Certain Cancer Therapies May Hold Promise in Treating COPD, Preclinical Study Suggests
Cancer therapies blocking specific protein receptors called ErbB reduced inflammation in animal models of inflammatory diseases — including those affecting the lung — by destroying neutrophils, a type of immune cell, a preclinical study found.
According to the researchers, these findings suggest that treatments blocking the activity of these receptors may possibly be repurposed to treat several inflammatory diseases, including chronic obstructive pulmonary disease (COPD).
The findings were reported in the study, “Inhibition of ErbB kinase signalling promotes resolution of neutrophilic inflammation,” published in the journal eLife.
COPD is characterized by excessive and sustained airway inflammation, and results in permanent lung damage. While neutrophils normally promote tissue healing following an infection or injury, their prolonged activation and survival may damage the tissue and lead to the onset of chronic inflammatory diseases, like COPD.
For this reason, therapies that promote the death of neutrophils have the potential to resolve inflammation and prevent further lung damage in COPD patients.
Cell-surface proteins called receptor tyrosine kinases (RTK) are known to control cell death, and are frequently used as therapeutic targets in many cancer therapies.
“However, it remains unclear which kinases regulate apoptosis [cell death] in neutrophils, or which kinase-inhibiting drugs may have the potential to treat COPD and other inflammatory diseases,” the investigators said.
To learn more, researchers from the University of Sheffield, in the U.K., teamed up with colleagues in the U.S., the Netherlands, and Scotland, and a scientist from GlaxoSmithKline in England, to investigate compounds targeting the ErbB family of RTK. The goal was to find compounds that could potentially eliminate neutrophils and reduce inflammation.
The team first tested a library of 367 publicly available RTK inhibitors in a fish model (zebrafish) of tissue injury and in human neutrophils grown in a lab dish.
The results showed that compounds blocking the activity of proteins from the ErbB family seemed to be the most effective at eliminating neutrophils and reducing inflammation.
Among these ErbB inhibitors, gefitinib (marketed as Iressa by AstraZeneca), CP-724714, erbstatin, and tyrphostin AG825 all were found to accelerate the death of human neutrophils. Erbstatin and tyrphostin AG825 also promoted the destruction of neutrophils taken from COPD patients, even in the presence of molecules that promoted their survival.
These findings highlighted that “ErbB inhibition engages neutrophil apoptosis [cell death] even in the presence of inflammatory stimuli and therefore has the potential to drive apoptosis at inflammatory sites,” the researchers said.
Using the fish model of tissue injury, the investigators also found that treatment with tyrphostin AG825 and genetic deletion of ErbB-related genes (namely egfra and erbb2) significantly reduced the number of neutrophils at the lesion site.
Data from mouse models of acute inflammation, including in the lung, showed that treatment with tyrphostin AG825 reduced inflammation and increased neutrophil death and clearance by macrophages. Macrophages are a type of immune cell responsible for removing debris and dead cells. The treatment with tyrphostin was given at the time of inflammatory stimulus or once inflammation had already set in.
“These findings suggest the ErbB family of kinases may be novel targets for treatments of chronic inflammatory disease [including COPD], and the potential for repurposing ErbB inhibitors currently in use for cancer may have significant clinical potential in a broader range of indications,” the researchers said.
“What is exciting about this research is that these drug compounds are available now, which means if our continued research can effectively find a lead compound to benefit people living with COPD, they are ready to use,” Stephen Renshaw, MD, PhD, co-senior author of the study, said in a press release.
“The hope of these [compounds] is that they can clear the damaging cells from the lungs of people living with COPD, preventing any further damage and therefore the progression of the disease for the first time,” added Lynne Prince, PhD, the other co-senior author of the study.
Renshaw noted that their next step is “to find a way to test these [compounds] in people with COPD to understand how the ErbB kinase signalling process has an effect on lung inflammation, and to address any potential side effects.”