Key Point

The anticancer drug imatinib mesylate may offer new hope to IPF patients through its antifibrotic action.

ROCHESTER, MINN—Current treatments for idiopathic pulmonary fibrosis (IPF) fail to cure the disease or prevent death. New research has shed some light on the biochemistry of this poorly understood disease and has found that the anticancer drug imatinib mesylate may stymie its course. The study established the following:

1. Transforming growth factor-β (TGF-β) targets the c-Abelson (c-Abl) proto-oncogene. It activates c-Abl as one component in the process of myofibroblast formation—a hallmark of IPF lung destruction.

2. Imatinib mesylate inhibits TGF-β–mediated c-Abl activity and thus halts myofibroblast formation.¹

Edward Leof, PhD, along with his colleagues, Craig Daniels, MD, Mark Wilkes, BS, Maryanne Edens, BS, Ted Kottom, MS, Stephen Murphy, PhD, and Andrew Limper, MD, evaluated the effects of imatinib mesylate on human lung and mouse cells. They also looked at the drug’s effects in an in vivo mouse model of IPF. According to Dr. Leof, Associate Director of Basic Sciences at the Mayo Clinic Cancer Center in Rochester, Minnesota, the findings show that “a single therapeutic agent affects multiple fibrotic cytokines, particularly TGF-β and platelet-derived growth factor [PDGF].”

MECHANISMS

The investigators found that c-Abl is a new target of TGF-β signaling in mesenchymal cells. TGF-β stimulation enhanced c-Abl activity in 15 minutes; levels returned to normal after one hour. However, treating the cells with imatinib mesylate extinguished c-Abl activity that was mediated by TGF-β or PDGF. The drug had no effect on the secretion of these growth factors; rather, its effect was exclusively against c-Abl, making it a “targeted drug.”

The researchers also found that imatinib mesylate inhibited TGF-β–induced fibroblast transformation but had little effect on unstimulated fibroblasts. TGF-β stimulated a 2.5-fold increase in the number of fibroblasts cultured; imatinib mesylate reduced this number to basal levels. Dr. Leof noted that TGF-β’s effects are dependent on the type of cell. It stimulates proliferation of mesenchymal cells but inhibits the growth of epithelial cells.

Fibronectin expression was also stimulated by TGF-β in a c-Abl–dependent manner. TGF-β increased fibronectin mRNA accumulation and activity by threefold to fourfold, and imatinib mesylate reduced these levels to baseline.

MOUSE MODEL OF IPF

Using hydroxyproline measurements as a marker of lung collagen that appears after bleomycin-induced pulmonary fibrosis in mice, the researchers found that imatinib mesylate prevented the condition. Bleomycin-injured mice that received the drug had significantly lower hydroxyproline levels than untreated mice (80.73 vs 102.71 µg/10 mg left lung, respectively). In the right lungs of untreated pulmonary fibrosis mice, there was dense deposition of collagen and destruction of normal tissues. In pulmonary fibrosis mice given imatinib mesylate, however, there was less collagen deposition and tissue destruction. The reduction of collagen may be a reflection of the disruption in c-Abl–mediated stimulation of myofibroblasts.

HUMAN FIBROTIC DISEASES

If the drug works so well in mice and human lung cells, could it work in humans? Imatinib mesylate “is a possible treatment for a disease [IPF] that is fatal and currently has no curative treatment,” stressed Dr. Leof. His colleague, Dr. Daniels, is currently the principal investigator of a phase II, randomized, placebo-controlled trial of the drug for IPF. The study is still in the recruitment phase, though with time, Dr. Daniels and his team hope to understand more about IPF and “get one step closer to some day having an effective therapy for [the disease].” Imatinib mesylate could also help patients suffering from other fibrotic diseases such as scleroderma, kidney fibrosis, and any fibrotic disease that is TGF-β–mediated. Dr. Leof believes that future research should focus on combination therapy. “This way we can go after different pathways so we can lower drug dosages and toxicities,” he concluded.

—Tamara Gibb

Reference
1. Daniels CE, Wilkes MC, Edens M, et al. Imatinib mesylate inhibits the profibrogenic activity of TGF-β and prevents bleomycin-mediated lung fibrosis. J Clin Invest. 2004;114:1308-1316.

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