TY - JOUR
T1 - Inhibition of breast cancer metastasis by presurgical treatment with an oral matrix metalloproteinase inhibitor
T2 - A preclinical proof-of-principle study
AU - Winer, Arthur
AU - Janosky, Maxwell
AU - Harrison, Beth
AU - Zhong, Judy
AU - Moussai, Dariush
AU - Siyah, Pinar
AU - Schatz-Siemers, Nina
AU - Zeng, Jennifer
AU - Adams, Sylvia
AU - Mignatti, Paolo
N1 - Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2016/10
Y1 - 2016/10
N2 - 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.
AB - 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.
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U2 - 10.1158/1535-7163.MCT-16-0194
DO - 10.1158/1535-7163.MCT-16-0194
M3 - Article
C2 - 27466357
AN - SCOPUS:84990875238
SN - 1535-7163
VL - 15
SP - 2370
EP - 2377
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 10
ER -