Abstract 4233: Wnt pathway antagonist ipafricept (FZD8-Fc, OMP-54F28) inhibits tumor growth and reduces tumor-initiating cell frequency in ovarian patient-derived xenograft models

• Published in: Cancer research (Chicago, Ill.) Ill.), 2015-08, Vol.75 (15_Supplement), p.4233-4233
• Main Authors: Fischer, Marcus M., Yen, Wan-Ching, Zheng, Chun, Henner, Randall, Cattaruzza, Fiore, Tang, Tracy, Yeung, Pete, Biswas, Tanuka, Lewicki, John, Gurney, Austin, Kapoun, Ann M., Hoey, Timothy
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2015-4233

Ovarian cancer is the deadliest gynecologic malignancy and the fifth leading cause of death from cancer in women in the U.S. 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 ipafricept (FZD8-Fc, OMP-54F28), a recombinant fusion protein consisting of the ligand-binding domain of FZD8 and a human IgG1 Fc fragment. This fusion protein blocks Wnt signaling induced by multiple Wnt family members by binding and sequestering WNT. Using minimally passaged ovarian patient-derived xenograft tumors (PDX), we demonstrate that ipafricept is efficacious in combination with chemotherapy in four of eight ovarian cancer PDX tumors examined. Utilizing an in vivo serial transplantation assay, we quantified a reduction of the tumor initiating cell frequency by ipafricept in combination with paclitaxel. Additionally, we have discovered that pre-treatment with ipafricept several days prior to paclitaxel therapy enhances the activity of both agents when compared to delivering the drugs simultaneously. The anti-tumor effect observed is directly associated with a modulation of Wnt pathway gene sets. In responsive tumors, we discovered that a large number of WNT target genes were significantly down-regulated by ipafricept (e.g, AXIN2, LRP5/6, and FZD8). Conversely, in non-responsive tumors, these genes were either unchanged or up-regulated by the combination therapy. Histologic analysis revealed that total beta-catenin protein levels were reduced by ipafricept alone and in combination with paclitaxel in responsive tumors but were unchanged in non-responsive tumors. We are using these tumors to develop biomarkers that can be used clinically. Our data demonstrates the potential therapeutic benefit of targeting Wnt signaling in ovarian cancer. A Phase 1b clinical trial is currently examining ipafricept in combination with paclitaxel and carboplatin in patients with recurrent platinum-sensitive ovarian cancer. Citation Format: Marcus M. Fischer, Wan-Ching Yen, Chun Zheng, Randall Henner, Fiore Cattaruzza, Tracy Tang, Pete Yeung, Tanuka Biswas, John Lewicki, Austin Gurney, Ann M. Kapoun, Timothy Hoey. Wnt pathway antagonist ipafricept (FZD8-Fc, OMP-54F28) inhibits tumor growth and reduces tumor-initiating cell frequency in ovarian patient-derived xenograft models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 201