Abstract 1118: The novel rexinoid V-125 reduces tumor growth in the MMTV-Neu model of breast cancer and the A/J model of lung cancer via immunomodulation

Abstract

Abstract Rexinoids are ligands which selectively bind to and activate Retinoid X Receptors (RXRs), regulating the transcription of genes involved in several cancer-relevant biological processes. Rexinoids have anti-neoplastic activity with low toxicities in multiple preclinical studies. Bexarotene, used to treat cutaneous T cell lymphoma, is the only FDA-approved rexinoid. Bexarotene has also been evaluated in clinical trials for metastatic breast cancer and non-small-cell lung carcinoma. Subsets of patients in these trials exhibited clinical responses despite advanced, late-stage disease and refractoriness to prior therapy. By modifying structures of known efficacious rexinoids, we can improve potency, increase selectivity for RXR, and minimize toxicity. We have screened a series of novel rexinoids, which are selective for RXR with minimal off-target activation. V-125 was selected as our lead based on its performance in an optimized in vitro screening paradigm. V-125 displayed potent anti-inflammatory activity without elevating triglycerides, a known adverse effect of other rexinoids. To validate our screening paradigm, the tumor-preventive effects of V-125 were assessed in two clinically relevant mouse models: the MMTV-Neu model of HER2+ breast cancer and the A/J model of lung carcinogenesis. V-125 significantly (p < 0.001) increased tumor-free survival of MMTV-Neu mice in comparison to controls, resulting in a ~10 week increase in mean time to tumor development. In A/J mice, V-125 significantly (p < 0.05) reduced lung surface tumor number, size, and burden without increasing plasma triglycerides. To assess the treatment efficacy of V-125, MMTV-neu mice with established tumors were treated with V-125 or control diet. Overall survival was significantly (p < 0.05) higher in mice treated with V-125 than the control. To characterize the mechanism of V-125, we evaluated a mouse breast cancer PCR array, which demonstrated that V-125 downregulates IL-6 mRNA expression in MMTV-Neu tumors over three-fold, suggesting that V-125 modulates crosstalk between cancer cells and immune cells. We have previously shown that rexinoids alter immune cell populations in tumors and modulate secretion of inflammatory cytokines. A growing body of literature also suggests that RXR plays a role in regulating phenotype and function of macrophages. To test the hypothesis that V-125 modulates macrophage populations in the tumor microenvironment, we evaluated the ability of V-125 to differentially skew tumor-educated macrophages. Bone marrow-derived macrophages were stimulated with conditioned media from MMTV-Neu tumor cells and treated with V-125, and the expression of phenotypic markers was assessed by qPCR. These studies provide insight into the mechanism of V-125, which has the potential to be effective in reducing cancer growth. Citation Format: Lyndsey Reich, Jessica Moerland, Ana S. Leal, Di Zhang, Sarah Carapellucci, Carl E. Wagner, Karen Liby. The novel rexinoid V-125 reduces tumor growth in the MMTV-Neu model of breast cancer and the A/J model of lung cancer via immunomodulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1118.