.lastname: Barr
authors.forename: Qun
authors.initials: Q
authors.lastname: Wang
authors.forename: Rebecca
authors.initials: R
authors.lastname: King
authors.forename: Nicholas
authors.initials: N
authors.lastname: Rhodin
authors.forename: Bruce
authors.initials: B
authors.lastname: Pawel
authors.forename: Huaqing
authors.initials: H
authors.lastname: Zhao
authors.forename: Scott A
authors.initials: SA
authors.lastname: Erickson
authors.forename: George S
authors.initials: GS
authors.lastname: Sheppard
authors.forename: Jieyi
authors.initials: J
authors.lastname: Wang
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
authors.forename: Suzanne
authors.initials: S
authors.lastname: Shusterman
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D002722:Chlorobenzenes / Q000494:pharmacology* / Q000627:therapeutic use; D003520:Cyclophosphamide / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D006801:Humans; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051379:Mice; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D016513:Mice, SCID; D008822:Mice, Transgenic; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000473:pathology / Q000517:prevention & control*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
chemical_list: C481161:A357300; D018906:Antineoplastic Agents, Alkylating; D002722:Chlorobenzenes; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D003520:Cyclophosphamide; D000626:Aminopeptidases; C106541:methionine aminopeptidase 2; D008666:Metalloendopeptidases