PET imaging of [Cu]copper(II) chloride and tetrathiomolybdate administration in animal models of triple-negative breast cancer.

Abstract

BACKGROUND: In the United States, breast cancer is the second leading cause of cancer-related death. Triple-negative breast cancer (TNBC) is of substantial concern, as it lacks the receptors usually targeted by conventional treatments. Triple-negative breast tumors have a high degree of copper metabolism for the synthesis of transporters, enzymes, and chaperones. Tetrathiomolybdate (TM) is a well-tolerated oral therapy that has been investigated for chelating copper from tumors in TNBC patients, resulting in extended remission. The overall goal of this research was to evaluate [Cu]CuClPET/CT imaging of copper utilization in this disease, in the presence and absence of TM. METHODS: Uptake, internalization, and efflux studies were performed in TNBC cells versus normal cells. Biodistribution experiments were then conducted in TNBC xenograft-bearing mice that were administered TM versus controls. PET/CT imaging of mice carrying TNBC tumors was also performed in the presence and absence of TM. Finally, imaging was performed in a healthy cat and in a cat with mammary carcinoma. RESULTS: SUM149 TNBC cells selectively took up, internalized, and retained [Cu]CuClmore avidly than normal fibroblasts. When SUM149-bearing mice were given TM, tumor uptake decreased and tracer accumulation shifted predominantly to the liver and kidneys, compared to control mice, in which large quantities ofCu were excreted into the intestines. These results were supported by PET/CT imaging of the mice. PET/CT of companion cats gave results similar to those obtained in mice, with high accumulation of radioactivity observed in the liver and gallbladder and moderate intestinal and renal clearance. In a cat with mammary carcinoma, tumor uptake of [Cu]CuClwas highly conspicuous, even in close proximity to the liver. CONCLUSIONS: Utilization of [Cu]CuClin triple-negative breast cancer can be detected efficiently in cell and animal models of this disease. The tracer was also used successfully to evaluate TM administration in the SUM149 TNBC mouse model. Furthermore, PET/CT imaging of both mice and cats with breast cancer shows the potential to monitor treatment with TM in a facile, noninvasive manner. We are currently conducting a clinical trial of [Cu]CuClPET/CT in companion cats with mammary carcinoma, with the future goal of evaluating the efficacy of TM in feline patients.