The TLR7/8/9 antagonist IMO-8503 inhibits cancer-induced cachexia

Muscle wasting is a feature of the cachexia syndrome, which contributes significantly to cancer patient mortality. We have previously demonstrated that miR-21 is secreted through extracellular vesicles (EVs) 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 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.

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