TY - JOUR
T1 - Methionine aminopeptidase 2 inhibition is an effective treatment strategy for neuroblastoma in preclinical models
AU - Morowitz, Michael J.
AU - Barr, Rosalind
AU - Wang, Qun
AU - King, Rebecca
AU - Rhodin, Nicholas
AU - Pawel, Bruce
AU - Zhao, Huaqing
AU - Erickson, Scott A.
AU - Sheppard, George S.
AU - Wang, Jieyi
AU - Maris, John M.
AU - Shusterman, Suzanne
PY - 2005/4/1
Y1 - 2005/4/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-04-1917
DO - 10.1158/1078-0432.CCR-04-1917
M3 - Article
C2 - 15814649
AN - SCOPUS:20244370722
SN - 1078-0432
VL - 11
SP - 2680
EP - 2685
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 7
ER -