title: Identification of biomarkers for the antiangiogenic and antitumour activity of the superoxide dismutase 1 (SOD1) inhibitor tetrathiomolybdate (ATN-224).
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.
authors.affiliation: Attenuon, LLC, San Diego, CA 92121, USA. donate@attenuon.com
authors.forename: F
authors.initials: F
authors.lastname: Doñate
authors.forename: J C
authors.initials: JC
authors.lastname: Juarez
authors.forename: M E
authors.initials: ME
authors.lastname: Burnett
authors.forename: M M
authors.initials: MM
authors.lastname: Manuia
authors.forename: X
authors.initials: X
authors.lastname: Guan
authors.forename: D E
authors.initials: DE
authors.lastname: Shaw
authors.forename: E L P
authors.initials: EL
authors.lastname: Smith
authors.forename: C
authors.initials: C
authors.lastname: Timucin
authors.forename: M J
authors.initials: MJ
authors.lastname: Braunstein
authors.forename: O A
authors.initials: OA
authors.lastname: Batuman
authors.forename: A P
authors.initials: AP
authors.lastname: Mazar
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D001773:Blood Cells / Q000187:drug effects / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D003300:Copper / Q000378:metabolism; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D007797:Laminin / Q000378:metabolism; D008255:Macaca radiata; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008982:Molybdenum / Q000494:pharmacology*; D011509:Proteoglycans / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000072105:Superoxide Dismutase-1
chemical_list: D020533:Angiogenesis Inhibitors; D015415:Biomarkers; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D007797:Laminin; D011509:Proteoglycans; C059485:matrigel; D003300:Copper; D008982:Molybdenum; D003094:Collagen; C020809:tetrathiomolybdate; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1