Abstract 2072: Inhibition of breast cancer stem cells by Hedgehog-inhibitory peptide conjugated with Elastin-like biopolymers

Abstract

Abstract The Hedgehog(Hh) signaling pathway has been reported to play a pivotal role in cancer. Studies have shown that suppression of this aberrantly activated Hh pathway may be effective in controlling the development and proliferation of many cancers. However, to date, there is no drug in clinical application that can be used to inhibit the Hh signaling pathway and suppress cancer growth. In attempt to address this problem, we developed a thermally responsive polypeptide inhibitor of the Hh pathway. This polypeptide is derived from a mammalian tropo-elastin protein which will aggregate and accumulate at the tumor site where local hyperthermia is applied. For this study, ELP was fused to a peptide that inhibits Hh signaling by blocking interaction of Sonic Hh ligand (Shh) with the Patch-1 docking site. To improve bioavailability, ELP was further modified by adding the cell penetrating peptide, Tat. The anti-proliferative activity of Tat-Hhi-ELP was examined in three breast cancer cell lines: MCF7, MDA-MB-231, and SKBR-3. Treatment of the cells with 20 uM of peptide for 2 days resulted in maximally 40% inhibition of cell proliferation. Observed cytotoxicity was further increased two fold by application of hyperthermia. To validate that Tat-Hhi-ELP is targeting the Hh pathway, we determined the levels of GLI-1, which is a downstream target in the Hh pathway. Treatment of the breast cancer cells with Tat-Hhi-ELP resulted in reduction of GLI-1 levels, indicating that the cytotoxicity is based on hedgehog pathway inhibition. Furthermore, the formation of mammospheres was significantly reduced by treatment with Tat-Hhi-ELP in SKBR-3 cells. These results suggest that thermal targeting of ELP-based Hedgehog inhibitory peptides to breast cancer cells may be an effective and promising treatment strategy against breast cancer stem cells. Citation Format: Jung Su Ryu, Drazen Raucher. Inhibition of breast cancer stem cells by Hedgehog-inhibitory peptide conjugated with Elastin-like biopolymers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2072.