tetrathiomolybdate and Triple-Negative-Breast-Neoplasms

Bone marrow-derived progenitor cells, including VEGFR2. Patients with stage II triple-negative breast cancer (TNBC), stage III and stage IV without any evidence of disease (NED), received oral tetrathiomolybdate to maintain ceruloplasmin (Cp) between 8 and 17 mg/dL for 2 years or until relapse. Endpoints were effect on EPCs and other biomarkers, safety, event-free (EFS), and overall survival (OS). For laboratory studies, MDA-LM2-luciferase cells were implanted into CB17-SCID mice and treated with tetrathiomolybdate or water. Tumor progression was quantified by bioluminescence imaging (BLI), copper depletion status by Cp oxidase levels, lysyl oxidase (LOX) activity by ELISA, and collagen deposition.. Seventy-five patients enrolled; 51 patients completed 2 years (1,396 cycles). Most common grade 3/4 toxicity was neutropenia (3.7%). Lower Cp levels correlated with reduced EPCs (P = 0.002) and LOXL-2 (P < 0.001). Two-year EFS for patients with stage II-III and stage IV NED was 91% and 67%, respectively. For patients with TNBC, EFS was 90% (adjuvant patients) and 69% (stage IV NED patients) at a median follow-up of 6.3 years, respectively. In preclinical models, tetrathiomolybdate decreased metastases to lungs (P = 0.04), LOX activity (P = 0.03), and collagen crosslinking (P = 0.012).. Tetrathiomolybdate is safe, well tolerated, and affects copper-dependent components of the tumor microenvironment. Biomarker-driven clinical trials in high risk for patients with recurrent breast cancer are warranted. Clin Cancer Res; 23(3); 666-76. ©2016 AACR.

Topics: Adenocarcinoma; Amino Acid Oxidoreductases; Animals; Breast Neoplasms; Cell Line, Tumor; Ceruloplasmin; Chelating Agents; Copper; Disease Progression; Disease-Free Survival; Endothelial Progenitor Cells; Female; Follow-Up Studies; Humans; Lung Neoplasms; Mice, SCID; Molybdenum; Neoplasm Proteins; Neovascularization, Pathologic; Neutropenia; Risk; Triple Negative Breast Neoplasms; Tumor Microenvironment; Xenograft Model Antitumor Assays

Treatment of advanced breast cancer remains challenging. Copper and some of the copper-dependent proteins are emerging therapeutic targets because they are essential for cell proliferation and survival, and have been shown to stimulate angiogenesis and metastasis. Here, we show that DCAC50, a recently developed small-molecule inhibitor of the intracellular copper chaperones, ATOX1 and CCS, reduces cell proliferation and elevates oxidative stress, triggering apoptosis in a panel of triple-negative breast cancer (TNBC) cells. Inhibition of ATOX1 activity with DCAC50 disrupts copper homeostasis, leading to increased copper levels, altered spatial copper redistribution, and accumulation of ATP7B to the cellular perinuclear region. The extent and impact of this disruption to copper homeostasis vary across cell lines and correlate with cellular baseline copper and glutathione levels. Ultimately, treatment with DCAC50 attenuates tumor growth and suppresses angiogenesis in a xenograft mouse model, and prevents endothelial cell network formation

Topics: Animals; Apoptosis; Benzothiazoles; Bromobenzenes; Cell Line, Tumor; Cell Movement; Cell Proliferation; Copper; Copper Transport Proteins; Copper-Transporting ATPases; Female; Fluorobenzenes; Gene Expression Regulation, Neoplastic; Humans; Mice; Molecular Chaperones; Molybdenum; Neovascularization, Pathologic; Oxidative Stress; Paclitaxel; Small Molecule Libraries; Triple Negative Breast Neoplasms; Tumor Microenvironment; Xenograft Model Antitumor Assays

Topics: Angiogenesis Inhibitors; Chelating Agents; Clinical Trials, Phase III as Topic; Copper; Female; Humans; Mammography; Molecular Targeted Therapy; Molybdenum; Triple Negative Breast Neoplasms