Abstract 3545: Stromal selective targeting by uPAR retargeted oncolytic measles virus inhibits breast cancer progression

Abstract

Stromal cells in the tumor microenvironment play an important role in breast cancer progression. Strategies directed against stromal cell components have been investigated in the preclinical and clinical setting. However, few studies have focused on stromal targeting by oncolytic viruses. The urokinase receptor (uPAR) is overexpressed in tumor and stromal cells, and plays a critical role in tumor progression. The aim of this study is to evaluate the antitumor effects of stromal retargeted oncolytic measles virus via urokinase receptor. We rescued and characterized fully retargeted oncolytic measles viruses against human (MV-h-uPA) and murine (MV-m-uPA) urokinase receptor (uPAR). In vitro, MV-m-uPA and MV-h-uPA infected and induced cytotoxicity to human (MDA-MB231, T47D and MCF-7) and murine (4T1) mammary cancer cells in a species specific manner. Efficient MV-m-uPA infection and replication were demonstrated in murine NIH-3T3 mouse fibroblast cells and MS1 murine endothelial cells. Selective infection of murine fibroblasts by the murine uPAR specific MV-m-uPA led to significant inhibition of human breast cancer proliferation in an in vitro 3-D collagen co-culture model of tumor-stromal interactions. To further validate the potential of stromal uPAR targeting as a therapeutic strategy, the effects of MV-uPA were assessed in a human breast cancer xenograft model (MDA-MD231), where tumor cells express human uPAR (target of MV-h-uPA) and the host stroma expresses murine uPAR (target of MV-m-uPA). Tumor bearing mice were treated with MV-h-uPA, MV-m-uPA or combination (MV-h-uPA and MV-m-uPA) by IV administration (3 doses). Surprisingly, MV-m-uPA (selectively targeting mouse uPAR) was associated with a measurable delay in tumor progression while on treatment, as well as prolongation in survival. Combination therapy (MV-m-uPA and MV-h-uPA) was associated with the best antitumor effects in vivo. To further characterize the in vivo effects of stromal uPAR targeting, repeat experiments were performed where tumor bearing mice received prolonged treatment with MV-m-uPA (12 treatments). This approach was shown to be safe and resulted in a significant delay in tumor progression and marked prolongation of survival. These effects were associated with the identification of viable viral particles and viral RNA from MDA-MB231 tumor xenograft treated with MV-m-uPA. In conclusion, our results demonstrate for the first time that oncolytic viral targeting of tumor stroma is feasible and associated with in vivo antitumor effects. These findings further validate the critical role of stromal uPAR in cancer progression. Citation Format: Yuqi Jing, Marcela Toro Bejarano, Krisztina Kovacs, Jaime Merchan. Stromal selective targeting by uPAR retargeted oncolytic measles virus inhibits breast cancer progression. [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 3545. doi:10.1158/1538-7445.AM2015-3545

Silencing of uPAR via RNA interference inhibits invasion and migration of oral tongue squamous cell carcinoma

“…uPAR focuses uPA proteolytic activity on the cell membrane, mediates cell adhesion to vitronectin and activates cell signaling pathways by associating with cell surface molecules (4). Previous studies have demonstrated that uPAR has an increased expression in numerous malignant tumor types, including oral squamous cell, breast and pancreatic carcinomas (5)(6)(7), and it has been indicated to regulate a number of events, including angiogenesis, immune suppression and cell migration (8). Therefore, it has been considered that activation of uPAR serves a notable role in cancer cell invasion and is correlated with a poor long-term prognosis (9).…”