Abstract P6-11-07: The Cancer Stem Cell-Targeting Wnt Inhibitor VS-507 Reduces Breast Cancer Growth and Metastasis

Abstract

Abstract Cancer stem cells (CSCs) support tumor viability and growth through their ability to self-renew and differentiate into heterogeneous tumor tissue. CSCs are typically resistant to standard cytotoxic agents, leading to their enrichment and the consequent regrowth of refractory tumors. While this population has been challenging to directly target therapeutically, we are actively developing novel agents, such as VS-507, that selectively target the cancer stem cell subpopulation in vivo. Previously, we and others have shown that VS-507, a cancer stem-cell specific agent, inhibits Wnt signaling with corresponding reduction of the LRP6 protein, a Frizzled co-receptor upregulated in breast cancer cell lines. In the current study, we have continued to examine the effect of VS-507 on the Wnt/Beta-catenin signaling pathway to further elucidate its mechanism of action. We determined that VS-507 also decreases expression of the second Frizzled co-receptor LRP5 in MDA-MB-231 breast cancer cells stimulated by Wnt3A. The combined inhibition of the co-receptors LRP5 and LRP6 may contribute to the observed inhibition of Beta-catenin-mediated transcription by VS-507 in a TOP-Flash assay. Accordingly, VS-507 reduced expression of Axin2, a transcriptional target of Beta-catenin. Because human breast cancer cell lines represent a mixed population of CSC and non-CSC cells, we evaluated VS-507 across a panel of cell lines by monitoring changes in viability and in the percentage of cancer stem cells. In SUM159 triple negative breast cancer cells, VS-507 had micromolar potency against the bulk population with preferential nanomolar potency against the ALDEFLUOR+ CSC population with similar effects observed in the Hoechst side population (SP) CSC assay. In contrast, cytotoxic anticancer drugs such as paclitaxel and cisplatin increased the percentage of ALDEFLUOR+ cancer stem cells under similar conditions. In vivo, oral administration of VS-507 (15 mg/kg, QD daily) as a single agent partially inhibited MDA-MB-231 tumor growth, consistent with its observed inhibition of the cancer stem cell subpopulation. Furthermore, VS-507 inhibited lung metastasis in a 4T1.2 murine breast cancer model. In summary, these results further elucidate the mechanism by which VS-507 inhibits Wnt/Beta-catenin signaling. VS-507 reduces tumor cell proliferation in vitro with preferential effects on cancer stem cells which translate to inhibition of tumor growth, enhancement of efficacy of cytotoxic agents such as docetaxel, and inhibition of metastasis in mouse models. These data provide additional support for the development of VS-507 as a novel anti-cancer stem cell agent. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-11-07.