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Novel TREM-1 Inhibitors Attenuate Tumor Growth and Prolong Survival in Experimental Pancreatic Cancer

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SignaBlok, Inc., P.O. Box 4064, Shrewsbury, Massachusetts 01545, United States
*Phone: 203-505-3807. E-mail: [email protected]
Cite this: Mol. Pharmaceutics 2017, 14, 12, 4572–4582
Publication Date (Web):November 2, 2017
Copyright © 2017 American Chemical Society

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    Abstract Image

    Pancreatic cancer (PC) is a highly lethal cancer with an urgent need to expand the limited treatment options for patients. Tumor-associated macrophages (TAMs) promote tumor aggressiveness and metastasis. High expression of triggering receptor expressed on myeloid cells 1 (TREM-1) on TAMs directly correlates with poor survival in patients with non-small cell lung cancer (NSCLC). We have previously hypothesized that blockade of TREM-1 could be a promising therapeutic strategy to treat cancer and shown that the novel, ligand-independent TREM-1 inhibitory peptides rationally designed using the signaling chain homooligomerization (SCHOOL) strategy suppress NSCLC growth in vivo. Here, we evaluated the therapeutic potential of these inhibitors in three human PC xenograft mouse models. Administration of SCHOOL peptides resulted in a strong antitumor effect achieving an optimal treatment/control (T/C) value of 19% depending on the xenograft and formulation used and persisting even after treatment was halted. The effect correlated significantly with increased survival and suppressed TAM infiltration. The peptides were well-tolerated when deployed either in free form or formulated into lipopeptide complexes for peptide half-life extension and targeted delivery. Finally, blockade of TREM-1 significantly reduced serum levels of interleukin (IL)-1α, IL-6, and macrophage colony-stimulating factor (M-CSF), but not vascular endothelial growth factor, suggesting M-CSF-dependent antitumor mechanisms. Collectively, these promising data suggest that SCHOOL TREM-1-specific peptide inhibitors have a cancer type independent, therapeutically beneficial antitumor activity and can be potentially used as a stand-alone therapy or as a component of combinational therapy for PC, NSCLC, and other solid tumors.

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    Cited By

    This article is cited by 28 publications.

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    17. Sen Yang, Qiaofei Liu, Quan Liao. Tumor-Associated Macrophages in Pancreatic Ductal Adenocarcinoma: Origin, Polarization, Function, and Reprogramming. Frontiers in Cell and Developmental Biology 2021, 8
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    21. Alexander B. Sigalov. Commentary: Triggering Receptor Expressed on Myeloid Cells-1 Inhibitor Targeted to Endothelium Decreases Cell Activation. Frontiers in Immunology 2020, 11
    22. Sébastien Gibot, Lucie Jolly, Jérémie Lemarié, Kevin Carrasco, Marc Derive, Amir Boufenzer. Triggering Receptor Expressed on Myeloid Cells-1 Inhibitor Targeted to Endothelium Decreases Cell Activation. Frontiers in Immunology 2019, 10
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    25. Paloma Honrubia-Gómez, María-Pilar López-Garrido, Carmen Gil-Gas, José Sánchez-Sánchez, Carmen Alvarez-Simon, Jorge Cuenca-Escalona, Ana Ferrer Perez, Enrique Arias, Raul Moreno, Francisco Sánchez-Sánchez, Carmen Ramirez-Castillejo. Pedf derived peptides affect colorectal cancer cell lines resistance and tumour re-growth capacity. Oncotarget 2019, 10 (31) , 2973-2986.
    26. David Tornai, Istvan Furi, Zu T. Shen, Alexander B. Sigalov, Sahin Coban, Gyongyi Szabo. Inhibition of Triggering Receptor Expressed on Myeloid Cells 1 Ameliorates Inflammation and Macrophage and Neutrophil Activation in Alcoholic Liver Disease in Mice. Hepatology Communications 2019, 3 (1) , 99-115.
    27. Modesto A. Rojas, Zu T. Shen, Ruth B. Caldwell, Alexander B. Sigalov. Blockade of TREM-1 prevents vitreoretinal neovascularization in mice with oxygen-induced retinopathy. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 2018, 1864 (9) , 2761-2768.
    28. Kouassi Kouassi, Palanikumar Gunasekar, Devendra Agrawal, Gopal Jadhav. TREM-1; Is It a Pivotal Target for Cardiovascular Diseases?. Journal of Cardiovascular Development and Disease 2018, 5 (3) , 45.

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