title: Inhibition of Breast Cancer Metastasis by Presurgical Treatment with an Oral Matrix Metalloproteinase Inhibitor: A Preclinical Proof-of-Principle Study.
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. We hypothesized 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 and metastatic burden by 50% to 60% (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 selective MMP inhibitors can lower the risk of recurrence and increase long-term disease-free survival. Mol Cancer Ther; 15(10); 2370-7. ©2016 AACR.
authors.affiliation: Department of Medicine, New York University School of Medicine, New York, New York.
authors.forename: Arthur
authors.initials: A
authors.lastname: Winer
authors.affiliation: Department of Medicine, New York University School of Medicine, New York, New York.
authors.forename: Maxwell
authors.initials: M
authors.lastname: Janosky
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, New York.
authors.forename: Beth
authors.initials: B
authors.lastname: Harrison
authors.affiliation: Department of Population Health, New York University School of Medicine, New York, New York.
authors.forename: Judy
authors.initials: J
authors.lastname: Zhong
authors.affiliation: Department of Medicine, New York University School of Medicine, New York, New York.
authors.forename: Dariush
authors.initials: D
authors.lastname: Moussai
authors.affiliation: Department of Medicine, New York University School of Medicine, New York, New York.
authors.forename: Pinar
authors.initials: P
authors.lastname: Siyah
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, New York.
authors.forename: Nina
authors.initials: N
authors.lastname: Schatz-Siemers
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, New York.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Zeng
authors.affiliation: Department of Medicine, New York University School of Medicine, New York, New York. Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, New York.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Adams
authors.affiliation: Department of Medicine, New York University School of Medicine, New York, New York. Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, New York. Department of Cell Biology, New York University School of Medicine, New York, New York. mignap01@nyumc.org.
authors.forename: Paolo
authors.initials: P
authors.lastname: Mignatti
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000556:secondary; D061965:Matrix Metalloproteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D061965:Matrix Metalloproteinase Inhibitors