Inhibition of breast cancer metastasis by presurgical treatment with an oral matrix metalloproteinase inhibitor: A preclinical proof-of-principle study

Arthur Winer, Maxwell Janosky, Beth Harrison, Judy Zhong, Dariush Moussai, Pinar Siyah, Nina Schatz-Siemers, Jennifer Zeng, Sylvia Adams, Paolo Mignatti

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Breast cancer has the second highest death toll in women worldwide, despite significant progress in early diagnosis and treatments. The main cause of death is metastatic disease. Matrix metalloproteinases (MMP) are required for the initial steps of metastasis, and have therefore been considered as ideal pharmacologic targets for antimetastatic therapy. However, clinical trials of MMP inhibitors were unsuccessful. These trials were conducted in patients with advanced disease, beyond the stage when these compounds could have been effective.Wehypothesized that early treatment with a selective MMP inhibitor between the time of diagnosis and definitive surgery, the so-called "window-of-opportunity," can inhibit metastasis and thereby improve survival. To investigate our hypothesis, we used the 4T1 mouse model of aggressive mammary carcinoma. We treated the animals with SD-7300, an oral inhibitor of MMP-2, -9, and -13, starting after the initial detection of the primary tumor. Seven days later, the primary tumors were excised and analyzed for MMP activity, and the SD-7300 treatment was discontinued. After 4 weeks, the animals were sacrificed and their lungs analyzed histologically for number of metastases and metastatic burden (metastases' area/lung section area). SD-7300 treatment inhibited 70% to 80% of tumor-associated MMP activity (P = 0.0003), reduced metastasis number andmetastatic burden by 50%to60% (P=0.002 and P= 0.0082, respectively), and increased survival (92% vs. 66.7%; P = 0.0409), relative to control vehicle. These results show that treatment of early invasive breast cancer with selectiveMMP inhibitors can lower the risk of recurrence and increase long-term disease-free survival.

Original languageEnglish (US)
Pages (from-to)2370-2377
Number of pages8
JournalMolecular cancer therapeutics
Volume15
Issue number10
DOIs
StatePublished - Oct 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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