Identification of biomarkers for the antiangiogenic and antitumour activity of the superoxide dismutase 1 (SOD1) inhibitor tetrathiomolybdate (ATN-224)

F. Doñate*, J. C. Juarez, M. E. Burnett, M. M. Manuia, X. Guan, D. E. Shaw, E. L P Smith, C. Timucin, M. J. Braunstein, O. A. Batuman, A. P. Mazar

*Corresponding author for this work

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

Tetrathiomolybdate (choline salt; ATN-224), a specific, high-affinity copper binder, is currently being evaluated in several phase II cancer trials. ATN-224 inhibits CuZn superoxide dismutase 1 (SOD1) leading to antiangiogenic and antitumour effects. The pharmacodynamics of tetrathiomolybdate has been followed by tracking ceruloplasmin (Cp), a biomarker for systemic copper. However, at least in mice, the inhibition of angiogenesis occurs before a measurable decrease in systemic copper is observed. Thus, the identification and characterisation of other biomarkers to follow the activity of ATN-224 in the clinic is of great interest. Here, we present the preclinical evaluation of two potential biomarkers for the activity of ATN-224: (i) SOD activity measurements in blood cells in mice and (ii) levels of endothelial progenitor cells (EPCs) in bonnet macaques treated with ATN-224. The superoxide dismutase activity in blood cells in mice is rapidly inhibited by ATN-224 treatment at doses at which angiogenesis is maximally inhibited. Furthermore, ATN-224 dosing in bonnet macaques causes a profound and reversible decrease in EPCs without significant toxicity. Thus, both SOD activity measurements and levels of EPCs may be useful biomarkers of the antiangiogenic activity of ATN-224 to be used in its clinical development.

Original languageEnglish (US)
Pages (from-to)776-783
Number of pages8
JournalBritish Journal of Cancer
Volume98
Issue number4
DOIs
StatePublished - Feb 26 2008

Keywords

  • Angiogenesis
  • Biomarkers
  • Circulating progenitor cells
  • Superoxide dismutase
  • Tetrathiomolybdate

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Doñate, F., Juarez, J. C., Burnett, M. E., Manuia, M. M., Guan, X., Shaw, D. E., Smith, E. L. P., Timucin, C., Braunstein, M. J., Batuman, O. A., & Mazar, A. P. (2008). Identification of biomarkers for the antiangiogenic and antitumour activity of the superoxide dismutase 1 (SOD1) inhibitor tetrathiomolybdate (ATN-224). British Journal of Cancer, 98(4), 776-783. https://doi.org/10.1038/sj.bjc.6604226