Abstract A28: Beta-escin inhibits ovarian cancer metastasis by targeting the tumor microenvironment

The high mortality rate that results from ovarian cancer (OvCa) is caused by the wide dissemination of cancer cells within the abdominal cavity. OvCa cells metastasize to the peritoneum, which is covered by a single layer of mesothelial cells, and invade into the underlying stroma, composed of extracellular matrices including fibronectin (FN) and stromal cells such as fibroblasts. Using a three-dimensional organotypic quantitative high-throughput screening platform (3D-qHTS) modeling the peritoneum, we discovered that beta-escin inhibited OvCa adhesion and invasion to the peritoneum. Beta-escin is a natural triterpenoid saponin from Chinese horse chestnut seeds and has a variety of known pharmacologic effects. We hypothesize that beta-escin targets both the cancer cells and the stromal cells to inhibit the metastatic niche. The therapeutic effects of beta-escin and horse chestnut seed extract were tested in vivo using xenograft and syngeneic models of OvCa prevention and intervention. The mechanisms of beta-escin action in cancer cells and microenvironmental cells was explored in vitro using OvCa cell lines and primary human mesothelial cells and fibroblasts, and in vivo using different mouse models of metastasis. Moreover, a collection of 160 analogs of beta-escin were gathered and screened using our 3D-qHTS platform for inhibitory activity in OvCa cell adhesion/invasion. Our results reveal that beta-escin and horse chestnut extract taken orally inhibit metastasis in both OvCa prevention and intervention models. In addition, beta-escin mechanistically depresses the pluripotent stem cell population, inflammatory cytokine secretion, HIF-1alpha expression, and fibronectin production, while it increases autophagy in the tumor microenvironment. Furthermore, three distant analogs of beta-escin inhibited OvCa metastasis, and all three are cardiac glycosides. Taken together, we reveal a potential therapeutic value for beta-escin and/or analogs of beta-escin in preventing and treating OvCa dissemination. Citation Format: Hilary A. Kenny, Madhu Lal, Min Shen, Betul Kara, Chun-Yi Chiang, Karen Watters, Peter Hart, Marc Ferrer, Ernst Lengyel. Beta-escin inhibits ovarian cancer metastasis by targeting the tumor microenvironment. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr A28.