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

BMC Cancer. 2020 Nov 4;20(1):1063. doi: 10.1186/s12885-020-07500-1.

Abstract

Background: Triple-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.

Methods: Treatment 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.

Results: The 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).

Conclusions: Conclusions: 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.

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

MeSH terms

  • Animals
  • Apoptosis
  • Cell Proliferation
  • Drug Therapy, Combination
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology*
  • Lymphocytes, Tumor-Infiltrating / drug effects
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Piperazines / pharmacology*
  • Quinoxalines / pharmacology*
  • Triple Negative Breast Neoplasms / drug therapy*
  • Triple Negative Breast Neoplasms / metabolism
  • Triple Negative Breast Neoplasms / pathology
  • Tumor Cells, Cultured
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / immunology*
  • Xenograft Model Antitumor Assays
  • beta Catenin / antagonists & inhibitors*
  • beta Catenin / metabolism

Substances

  • CTNNB1 protein, human
  • Immune Checkpoint Inhibitors
  • Piperazines
  • Quinoxalines
  • RX-5902
  • beta Catenin