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

Frontiers in Immunology

Immunology

Giulia Monticone¹  Chindo Hicks¹  Kristina Larter¹  Yaguang Xi¹  Deniz A. Ucar¹  Lucio Miele¹  Fokhrul Hossain¹  Samarpan Majumder¹  Hanh Luu¹  Soroor Heidari¹  Dorota Wyczechowska²  Jovanny Zabaleta²  Luis Del Valle³  Keli Xu⁴  Yong Ran⁵  Todd Golde⁵  Barbara Osborne⁶  Sudarvili Shanthalingam⁶  Matthew Burow⁷  Margarite Matossian⁷  Bridgette Collins-Burow⁷ 

[1] Department of Genetics, Louisiana State University Health Sciences Center, New Orleans (LSUHSC-NO), New Orleans, LA, United States;Department of Interdisciplinary Oncology, LSUHSC-NO, New Orleans, LA, United States;Department of Interdisciplinary Oncology, LSUHSC-NO, New Orleans, LA, United States;Department of Pathology, Louisiana State University Health Sciences Center - New Orleans (LSUHSC-NO), New Orleans, LA, United States;Department of Neurobiology and Anatomical Sciences, University of Mississippi Medical Center, Jackson, MS, United States;Department of Pharmacological and Chemical Biology, Emory University, Atlanta, GA, United States;Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA, United States;School of Medicine, Tulane University, New Orleans, LA, United States;

关键词: triple-negative breast cancer;    sulindac sulfide;    immunotherapy;    Notch;    T-cells;   

DOI  :  10.3389/fimmu.2023.1244159

 received in 2023-06-21, accepted in 2023-09-18,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionTriple-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.MethodsWe investigated the pharmacological and immunotherapeutic properties of SS in TNBC models in vitro, ex-vivo and in vivo.ResultsWe 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.DiscussionOur 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.

【 授权许可】

Unknown   
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