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

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


: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Autophagy / drug effects
  • Cachexia / drug therapy
  • Cachexia / etiology*
  • Cachexia / metabolism*
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Extracellular Vesicles / metabolism
  • Heterografts
  • Humans
  • Mice
  • MicroRNAs / genetics
  • Myoblasts / drug effects
  • Myoblasts / metabolism
  • Neoplasms / complications*
  • Toll-Like Receptor 7 / antagonists & inhibitors*
  • Toll-Like Receptor 8 / antagonists & inhibitors*
  • Toll-Like Receptor 9 / antagonists & inhibitors*


  • Antineoplastic Agents
  • MicroRNAs
  • Toll-Like Receptor 7
  • Toll-Like Receptor 8
  • Toll-Like Receptor 9