Abstract A254: Systemic injection of human neural stem cells expressing anti-cancer agent targets invasive gliomas and induces tumor regression in combination with a cardiac glycoside.

Abstract

Abstract Glioblastoma multiforme (GBM) is the most common and most aggressive malignant form of brain tumors in human. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is regarded as an anticancer agent, however, a considerable number of tumor types, including GBM, are resistant to TRAIL. Also, TRAIL therapeutic use in vivo is limited by a short half-life in plasma due to a rapid clearance by the kidney and a poor penetration across the blood-brain barrier. The tumor-tropic properties of neural stem cells (NSCs) could serve as a novel strategy to deliver therapeutic genes to tumors in the brain. Furthermore, we have previously reported that the cardiac glycoside lanatoside C sensitizes GBM cells to TRAIL-induced apoptosis. In this study, we engineered human neural stem cell to synthesize and secrete an active form of TRAIL (NSC-sTRAIL) as well as the secreted Gaussia luciferase (Gluc) as a blood marker for cell proliferation. We showed that these cells selectively migrate toward GBM stem-like cells (GSCs) in a transwell assay. However, GSCs’ growth was only decreased by 11.6%. When this co-culture was treated with lanatoside C, GSCs’ growth was inhibited by 81.5% in a caspase-mediated manner. We then tested this combined therapy in an invasive orthotopic model using primary GSC neurospheres expressing firefly luciferase. Upon systemic injection, Gluc blood assay showed that at the next day at least 30% of NSC-sTRAIL, and after 5 weeks up to 0.5% of these cells survived. Histological analysis showed that the NSC-sTRAIL cells crossed the blood-brain barrier and migrated toward invasive GSC tumors. Bioluminescence imaging showed that tumors in mice treated with NSC-sTRAIL cells in combination with lanatoside C resulted in significant tumor regression and mouse survival elongation as compared to single therapy. Taken together, this study demonstrated that systemic injection of neural stem cells targets invasive brain tumors and could be used to deliver an anticancer agent such as sTRAIL which yields significant tumor regression when used in combination with lanatoside C. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A254. Citation Format: Jian Teng, Seyedali Hejazi, Christian E. Badr, Bakhos A. Tannous. Systemic injection of human neural stem cells expressing anti-cancer agent targets invasive gliomas and induces tumor regression in combination with a cardiac glycoside. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A254.