RX-5902, a novel β-catenin modulator, potentiates the efficacy of immune checkpoint inhibitors in preclinical models of triple-negative breast Cancer

BMC Cancer

S. Gail Eckhardt¹  Anna Capasso¹  Roberta Pelanda²  Julie Lang²  Brian Gittleman³  Betelehem W. Yacob³  Stacey M. Bagby³  Sarah J. Hartman³  Jennifer R. Diamond⁴  John J. Tentler⁴  Todd M. Pitts⁴  Andrew Eisen⁵  Young B. Lee⁵  Deog Joong Kim⁵  Ely Benaim⁵ 

[1] Dell Medical School, Department of Oncology, University of Texas at Austin, Austin, TX, USA;Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, USA;Division of Medical Oncology, School of Medicine, University of Colorado Anschutz Medical Campus, 12801 E 17th Ave, MS8117, 80045, Aurora, CO, USA;Division of Medical Oncology, School of Medicine, University of Colorado Anschutz Medical Campus, 12801 E 17th Ave, MS8117, 80045, Aurora, CO, USA;University of Colorado Cancer Center, Anschutz Medical Campus, 12801 E 17th Ave, MS8117, 80045, Aurora, CO, USA;Rexahn Pharmaceuticals Inc., Rockville, MD, USA;

关键词: RX-5902;    Triple-negative breast cancer;    p68;    β-Catenin;    PD-1 inhibitor;    Immunotherapy;    Humanized mouse models;   

DOI  :  10.1186/s12885-020-07500-1

来源: Springer

【 摘 要 】

BackgroundTriple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited systemic treatment options. RX-5902 is a novel anti-cancer agent that inhibits phosphorylated-p68 and thus attenuates nuclear β-catenin signaling. The purpose of this study was to evaluate the ability of β-catenin signaling blockade to enhance the efficacy of anti-CTLA-4 and anti-PD-1 immune checkpoint blockade in immunocompetent, preclinical models of TNBC.MethodsTreatment with RX-5902, anti-PD-1, anti-CTLA-4 or the combination was investigated in BALB/c mice injected with the 4 T1 TNBC cell line. Humanized BALB/c-Rag2nullIl2rγnullSIRPαNOD (hu-CB-BRGS) mice transplanted with a human immune system were implanted with MDA-MB-231 cells. Mice were randomized into treatment groups according to human hematopoietic chimerism and treated with RX-5902, anti-PD-1 or the combination. At sacrifice, bone marrow, lymph nodes, spleen and tumors were harvested for flow cytometry analysis of human immune cells.ResultsThe addition of RX-5902 to CTLA-4 or PD-1 inhibitors resulted in decreased tumor growth in the 4 T1 and human immune system and MDA-MB-231 xenograft models. Immunologic analyses demonstrated a significant increase in the number of activated T cells in tumor infiltrating lymphocytes (TILs) with RX-5902 treatment compared to vehicle (p < 0.05). In the RX-5902/nivolumab combination group, there was a significant increase in the percentage of CD4+ T cells in TILs and increased systemic granzyme B production (p < 0.01).ConclusionsConclusions: RX-5902 enhanced the efficacy of nivolumab in a humanized, preclinical model of TNBC. Several changes in immunologic profiles were noted in mice treated with RX-5902 and the combination, including an increase in activated TILs and a decrease in human myeloid populations, that are often associated with immunosuppression in a tumor microenvironment. RX-5902 also was shown to potentiate the effects of checkpoint inhibitors of CTLA4 and the PD-1 inhibitor in the 4 T-1 murine TNBC model. These findings indicate that RX-5902 may have important immunomodulatory, as well as anti-tumor activity, in TNBC when combined with a checkpoint inhibitor.

【 授权许可】

CC BY