Abstract 4127: RX-5902 exhibits direct and immunomodulatory anti-tumor activities in melanoma PDX models

Abstract

Abstract Background: Nuclear β-catenin promotes deleterious processes in tumors and their microenvironment. Diminishing nuclear β-catenin attenuates these oncogenic processes. RX-5902 is an oral, small molecule inhibitor of β-catenin nuclear translocation mediated by phosphorylated p68 (DDX5). RX-5902 exhibits potent anti-cancer activity in many cancer cell lines, xenograft models in immunodeficient mice and immune competent mice and in patients. This study examines the relative contribution and context of the direct and immunomodulatory effects on the anti-tumor activities of RX-5902. Methods: Four patient-derived melanoma xenograft models were implanted into either immunodeficient nude mice or NOG mice “humanized” with HLA unmatched CD34+ stem cells with average humanization of 36%. The PDX models were derived from 2 tumors that were clinically unresponsive to an anti-PD-1 agent and 2 tumors obtained prior to any immune treatment. In each category one tumor had BRAF WT and one a V600E mutation. Mice were randomized to receive either vehicle or RX-5902 at 5, 15 or 50 mg/kg po QDx5/Off x2 when implanted tumors reached 100-120 mm3 and began treatment when tumors reached 200mm3. Treatment lasted for 28 days and animals were observed for an additional 14 off therapy. Results: The tumor growth inhibition data at 50 mg/kg is found in the table below. There was evidence of an immune contribution to the TGI in those tumors derived from subjects who did not benefit from I/O (Nivolumab) therapy. In each category the response was greater in tumors with WT BRAF. Conclusion: RX-5902 provided greater TGI in the two melanoma PDX models derived from subjects who were resistant to I/O therapy compared to the models from I/O naïve subjects and, regardless, is greater in BRAF WT vs mutant tumors. The RX-5902 immune-mediated anti-tumoral activity may benefit the majority of melanoma subjects with limited response to BRAF-directed and/or I/O therapy. Citation Format: Andrew Eisen. RX-5902 exhibits direct and immunomodulatory anti-tumor activities in melanoma PDX models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4127.