Abstract 2576: Enhanced antitumor efficacy by sequential application of Wnt pathway antagonists in combination with taxanes

Abstract

Abstract The Wnt/beta-catenin pathway, which signals through the Frizzled (FZD) receptor family and several co-receptors, has long been implicated in cancer. We have previously demonstrated that inhibition of Wnt/beta-catenin signaling by vantictumab (anti-Fzd7, OMP-18R5) or ipafricept (FZD8-Fc, OMP-54F28) inhibits tumor growth, decreases tumorigenicity and induces differentiation in solid tumors. The anti-tumor effect of our Wnt antagonists is most evident in combination with chemotherapeutic agents. We sought to determine if the anti-tumor effect of Wnt pathway inhibitors varied with different chemotherapeutic agents. We compared the growth inhibitory effect of vantictumab and ipafricept with either taxanes (paclitaxel and nab-paclitaxel) or with DNA synthesis inhibitors (gemcitabine and carboplatin) in patient-derived tumor xenografts. We observed enhanced anti-tumor activity when combining vantictumab or ipafricept with nab-paclitaxel or paclitaxel compared to the combination with gemcitabine or carboplatin in pancreatic ductal carcinoma and serous ovarian cancer xenograft models. Histologic analysis in a pancreatic ductal carcinoma indicated that nab-paclitaxel increased mitotic cells and beta-catenin levels. Importantly, the addition of vantictumab to nab-paclitaxel reversed the nab-paclitaxel-induced increase in mitotic cells and beta-catenin expression. A potential mechanism to account for these results involves the observation that Wnt/beta-catenin signaling is under cell cycle control and peaks at the G2/M phase. Taxanes inhibit microtubule function and block the cell cycle at G2/M. In contrast, other chemotherapeutic agents, such as platinum compounds and nucleoside analogs, inhibit DNA synthesis and block cell proliferation at S phase. Our findings suggest that combination of Wnt blockade with chemotherapeutic agents, such as taxanes, that induce G2/M arrest may resulted in enhanced anti-tumor activity. The optimal synergy of anti-Wnt plus taxane combination occurs when the antibody was applied prior to taxane. Further analyses in serous ovarian tumors reveal that pre-treatment with ipafricept resulted in dysregulated beta-cetenin localization within giant multi-nucleated cells and up-regulation of genes associated with negative regulators of G1 progression. Our work provides evidence for the enhanced anti-tumor effect of Wnt pathway inhibitors in combination with taxanes and highlights the importance of preclinical examination to identify the most efficacious combination therapy regimens and the timing of antibody action for Wnt antagonists in combination with taxanes for optimal treatment efficacy. Citation Format: Wan-Ching Yen, Marcus Fischer, Belinda Cancilla, Fiore Cattaruzza, Tracy Tang, Pete Yeung, John Lewicki, Austin Gurney, Timothy Hoey. Enhanced antitumor efficacy by sequential application of Wnt pathway antagonists in combination with taxanes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2576. doi:10.1158/1538-7445.AM2015-2576