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

Molecular Pharmaceutics
Zu T Shen, Alexander B Sigalov

Abstract

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...Continue Reading

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Citations

May 21, 2019·Oncotarget·Paloma Honrubia-GómezCarmen Ramirez-Castillejo
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