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.

B80 This single-arm, open-label trial evaluated the efficacy and safety of low-dose thalidomide in combination with dexamethasone and zoledronate (TDZ) for the treatment of multiple myeloma (MM) in a largely African-Caribbean inner-city population with high prevalence of HIV/AIDS. TDZ is non-myelotoxic and compatible with HAART, and thus appropriate for HIV+ patients with MM. Methods: 45 consecutive patients with newly diagnosed MM were enrolled. TDZ was given for 24 months or until progression, and consisted of: thalidomide, 100 mg daily; dexamethasone, 10-40 mg for 4 days/week for 3 weeks each month for 6 months, then reduced to 4 days each month; zoledronate, 4 mg IV monthly; and ASA, 81 mg daily. Response was stratified by reduction of M protein levels: > 75% (very good partial response [VPR]), > 50-75% (partial response [PR]), or 25-50% (minor response [MR]). Kaplan-Meier survival analyses provided estimates of longitudinal survival. Differences between HIV+ and HIV- patients were assessed by the log-rank test or the Fisher Exact Test with mid-P correction for small samples. Results: 8 of 45 enrollees were HIV seropositive, 7 of whom had AIDS and were on HAART. 38 (27F/11M; median age = 60.4 years) were evaluable, including all 8 HIV patients. Patients with HIV were younger (Mann-Whitney U test, P .2 for both). Despite prophylactic ASA, thromboembolism occurred in 6 patients (16%), all of whom were successfully treated with full anticoagulation. Other toxicities ≥ Grade 2, were not observed. Skeletal events occurred in 8% of patients; osteonecrosis of the jaw was not encountered. Conclusion: Thalidomide administered at half the standard dose in combination with zoledronate and dexamethasone provides safe, efficacious long-term treatment of MM in HIV and HIV+ patients. The modest frequency of toxicity and skeletal events under TDZ improves quality of life as well as survival. The high incidence of HIV in our study cohort suggests a pathogenetic role in MM.