TY - JOUR
T1 - The TLR7/8/9 antagonist IMO-8503 inhibits cancer-induced cachexia
AU - Calore, Federica
AU - Londhe, Priya
AU - Fadda, Paolo
AU - Nigita, Giovanni
AU - Casadei, Lucia
AU - Marceca, Gioacchino Paolo
AU - Fassan, Matteo
AU - Lovat, Francesca
AU - Gasparini, Pierluigi
AU - Rizzotto, Lara
AU - Zanesi, Nicola
AU - Jackson, Devine
AU - Mehta, Svasti
AU - Nana-Sinkam, Patrick
AU - Sampath, Deepa
AU - Pollock, Raphael E.
AU - Guttridge, Denis C.
AU - Croce, Carlo M.
N1 - Publisher Copyright:
2018 American Association for Cancer Research.
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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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U2 - 10.1158/0008-5472.CAN-17-3878
DO - 10.1158/0008-5472.CAN-17-3878
M3 - Article
C2 - 30209066
AN - SCOPUS:85057825221
SN - 0008-5472
VL - 78
SP - 6680
EP - 6690
JO - Cancer Research
JF - Cancer Research
IS - 23
ER -