Molecular Insights Pinpoint Cancer Therapy as Potential Lung Fibrosis Treatment

Molecular Insights Pinpoint Cancer Therapy as Potential Lung Fibrosis Treatment

A cancer drug in clinical development might be used to treat pulmonary fibrosis (PF), or as a starting point to develop better antifibrotic treatments, German researchers suggest.

Their study, “FoxO3 an important player in fibrogenesis and therapeutic target for idiopathic pulmonary fibrosis,” appeared in the journal EMBO Molecular Medicine. In it, the team from Germany’s Max Planck Institute for Heart and Lung Research explored how a molecule called FoxO3 is linked to fibrosis.

The drug reactivates a factor involved in cell growth, which acts as a molecular hub in several fibrotic processes, the team showed. FoxO3 normally acts to dampen cell growth and the development of fibrosis-producing cell types. In patients with lung fibrosis, it fails to do so.

But the starting point of the research was the finding that PF patients have lower levels of the molecule in their lungs.

“The results were even clearer once we looked at FoxO3 activity. It was much lower in fibroblasts from patients with pulmonary fibrosis than in cells from healthy people,” Soni Pullamsetti, a senior author of the study, said in a press release.

In people with lung fibrosis, cells called fibroblasts start taking on a different look and behavior. These cells, called myofibroblasts, are key to fibrosis buildup.

“The fibroblasts undergo a kind of personality change,” said Pullamsetti. “In patients with pulmonary fibrosis, these cells contain increased amounts of contractile proteins, like those involved in muscle cell function.”

To understand how FoxO3 affects this process, the team used both lab-grown human lung cells and mice treated to develop lung fibrosis. When researchers exposed lung cells from fibrosis patients to various known fibrosis-triggering molecules, the cells lowered their production and activity of FoxO3. This did not happen in cells from healthy controls.

When researchers removed the factor from lab-grown fibroblast cells, those cells started looking and behaving more like myofibroblasts, suggesting that FoxO3 was necessary to prevent the process from occurring.

Moreover, mice that lacked the factor and were exposed to the fibrosis-triggering chemical bleomycin developed more rapid and severe fibrosis. These mice also died earlier than mice with normal levels of FoxO3.

“These mice developed idiopathic pulmonary fibrosis much more quickly than control animals — so quickly, in fact, that we were forced to shorten the experiment,” said Pullamsetti.

The team’s experiments suggest that if FoxO3 could be reactivated, it might prevent some of the processes leading to fibrosis.

Searching databases of compounds, researchers came across a drug that activated FoxO3. The compound, called UCN-01, has been explored in clinical trials for cancer, since FoxO3 is also involved in cancer processes.

The drug reduced several fibrotic molecules and processes in mice. It also activated FoxO3 through actions on other molecular fibrotic pathways, which prevented cells to turn into myofibroblasts. UCN-01 also improved lung function and reduced disease severity in mice exposed to a fibrosis trigger.

“Our study shows that reduced FoxO3 activity plays an important role in the development of idiopathic pulmonary fibrosis, and that FoxO3 is a good place to start in developing a treatment for the disease,” said Werner Seeger, a study co-author.

The compound is particularly alluring, since FoxO3 was related to several fibrotic molecular pathways and cellular processes, researchers said.

“We observed that FoxO3 is a critical integrator of various growth factor signaling pathways and plays a crucial role in suppression of the phenotypic change from fibroblasts to activated myofibroblasts,” the team wrote. “Repurposing of UCN-01 for the treatment of IPF may offer as novel therapeutic option for this devastating disease.”

4 comments

        • Magdalena Kegel says:

          Hi Jim, please search the registry to find locations. There are more than 70 trials that are recruiting participants at various locations. The drug in the article is not yet available.

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