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 developed OMP-54F28, a recombinant fusion protein consisting of the ligand-binding domain of FZD8 and a human IgG1 Fc fragment. OMP-54F28 acts as a decoy receptor in sequestering Wnts and preventing them from binding to FZD receptors and thereby inhibiting Wnt signaling. The Wnt pathway is important for stem cell self renewal, differentiation, tumorigenicity, and epithelial-mesenchymal transition (EMT). Using minimally passaged human patient-derived xenograft tumors, we demonstrate that OMP-54F28 is efficacious as a single agent and in combination with standard of care in four hepatocellular carcinoma (HCC) and two ovarian cancer models. In the HCC models, OMP-54F28 shows tumor growth inhibition (TGI) as a single agent (average of 46%, p<0.05 vs. control) and displays additive TGI in combination with Sorafenib (average of 78%, p<0.05; 48% Sorafenib alone). Also, in the ovarian cancer models, treatment with OMP-54F28 results in TGI as a single agent (average of 32% vs. control) and shows additive TGI in combination with Paclitaxel (average of 78%, p<0.05; 48% with Paclitaxel alone). We also performed in vivo serial transplantation assays and found that OMP-54F28 as a single agent and in combination with standard of care reduces tumor-initiating cell frequency in both HCC and ovarian cancer xenografts. The anti-tumor effect was associated with a decrease in cell proliferation, induction of cell differentiation, and modulation of target Wnt pathway genes. Our data demonstrate the potential therapeutic benefit of targeting Wnt signaling in HCC and ovarian cancer. OMP-54F28 is being tested in Phase 1b clinical studies in these indications.

Citation Format: Pete Yeung, Lucia Beviglia, Belinda Cancilla, Cristina Dee-Hoskins, James W. Evans, Marcus M. Fischer, Wan-Ching Yen, Austin Gurney, John Lewicki, Timothy Hoey, Ann M. Kapoun. Wnt pathway antagonist OMP-54F28 (FZD8-Fc) inhibits tumor growth and reduces tumor-initiating cell frequency in patient-derived hepatocellular carcinoma and ovarian cancer xenograft models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1907. doi:10.1158/1538-7445.AM2014-1907