Utilizing porcupine (PORCN) and DKK1 inhibition to improve anti-tumor immunity in a murine model of ovarian cancer

• Published in: Journal of clinical oncology Vol. 38; no. 15_suppl; p. e18041
• Main Authors: Wall, Jaclyn, Katre, Ashwini A., Meza-Perez, Selene, Londono, Angelina, Norian, Lyse, Arend, Rebecca Christian
• Format: Journal Article
• Language: English
• Published: 20.05.2020
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2020.38.15_suppl.e18041

Abstract only e18041 Background: Epithelial ovarian cancers (EOC) are immunologically “cold” tumors and consequently have seen limited success with immunotherapy. Wnt-beta/catenin signaling is dysregulated in multiple cancers, including EOC, and is characterized by immune exclusion. Porcupine (PORCN) is the enzyme necessary for secretion of Wnt ligands, which is required for activation of Wnt/beta-catenin signaling. Up-regulation of the Wnt/beta-catenin pathway leads to increased levels of the target gene DKK1, which plays a role in immune exclusion. Our goal is to improve the tumor immune response via targeting Wnt-signaling in EOC. Methods: We utilized a syngeneic murine model (ID8 cell line) deficient in p53 (ID8p53 −/− ) with and without the addition of a Luciferase tag (Luc+/-) to assess the effect of treatment with a PORCN inhibitor, CGX-1321, with and without DKN-01, a monoclonal antibody targeting DKK1. Mice were treated with vehicle/control, CGX-1321, DKN-01, or CGX-1321/DKN-01. Treatment was given for either 14 or 31 days. In Luc+ mice, bioluminescence imaging was performed weekly. Following mouse sacrifice, omental weights and ascites volume were measured. Omental tumor was used for flow cytometry and representative samples were sent for NanoString analysis. Results: Treatment with CGX-1321 for 14 days reduced omental weight and ascites volume in Luc- mice only (p = 0.02); however, earlier and extended treatment with CGX-1321 and CGX-1321/DKN-01 in Luc+ mice decreased omental weight (p = 0.008 and 0.0025); mice treated with CGX did not develop any ascites with the same treatment schedule. While treatment with DKN-01 alone did not decrease omental weight, treatment with DKN-01 and combination CGX-1321/DKN-01 increased total percentage of NK cells (p = 0.0192 and 0.0070). CGX-1321 and DKN-01 alone and in combination increased the total percentage of CD8+ T cells in omental tumors (p = 0.0238, 0.037, and 0.0127). Conclusions: CGX-1321 decreased omental weight and ascites volume, while DKN-01 increased the cellular percentage of NK cells. Both DKN-01 and CGX-1321 increased CD8+ T cells. Wnt-inhibition is therapeutically promising in EOC, and the combination of a PORCN inhibitor with DKN-01 could improve the response to immune checkpoint blockage and further investigation is warranted.