ACS Publications. Most Trusted. Most Cited. Most Read
My Activity
CONTENT TYPES

Figure 1Loading Img

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

View Author Information
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
https://doi.org/10.1021/acs.molpharmaceut.7b00711
Copyright © 2017 American Chemical Society

    Article Views

    1264

    Altmetric

    -

    Citations

    LEARN ABOUT THESE METRICS
    Other access options

    Abstract

    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.

    Read this article

    To access this article, please review the available access options below.

    Get instant access

    Purchase Access

    Read this article for 48 hours. Check out below using your ACS ID or as a guest.

    Recommended

    Access through Your Institution

    You may have access to this article through your institution.

    Your institution does not have access to this content. You can change your affiliated institution below.

    Cited By

    This article is cited by 28 publications.

    1. Balachander Kannan, Chandra Pandi, Anitha Pandi, Vijayashree Priyadharsini Jayaseelan, Paramasivam Arumugam. Triggering receptor expressed in myeloid cells 1 (TREM1) as a potential prognostic biomarker and association with immune infiltration in oral squamous cell carcinoma. Archives of Oral Biology 2024, 133 , 105926. https://doi.org/10.1016/j.archoralbio.2024.105926
    2. Meng-Qi Liu, Jia-Wei Zhang, Jian-Wei Zhu. Roles of Tumor-Associated Macrophages in Tumor Environment and Strategies for Targeting Therapy. Pharmaceutical Fronts 2023, 05 (04) , e254-e273. https://doi.org/10.1055/s-0043-1777704
    3. Jannat Pervin, Mohammad Asad, Shaolong Cao, Gun Ho Jang, Nikta Feizi, Benjamin Haibe-Kains, Joanna M. Karasinska, Grainne M. O’Kane, Steven Gallinger, David F. Schaeffer, Daniel J. Renouf, George Zogopoulos, Oliver F. Bathe. Clinically impactful metabolic subtypes of pancreatic ductal adenocarcinoma (PDAC). Frontiers in Genetics 2023, 14 https://doi.org/10.3389/fgene.2023.1282824
    4. Marco Colonna. The biology of TREM receptors. Nature Reviews Immunology 2023, 23 (9) , 580-594. https://doi.org/10.1038/s41577-023-00837-1
    5. Ke Ma, Qianqian Guo, Xianwei Zhang, Yanxin Li. High Expression of Triggering Receptor Expressed on Myeloid Cells 1 Predicts Poor Prognosis in Glioblastoma. OncoTargets and Therapy 2023, Volume 16 , 331-345. https://doi.org/10.2147/OTT.S407892
    6. Chunyan Zhang, Xugang Kan, Baole Zhang, Haibo Ni, Jianfeng Shao. The role of triggering receptor expressed on myeloid cells-1 (TREM-1) in central nervous system diseases. Molecular Brain 2022, 15 (1) https://doi.org/10.1186/s13041-022-00969-w
    7. Xue Li, Srinivas Chatla, Andrew F. Wilson, Limei Wu, Neha Atale, Wei Du. Persistent DNA damage and oncogenic stress-induced Trem1 promotes leukemia in mice. Haematologica 2022, 107 (11) , 2576-2588. https://doi.org/10.3324/haematol.2021.280404
    8. Alexander B. Sigalov. Inhibition of TREM-2 Markedly Suppresses Joint Inflammation and Damage in Experimental Arthritis. International Journal of Molecular Sciences 2022, 23 (16) , 8857. https://doi.org/10.3390/ijms23168857
    9. Marie Muller, Vincent Haghnejad, Anthony Lopez, Angelica Tiotiu, Stéphane Renaud, Marc Derive, Jean-Pierre Bronowicki. Triggering Receptors Expressed on Myeloid Cells 1 : Our New Partner in Human Oncology?. Frontiers in Oncology 2022, 12 https://doi.org/10.3389/fonc.2022.927440
    10. Xiangyang Wei, Liting Hu, Guibo Liu, Xiaoni Yin, Ning Duan, Qinghua Li, Ying Li, Guiqiu Zhao, Zhaodong Du. Inhibition of TREM-1 Alleviates Choroidal Neovascularization in a Mouse Model. SSRN Electronic Journal 2022, 15 https://doi.org/10.2139/ssrn.4073020
    11. Zhijun Xiao, Jinyin Li, Qian Yu, Ting Zhou, Jingjing Duan, Zhen Yang, Cuicui Liu, Feng Xu. An Inflammatory Response Related Gene Signature Associated with Survival Outcome and Gemcitabine Response in Patients with Pancreatic Ductal Adenocarcinoma. Frontiers in Pharmacology 2021, 12 https://doi.org/10.3389/fphar.2021.778294
    12. Ashok K. Pullikuth, Eric D. Routh, Kip D. Zimmerman, Julia Chifman, Jeff W. Chou, Michael H. Soike, Guangxu Jin, Jing Su, Qianqian Song, Michael A. Black, Cristin Print, Davide Bedognetti, Marissa Howard-McNatt, Stacey S. O’Neill, Alexandra Thomas, Carl D. Langefeld, Alexander B. Sigalov, Yong Lu, Lance D. Miller. Bulk and Single-Cell Profiling of Breast Tumors Identifies TREM-1 as a Dominant Immune Suppressive Marker Associated With Poor Outcomes. Frontiers in Oncology 2021, 11 https://doi.org/10.3389/fonc.2021.734959
