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Cancer Res. 2018 Dec 1;78(23):6680-6690. doi: 10.1158/0008-5472.CAN-17-3878. Epub 2018 Sep 12.

The TLR7/8/9 Antagonist IMO-8503 Inhibits Cancer-Induced Cachexia.

Author information

1
Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
2
The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
3
Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, Columbus, Ohio.
4
Bioinformatics Unit, Department of Clinical and Experimental Medicine, University of Catania, c/o Dipartimento di Matematica e Informatica, Catania, Italy.
5
Surgical Pathology & Cytopathology Unit, Department of Medicine, University of Padua, Padua, Italy.
6
Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
7
Division of Pulmonary Disease and Critical Care Medicine, Virginia Commonwealth University, Virginia.
8
Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio. carlo.croce@osumc.edu guttridg@musc.edu.

Abstract

: Muscle wasting is a feature of the cachexia syndrome, which contributes significantly to the mortality of patients with cancer. We have previously demonstrated that miR-21 is secreted through extracellular vesicles (EV) by lung and pancreatic cancer cells and promotes JNK-dependent cell death through its binding to the TLR7 receptor in murine myoblasts. Here, we evaluate the ability of IMO-8503, a TLR7, 8, and 9 antagonist, to inhibit cancer-induced cachexia. Using EVs isolated from lung and pancreatic cancer cells and from patient plasma samples, we demonstrate that IMO-8503 inhibits cell death induced by circulating miRNAs with no significant toxicity. Intraperitoneal administration of the antagonist in a murine model for Lewis lung carcinoma (LLC-induced cachexia) strongly impaired several cachexia-related features, such as the expression of Pax7 as well as caspase-3 and PARP cleavage in skeletal muscles, and significantly prevented the loss of lean mass in tumor-bearing mice. IMO-8503 also impaired circulating miRNA-induced cell death in human primary myoblasts. Taken together, our findings strongly indicate that IMO-8503 serves as a potential therapy for the treatment of cancer cachexia. SIGNIFICANCE: Cancer-associated cachexia is a significant problem for patients with cancer that remain poorly understood, understudied, and inadequately treated; these findings report a potential new therapeutic for the treatment of TLR7-mediated cancer cachexia.

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