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

Federica Calore, Priya Londhe, Paolo Fadda, Giovanni Nigita, Lucia Casadei, Gioacchino Paolo Marceca, Matteo Fassan, Francesca Lovat, Pierluigi Gasparini, Lara Rizzotto, Nicola Zanesi, Devine Jackson, Svasti Mehta, Patrick Nana-Sinkam, Deepa Sampath, Raphael E. Pollock, Denis C. Guttridge, Carlo M. Croce

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.