    13. Xiaobin Song, Longjie Li, Liang Shi, Xinyu Liu, Xun Qu, Fengcai Wei, Ketao Wang. C1QTNF6 promotes oral squamous cell carcinoma by enhancing proliferation and inhibiting apoptosis. Cancer Cell International 2021, 21 (1) https://doi.org/10.1186/s12935-021-02377-x
    14. Liang Dong, Cheng-Wei Tan, Peng-Jiu Feng, Fu-Bing Liu, De-Xing Liu, Jun-Jie Zhou, Yan Chen, Xin-Xin Yang, Yu-Hang Zhu, Zhao-Qiong Zhu. Activation of TREM-1 induces endoplasmic reticulum stress through IRE-1α/XBP-1s pathway in murine macrophages. Molecular Immunology 2021, 135 , 294-303. https://doi.org/10.1016/j.molimm.2021.04.023
    15. Harbinder Singh, Vikrant Rai, Sunil K. Nooti, Devendra K. Agrawal. Novel ligands and modulators of triggering receptor expressed on myeloid cells receptor family: 2015-2020 updates. Expert Opinion on Therapeutic Patents 2021, 31 (6) , 549-561. https://doi.org/10.1080/13543776.2021.1883587
    16. Samantha B Kemp, Nina G Steele, Eileen S Carpenter, Katelyn L Donahue, Grace G Bushnell, Aaron H Morris, Stephanie The, Sophia M Orbach, Veerin R Sirihorachai, Zeribe C Nwosu, Carlos Espinoza, Fatima Lima, Kristee Brown, Alexander A Girgis, Valerie Gunchick, Yaqing Zhang, Costas A Lyssiotis, Timothy L Frankel, Filip Bednar, Arvind Rao, Vaibhav Sahai, Lonnie D Shea, Howard C Crawford, Marina Pasca di Magliano. Pancreatic cancer is marked by complement-high blood monocytes and tumor-associated macrophages. Life Science Alliance 2021, 4 (6) , e202000935. https://doi.org/10.26508/lsa.202000935
    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 https://doi.org/10.3389/fcell.2020.607209
    18. Bianca Cioni, Anniek Zaalberg, Judy R. van Beijnum, Monique H. M. Melis, Johan van Burgsteden, Mauro J. Muraro, Erik Hooijberg, Dennis Peters, Ingrid Hofland, Yoni Lubeck, Jeroen de Jong, Joyce Sanders, Judith Vivié, Henk G. van der Poel, Jan Paul de Boer, Arjan W. Griffioen, Wilbert Zwart, Andries M. Bergman. Androgen receptor signalling in macrophages promotes TREM-1-mediated prostate cancer cell line migration and invasion. Nature Communications 2020, 11 (1) https://doi.org/10.1038/s41467-020-18313-y
    19. Alexander B. Sigalov. SCHOOL of nature: ligand-independent immunomodulatory peptides. Drug Discovery Today 2020, 25 (8) , 1298-1306. https://doi.org/10.1016/j.drudis.2020.05.005
    20. Federica Raggi, Maria Bosco. Targeting Mononuclear Phagocyte Receptors in Cancer Immunotherapy: New Perspectives of the Triggering Receptor Expressed on Myeloid Cells (TREM-1). Cancers 2020, 12 (5) , 1337. https://doi.org/10.3390/cancers12051337
    21. Alexander B. Sigalov. Commentary: Triggering Receptor Expressed on Myeloid Cells-1 Inhibitor Targeted to Endothelium Decreases Cell Activation. Frontiers in Immunology 2020, 11 https://doi.org/10.3389/fimmu.2020.00173
    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 https://doi.org/10.3389/fimmu.2019.02314
    23. Chien-Wei Feng, Nan-Fu Chen, Chun-Sung Sung, Hsiao-Mei Kuo, San-Nan Yang, Chien-Liang Chen, Han-Chun Hung, Bing-Hung Chen, Zhi-Hong Wen, Wu-Fu Chen. Therapeutic Effect of Modulating TREM-1 via Anti-inflammation and Autophagy in Parkinson’s Disease. Frontiers in Neuroscience 2019, 13 https://doi.org/10.3389/fnins.2019.00769
    24. Qinchuan Wu, Wuhua Zhou, Shengyong Yin, Yuan Zhou, Tianchi Chen, Junjie Qian, Rong Su, Liangjie Hong, Haohao Lu, Feng Zhang, Haiyang Xie, Lin Zhou, Shusen Zheng. Blocking Triggering Receptor Expressed on Myeloid Cells‐1‐Positive Tumor‐Associated Macrophages Induced by Hypoxia Reverses Immunosuppression and Anti‐Programmed Cell Death Ligand 1 Resistance in Liver Cancer. Hepatology 2019, 70 (1) , 198-214. https://doi.org/10.1002/hep.30593
    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. https://doi.org/10.18632/oncotarget.26085
    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. https://doi.org/10.1002/hep4.1269
    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. https://doi.org/10.1016/j.bbadis.2018.05.001
    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. https://doi.org/10.3390/jcdd5030045

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    You’ve supercharged your research process with ACS and Mendeley!

    STEP 1:
    Click to create an ACS ID

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    MENDELEY PAIRING EXPIRED
    Your Mendeley pairing has expired. Please reconnect