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

F Donate, JC Juarez, ME Burnett, MM Manuia… - British journal of …, 2008 - nature.com
F Donate, JC Juarez, ME Burnett, MM Manuia, X Guan, DE Shaw, ELP Smith, C Timucin
British journal of cancer, 2008nature.com
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 …
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.
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