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.

Redox-Directed Cancer Therapeutics: Molecular Mechanisms and Opportunities

“…However, anticancer activity of this SOD1 inhibitor may at least in part originate from copper depletion known to exert antiangiogenic and antiprolferative effects, and systemic copper depletion has indeed been observed in a recent Phase I study that examined pharmacokinetic profile and dose-limiting toxicity in patients with advanced solid tumors (228). However, in a recent biomarker study in mice and macaques aiming at the identification of clinical routine parameters that indicate antiangiogenic and antitumor activity of ATN-224, it was found that inhibition of angiogenesis occurred before a measurable decrease in systemic copper as followed by tracking ceruloplasmin, a biomarker for systemic copper (87). In the same study, a rapid drop in blood cell SOD1 activity was observed upon ATN-224 exposure, supporting the importance of SOD1 inhibition as an early pharmacodynamic effect of this investigational cancer drug.…”

Targeting SOD1 reduces experimental non–small-cell lung cancer

“…This SOD1 inhibition led to an increase in steady-state levels of superoxide. ATN-224 has been shown to induce antiangiogenic effects as well as proliferation inhibition and cell death in various cancer cells (16)(17)(18). ATN-224 has also been tested in phase 2 clinical trials involving prostate cancer patients (19,20), however without showing an efficient drug dose-response effect, which halted further trials.…”

Superoxide dismutase 1 (SOD1) is essential for H 2 O 2 -mediated oxidation and inactivation of phosphatases in growth factor signaling

“…T etrathiomolybdate (TM) is a copper-binding drug that has been shown to have efficacy as an anti-angiogenic and anti-tumor agent in several mouse models of cancer (1)(2)(3)(4)(5)(6)(7)(8) and has been tested in several oncology clinical trials (9)(10)(11). ATN-224 is a secondgeneration analogue of TM, which is currently being evaluated in several phase II trials in cancer patients (11).…”