Abstract
Abstract The cancer stem cell (CSC) theory indicates that only a subset of the cancer cells is capable of tumor-initiation, self renewal and differentiation. CSC is also thought to be treatment resistant and responsible for recurrence. Different antigens are being used to identify CSC markers and are potential targets for CSC-based therapy. Due to the expression of the same antigens on normal stem cells it is of paramount importance that CSC-targeting cytotoxins are specifically and efficiently delivered to malignant tissues. Photochemical internalization (PCI) is a method for specific delivery of membrane impermeable macromolecules from endocytic vesicles to the cytosol of targeted cells. In this study we show that PCI increase the cytotoxic effect of immunotoxins (IT) targeting stem cell markers on different cell lines. The IT consists of a CSC-targeting mAb biotinylated to the ribosome inactivating plant (RIP) toxin saporin. TPCS2a-PCI of one of the ITs showed to be very cytotoxic at sub picomolar levels. Cytotoxicity of the IT was blocked by using excess concentration of unconjugated Ab. In addition, no difference in cytotoxicity was obtained between mAb-toxin and toxin alone in marker negative cell lines, confirming specificity. In order to asses enrichment of CSC-activity in vitro we used flow cytometry to sort cells based on the degree of expression of CSC-markers and compared the ability of different cell fractions to establish colonies in both 2D and 3D cell cultures growing in serum-free stem cell media. Cells with high expression of CSC-markers had significantly higher capacity to initiate colonies than low expressing cells. CSC enrichment was confirmed by an in vivo limiting dilution assay. The present study demonstrates that PCI is an efficient method for selective killing of cancer cells expressing stem cell markers and will be further explored for the targeting of tumors that express these markers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3381. doi:1538-7445.AM2012-3381
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