Abstract 4710: The effect of Wnt inhibition combined with paclitaxel on tumor burden and CD8+ T cell infiltration in syngeneic murine models of ovarian cancer
Authors: Doo David W. , Londono Angelina I. , Moore Dylana J. , Meza-Perez Selene , Katre Ashwini A. , McCaw Tyler R. , Smith Haller J. , Lin Carol Y. , Cooper Sara J. , Straughn J Michael , Buchsbaum Donald J. , Norian Lyse A. , Randall Troy D. , Arend Rebecca C. 
Published: August 2018

Objective: The Wnt/β-catenin pathway is a major signal transduction pathway involved in ovarian cancer (OVCA) metastasis and resistance to chemotherapy. This pathway downregulates protective immunity mediated by intra-tumoral CD8+T cells in other cancer types. WNT974 is a novel drug that inhibits the enzyme Porcupine, which controls Wnt protein secretion. Our objective was to measure the effect of WNT974 alone and in combination with dose dense paclitaxel (ddPac) on tumor growth and on infiltrating CD8+ T cells in two syngeneic OVCA mouse models.

Methods: C57BL/6 mice were injected subcutaneously (SC) (n=20) or intraperitoneally (IP) (n=24) with 7 x 106 ID8 mouse OVCA cells. Mice were treated with vehicle control, ddPac, WNT974, or the combination (combo). C57BL/6 TgMISIIR-Tag-Low transgenic mice were injected with 7 x 106 MOVCAR cells IP (n=8) and treated with vehicle control or combo. WNT974 was given by oral gavage twice a day (5mg/kg for 7 days then decreased to 2.5mg/kg twice a day for up to 4 weeks). Paclitaxel was given IP (5mg/kg) 3 days on and 3 days off for a total of 9 doses. SC tumors were measured with calipers twice per week. In the IP model, mice were sacrificed after 13 days of treatment and tumor weights and ascites volume were determined. Flow cytometry was used to evaluate the presence of CD8+ T cells in IP tumors.

Results: In the ID8 SC model, combo therapy reduced tumor size compared to vehicle control (18 vs. 40mm2, p&lt;0.01) or ddPac alone (18 vs. 39mm2, p&lt;0.01). In the ID8 IP model, tumor weights trended down after treatment (p=NS) and the percentage of intra-tumoral CD8+T cells increased after ddPac or combo treatment (control 4.9%; WNT974 8.3%, p=0.12; ddPac 12.3%, p=0.01; combo 14.9%, p&lt;0.01). In the MOVCAR IP model, combo therapy reduced tumor weight (0.13 vs. 0.19g, p=0.05) and ascites volume (1.0 vs. 8.5 mL, p&lt;0.05), and trended toward increased intra-tumoral CD8+ T cells (33.5 vs. 13.5%, p=0.13).

Conclusions: The combination of WNT974 and ddPac reduced tumor size and increased tumor infiltration of CD8+ T cells in syngeneic OVCA mouse models. This suggests that the improved response observed with the ddPac and WNT974 combination is in part due to upregulation of the intra-tumoral immune response. Further investigation of this pathway is warranted as an immune modulator and a potential therapeutic target in ovarian cancer.

Citation Format: David W. Doo, Angelina I. Londono, Dylana J. Moore, Selene Meza-Perez, Ashwini A. Katre, Tyler R. McCaw, Haller J. Smith, Carol Y. Lin, Sara J. Cooper, J Michael Straughn, Donald J. Buchsbaum, Lyse A. Norian, Troy D. Randall, Rebecca C. Arend. The effect of Wnt inhibition combined with paclitaxel on tumor burden and CD8+ T cell infiltration in syngeneic murine models of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4710.