OncoMed researchers publish new findings on WNT drug combinatorial anti-tumor activity in multiple tumor types including breast, pancreatic, lung and ovarian cancer.
Hyperactive Wnt signaling is a key oncogenic signal in many types of cancer, and recently has been associated with resistance to cancer immunotherapeutics. OncoMed scientists have published a manuscript in Science Advances on June 21 2017 titled “WNT antagonists exhibit unique combinatorial anti-tumor activity with taxanes by potentiating mitotic cell death”. In this paper we describe a series of experiments in a large number of patient derived xenografts with two OncoMed developed compounds, vantictumab (anti-FZD) and ipafricept (FZD8-Fc). These two biologics are the most advanced Wnt pathway antagonists in clinical development. We discovered that these agents exhibit much better combination activity with taxanes than with other classes of chemotherapeutic agents, such as gemcitabine or platinum compounds. This is a robust phenomenon and occurs in diverse tumor types including breast, pancreatic, lung and ovarian cancers. Furthermore, we report that combination activity is enhanced by administration of the Wnt antagonist prior to taxane treatment. The combination of Wnt blockade and taxane treatment leads to a dramatic histological phenotype - mitotic cell death in tumor cells. Our hypothesis is that the unique combination activity relies on the action of taxane chemotherapy and inhibition of beta-catenin at the M phase of the cell cycle. This discovery has informed our clinical testing strategy and the mechanism of synergy has implications in understanding the role of Wnt/beta-catenin signaling in regulating the proliferation and differentiation of cancer cells.