Purpose The urokinase receptor (uPAR) plays a critical role in breast cancer (BC) progression and metastases, and is a validated target for novel therapies. The current study investigates the effects of MV-uPA, an oncolytic measles virus fully retargeted against uPAR in syngeneic and xenograft BC metastases models. Methods In vitro replication and cytotoxicity of MVs retargeted against human (MV-h-uPA) or mouse (MV-m-uPA) uPAR were assessed in human and murine cancer and non-cancer mammary epithelial cells. The in vivo effects of species-specific uPAR retargeted MVs were assessed in syngeneic and xenograft models of experimental metastases, established by intravenous administration of luciferase expressing 4T1 or MDA-MD-231 cells. Metastases progression was assessed by in vivo bioluminescence imaging. Tumor targeting was evaluated by qRT-PCR of MV-N, rescue of viable viral particles and immunostaining of MV particles in lungs from tumor bearing mice. Results In vitro, MV-h-uPA and MV-m-uPA selectively infected, replicated and induced cytotoxicity in cancer compared to non-cancer cells in a species-specific manner. In vivo, MV-m-uPA delayed 4T1 lung metastases progression and prolonged survival. These effects were associated with identification of viable viral particles, viral RNA and detection of MV-N by immunostaining from lung tissues in treated mice. In the human MDA-MB-231 metastases model, intravenous administration of MV-h-uPA markedly inhibited metastases progression and significantly improved survival, compared to controls. No significant treatment related toxicity was observed in treated mice. Conclusions The above preclinical findings strongly suggest that uPAR retargeted measles virotherapy is a novel and feasible systemic therapy strategy against metastatic breast cancer.
The oncolytic virotherapy field has made significant advances in the last decade, with a rapidly increasing number of early- and late-stage clinical trials, some of them showing safety and promising therapeutic efficacy. Targeting tumor vasculature by oncolytic viruses (OVs) is an attractive strategy that offers several advantages over nontargeted viruses, including improved tumor viral entry, direct antivascular effects, and enhanced antitumor efficacy. Current understanding of the biological mechanisms of tumor neovascularization, novel vascular targets, and mechanisms of resistance has allowed the development of oncolytic viral vectors designed to target tumor neovessels. While some OVs (such as vaccinia and vesicular stomatitis virus) can intrinsically target tumor vasculature and induce vascular disruption, the majority of reported vascular-targeted viruses are the result of genetic manipulation of their viral genomes. Such strategies include transcriptional or transductional endothelial targeting, “armed” viruses able to downregulate angiogenic factors, or to express antiangiogenic molecules. The above strategies have shown preclinical safety and improved antitumor efficacy, either alone, or in combination with standard or targeted agents. This review focuses on the recent efforts toward the development of vascular-targeted OVs for cancer treatment and provides a translational/clinical perspective into the future development of new generation biological agents for human cancers.
Background: There are no accepted best practices for clinicians to report their non-English language (NEL) fluencies. Language discordance between patients with limited English proficiency and their clinicians may contribute to suboptimal quality of care.
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
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