DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Mitochondria-Targeted Copper-Depleting Nanoparticle Inhibits Triple-Negative Breast Cancer Progression in Mice

Posted April 9, 2021

Liyang Cui, Ph.D., Stanford University

Liyang Cui, Ph.D., Stanford University
Dr. Liyang Cui

Higher levels of copper have been detected in serum and cancerous tissue samples collected from patients diagnosed with triple-negative breast cancer (TNBC), and depletion of copper has been identified as a potential therapeutic option. However due to the toxicity associated with systemic copper depletion, researchers have focused on copper trafficking in cancer cells to develop a more targeted treatment approach. Studies suggest that a metabolic shift to glycolysis can result in decreased energy production for certain types of cancer cells, such as TNBC, and therefore more effective copper chelators that selectively target and deplete copper in the mitochondria of cancer cells, rather than causing systemic depletion, are needed. With a Fiscal Year 2017 Breakthrough Fellowship Award, Dr. Liyang Cui sought to develop a polymer-based copper-depleting nanoparticle (CDN) that selectively delivers a copper chelator to cancer cells for the treatment of TNBC. 

As reported in a recently published article in Nature Biotechnology , Dr. Cui and her team demonstrated the ability of the newly developed CDN to selectively deplete intracellular copper and inhibit tumor growth and progression in a mouse model of TNBC. In this study, a control group (administered saline) demonstrated rapid tumor growth with a median survival of 25.5 days. In contrast, mice treated with the CDN exhibited a significant delay in tumor progression and half of the treated mice survived greater than 68 days, compared to a median survival of 32 to 35 days with other copper chelators. Tumor analyses also confirmed that the CDN treatment resulted in elevated glycolysis, confirming that there was a metabolic shift in the tumor cells. In separate studies investigating the biodistribution and copper depleting effects of the CDN in tumor-bearing mice, the researchers found that there was a high level of nanoparticle accumulation and effective copper binding in the tumor. Although CDN was also localized in the liver, the nanoparticles did not appear to deplete copper in this tissue. With respect to toxicity, the researchers reported that there were no adverse findings following weekly administration of the CDN to mice for up to seven weeks.  

Findings from Dr. Cui’s preclinical studies of the newly developed CDN present a potential breakthrough in a targeted treatment strategy for TNBC. Although additional preclinical and clinical research must be done, the early efficacy and safety data of CDNs suggest the potential clinical relevance of this treatment strategy and could provide a future therapeutic option for women with TNBC tumors.  

 

Publication:

Cui L, Gouw AM, LaGory EL, et al. 2019. Mitochondrial copper depletion suppresses triple-negative breast cancer in mice. Nature Biotechnology. doi: 10.1038/s41587-020-0707-9. Epub ahead of print. PMID: 33077961.

Link:

Public and Technical Abstracts: Targeting Metastatic Breast Cancer with Copper Trap Assembled In Situ

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Last updated Friday, April 9, 2021