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      Sulindac sulfide as a non-immune suppressive γ-secretase modulator to target triple-negative breast cancer

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          Abstract

          Introduction

          Triple-negative breast cancer (TNBC) comprises a heterogeneous group of clinically aggressive tumors with high risk of recurrence and metastasis. Current pharmacological treatment options remain largely limited to chemotherapy. Despite promising results, the efficacy of immunotherapy and chemo-immunotherapy in TNBC remains limited. There is strong evidence supporting the involvement of Notch signaling in TNBC progression. Expression of Notch1 and its ligand Jagged1 correlate with poor prognosis. Notch inhibitors, including g-secretase inhibitors (GSIs), are quite effective in preclinical models of TNBC. However, the success of GSIs in clinical trials has been limited by their intestinal toxicity and potential for adverse immunological effects, since Notch plays key roles in T-cell activation, including CD8 T-cells in tumors. Our overarching goal is to replace GSIs with agents that lack their systemic toxicity and ideally, do not affect tumor immunity. We identified sulindac sulfide (SS), the active metabolite of FDA-approved NSAID sulindac, as a potential candidate to replace GSIs.

          Methods

          We investigated the pharmacological and immunotherapeutic properties of SS in TNBC models in vitro, ex-vivo and in vivo.

          Results

          We confirmed that SS, a known γ-secretase modulator (GSM), inhibits Notch1 cleavage in TNBC cells. SS significantly inhibited mammosphere growth in all human and murine TNBC models tested. In a transplantable mouse TNBC tumor model (C0321), SS had remarkable single-agent anti-tumor activity and eliminated Notch1 protein expression in tumors. Importantly, SS did not inhibit Notch cleavage in T- cells, and the anti-tumor effects of SS were significantly enhanced when combined with a-PD1 immunotherapy in our TNBC organoids and in vivo.

          Discussion

          Our data support further investigation of SS for the treatment of TNBC, in conjunction with chemo- or -chemo-immunotherapy. Repurposing an FDA-approved, safe agent for the treatment of TNBC may be a cost-effective, rapidly deployable therapeutic option for a patient population in need of more effective therapies.

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          Most cited references163

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          Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

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            Gene Ontology: tool for the unification of biology

            Genomic sequencing has made it clear that a large fraction of the genes specifying the core biological functions are shared by all eukaryotes. Knowledge of the biological role of such shared proteins in one organism can often be transferred to other organisms. The goal of the Gene Ontology Consortium is to produce a dynamic, controlled vocabulary that can be applied to all eukaryotes even as knowledge of gene and protein roles in cells is accumulating and changing. To this end, three independent ontologies accessible on the World-Wide Web (http://www.geneontology.org) are being constructed: biological process, molecular function and cellular component.
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              limma powers differential expression analyses for RNA-sequencing and microarray studies

              limma is an R/Bioconductor software package that provides an integrated solution for analysing data from gene expression experiments. It contains rich features for handling complex experimental designs and for information borrowing to overcome the problem of small sample sizes. Over the past decade, limma has been a popular choice for gene discovery through differential expression analyses of microarray and high-throughput PCR data. The package contains particularly strong facilities for reading, normalizing and exploring such data. Recently, the capabilities of limma have been significantly expanded in two important directions. First, the package can now perform both differential expression and differential splicing analyses of RNA sequencing (RNA-seq) data. All the downstream analysis tools previously restricted to microarray data are now available for RNA-seq as well. These capabilities allow users to analyse both RNA-seq and microarray data with very similar pipelines. Second, the package is now able to go past the traditional gene-wise expression analyses in a variety of ways, analysing expression profiles in terms of co-regulated sets of genes or in terms of higher-order expression signatures. This provides enhanced possibilities for biological interpretation of gene expression differences. This article reviews the philosophy and design of the limma package, summarizing both new and historical features, with an emphasis on recent enhancements and features that have not been previously described.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                13 October 2023
                2023
                : 14
                : 1244159
                Affiliations
                [1] 1Department of Genetics, Louisiana State University Health Sciences Center, New Orleans (LSUHSC-NO) , New Orleans, LA, United States
                [2] 2Department of Pharmacological and Chemical Biology, Emory University , Atlanta, GA, United States
                [3] 3Department of Interdisciplinary Oncology, LSUHSC-NO , New Orleans, LA, United States
                [4] 4Department of Neurobiology and Anatomical Sciences, University of Mississippi Medical Center , Jackson, MS, United States
                [5] 5Department of Veterinary and Animal Sciences, University of Massachusetts , Amherst, MA, United States
                [6] 6School of Medicine, Tulane University , New Orleans, LA, United States
                [7] 7Department of Pathology, Louisiana State University Health Sciences Center - New Orleans (LSUHSC-NO) , New Orleans, LA, United States
                Author notes

                Edited by: Damien Thevenin, Lehigh University, United States

                Reviewed by: Isabella Screpanti, Sapienza University of Rome, Italy; Hui Jia, Shenyang Medical College, China

                *Correspondence: Lucio Miele, lmiele@ 123456lsuhsc.edu

                †Present addresses: Deniz A. Ucar, Tulane Brain Institute, Tulane University, New Orleans, LA, United States; Hanh Luu, NOPS Urology, West Jefferson Medical Center, Marrero, LA, United States

                Article
                10.3389/fimmu.2023.1244159
                10612326
                37901240
                591787c7-89a8-4b92-9d59-5dada8b3b1e6
                Copyright © 2023 Hossain, Ucar, Monticone, Ran, Majumder, Larter, Luu, Wyczechowska, Heidari, Xu, Shanthalingam, Matossian, Xi, Burow, Collins-Burow, Del Valle, Hicks, Zabaleta, Golde, Osborne and Miele

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 21 June 2023
                : 18 September 2023
                Page count
                Figures: 8, Tables: 0, Equations: 0, References: 163, Pages: 16, Words: 7899
                Funding
                This work was supported in part by the National Institute of Health (NIH; P20CA233374; PIs: Miele L. and Ochoa A.). This research was also supported in part by U54 GM104940 from the National Institute of General Medical Sciences of the NIH, which funds the Louisiana Clinical and Translational Science Center (LACaTS).
                Categories
                Immunology
                Original Research
                Custom metadata
                Cancer Immunity and Immunotherapy

                Immunology
                triple-negative breast cancer,sulindac sulfide,immunotherapy,notch,t-cells
                Immunology
                triple-negative breast cancer, sulindac sulfide, immunotherapy, notch, t-cells

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