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 th...
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doaj-1dcda43bbcb945d6ae883320daa5d6482020-11-25T03:59:54ZengBMCBMC Cancer1471-24072020-11-0120111310.1186/s12885-020-07500-1RX-5902, a novel β-catenin modulator, potentiates the efficacy of immune checkpoint inhibitors in preclinical models of triple-negative breast CancerJohn J. Tentler0Julie Lang1Anna Capasso2Deog Joong Kim3Ely Benaim4Young B. Lee5Andrew Eisen6Stacey M. Bagby7Sarah J. Hartman8Betelehem W. Yacob9Brian Gittleman10Todd M. Pitts11Roberta Pelanda12S. Gail Eckhardt13Jennifer R. Diamond14Division of Medical Oncology, School of Medicine, University of Colorado Anschutz Medical CampusDepartment of Immunology and Microbiology, University of Colorado Anschutz Medical CampusDell Medical School, Department of Oncology, University of Texas at AustinRexahn Pharmaceuticals Inc.Rexahn Pharmaceuticals Inc.Rexahn Pharmaceuticals Inc.Rexahn Pharmaceuticals Inc.Division of Medical Oncology, School of Medicine, University of Colorado Anschutz Medical CampusDivision of Medical Oncology, School of Medicine, University of Colorado Anschutz Medical CampusDivision of Medical Oncology, School of Medicine, University of Colorado Anschutz Medical CampusDivision of Medical Oncology, School of Medicine, University of Colorado Anschutz Medical CampusDivision of Medical Oncology, School of Medicine, University of Colorado Anschutz Medical CampusDepartment of Immunology and Microbiology, University of Colorado Anschutz Medical CampusDell Medical School, Department of Oncology, University of Texas at AustinDivision of Medical Oncology, School of Medicine, University of Colorado Anschutz Medical CampusAbstract 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.http://link.springer.com/article/10.1186/s12885-020-07500-1RX-5902Triple-negative breast cancerp68β-CateninPD-1 inhibitorImmunotherapy |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 RX-5902, a novel β-catenin modulator, potentiates the efficacy of immune checkpoint inhibitors in preclinical models of triple-negative breast Cancer BMC Cancer RX-5902 Triple-negative breast cancer p68 β-Catenin PD-1 inhibitor Immunotherapy |
author_facet |
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 |
author_sort |
John J. Tentler |
title |
RX-5902, a novel β-catenin modulator, potentiates the efficacy of immune checkpoint inhibitors in preclinical models of triple-negative breast Cancer |
title_short |
RX-5902, a novel β-catenin modulator, potentiates the efficacy of immune checkpoint inhibitors in preclinical models of triple-negative breast Cancer |
title_full |
RX-5902, a novel β-catenin modulator, potentiates the efficacy of immune checkpoint inhibitors in preclinical models of triple-negative breast Cancer |
title_fullStr |
RX-5902, a novel β-catenin modulator, potentiates the efficacy of immune checkpoint inhibitors in preclinical models of triple-negative breast Cancer |
title_full_unstemmed |
RX-5902, a novel β-catenin modulator, potentiates the efficacy of immune checkpoint inhibitors in preclinical models of triple-negative breast Cancer |
title_sort |
rx-5902, a novel β-catenin modulator, potentiates the efficacy of immune checkpoint inhibitors in preclinical models of triple-negative breast cancer |
publisher |
BMC |
series |
BMC Cancer |
issn |
1471-2407 |
publishDate |
2020-11-01 |
description |
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. |
topic |
RX-5902 Triple-negative breast cancer p68 β-Catenin PD-1 inhibitor Immunotherapy |
url |
http://link.springer.com/article/10.1186/s12885-020-07500-1 |
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