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

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.

• Authors: John J Tentler, Julie Lang, Anna Capasso, Deog Joong Kim, Ely Benaim, Young B Lee, Andrew Eisen, Stacey M Bagby, Sarah J Hartman, Betelehem W Yacob, Brian Gittleman, Todd M Pitts, Roberta Pelanda, S Gail Eckhardt, Jennifer R Diamond
• Journal: BMC cancer (BMC Cancer) Vol. 20 Issue 1 Pg. 1063 (Nov 04 2020) ISSN: 1471-2407 [Electronic] England
• PMID: 33148223 (Publication Type: Journal Article)

Chemical References

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

Topics

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