Abstract LB-273: Molecular targeting Neu1 with oseltamivir phosphate abrogates tumor neovascularization, growth, and metastasis in mouse model of human triple-negative breast cancer

Patients with triple-negative breast cancers (TNBCs) lacking the estrogen, progesterone, and epidermal growth factor (EGF) receptor-2 (HER2/neu) receptors have typical high grading, frequent relapses, and exhibit poorer outcomes or prognosis compared with the other subtypes. No current targeted therapies are effective for TNBC. Here, preclinical studies on the antitumor activity of oseltamivir phosphate (OP) monotherapy was investigated to identify its role in tumor neovascularization, growth, invasiveness, and long-term survival in RAGxCγ double mutant mouse model of human TNBC. Sialidase, WST-1, and immunohistochemistry assays were used to evaluate sialidase activity, cell viability, and expression levels of E-, and N-cadherins, and host CD31+/PECAM-1 cells in paraffin-embedded TNBC MDA-MB-231 tumors grown in these mice. OP, anti-Neu1, and matrix metalloproteinase-9-specific inhibitor blocked Neu1 activity associated with EGF-stimulated MDA-MB-231 cells. OP treatment of MDA-MB-231 and MCF-7 cells and their stable tamoxifen-resistant clones reproducibly and dose-dependently reduced the sialidase activity associated with EGF-stimulated live cells and the cell viability after 72 hours of incubation. Combination of 1 μM cisplatin, 5-fluorouracil, paclitaxel, gemcitabine, or tamoxifen with OP in a dose-dependent manner significantly reduced cell viability at 24, 48, and 72 hrs when compared to the chemotherapeutic alone. Heterotopic xenografts of MDA-MB-231 tumors developed bloody tumor vascularization in these mice. OP treatment at 30 mg/kg daily I.P. treatment reduced tumor vascularization and growth rate with significant reduction in tumor weight and spread to the lungs compared with the untreated cohorts. OP treatment at 50 mg/kg completely ablated tumor vascularization, growth and spread to the lungs, with significant long-term survival for 180 days post-implantation, tumor shrinking, and no relapses after 56 days off-drug. OP 30 mg/kg cohort tumors had significantly reduced levels of human N-cadherins and host CD31+ endothelial cells with concomitant significant expression of E-cadherins compared to the untreated cohorts. These findings signify a novel treatment therapy for TNBC. Citation Format: Myron R. Szewczuk, Fiona Haxho, Stephanie Allison, Farah Alghamdi, Lacey Brodhagen, Victoria Kuta, Samar Abdulkhalek, Ronald Neufeld. Molecular targeting Neu1 with oseltamivir phosphate abrogates tumor neovascularization, growth, and metastasis in mouse model of human triple-negative breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-273. doi:10.1158/1538-7445.AM2015-LB-273