Breakthrough Finding in IPF Fibroblast Growth
Researchers at Cincinnati Children’s have made a key discovery into what causes the development of fibrotic lesions in pulmonary fibrosis (PF). The scientists, led by Satish Madala, PhD, associate professor in the Division of Pulmonary Medicine, have also identified a therapy that appears to slow this fibrotic growth.
Pulmonary fibrosis is the leading cause of morbidity and mortality for many respiratory diseases. Madala and his laboratory team work to uncover its cellular and molecular mechanisms.
“Recent studies identified that abnormal activation of the transcription factors involved in lung development can lead to excess growth of fibroblasts in idiopathic pulmonary fibrosis (IPF),” says Madala. His team took the research a step further, finding that one of those transcription factors in particular - Wilms’ Tumor 1 (WT1) - is a particular culprit in spurring fibroblast development. WT1 induces Aurora kinase B (AURKB), a gene that controls cell proliferation, to cause scarring of the lungs.
“This study provides the first evidence that AURKB functions as a positive regulator for fibroproliferation in the expansion of fibrotic lesions in IPF,” says Madala. “Our findings support the mechanism of the WT1-AURKB axis in inducing this fibroproliferation.”
The finding proved valid in human tissue derived from lung biopsies of IPF patients, as well as in mouse models. AURKB was up-regulated, driven by multiple pro-fibrotic growth factors including TGFa. Madala’s team also found that the pharmacologic inhibition of AURKB with the drug Barasertib, currently in early phase trials for cancer treatment, slowed fibrotic growth.
“Understanding these converging points in fibroblast activation is essential to identifying novel and effective therapies against IPF,” says Madala. “Barasertib treatment may prove useful as a potential therapeutic option.”
Currently, two FDA-approved drugs, Ofev (nintedanib) and Esbriet (pirfenidone), are used to treat patients with IPF, but neither provides a cure and both have serious side effects.
Between 30,000 and 40,000 new cases of IPF are diagnosed each year. Average life expectancy is about five years from diagnosis, so finding effective treatment is vital, says Madala. He believes that repurposing Barasertib for IPF patients may provide an answer. “Through informatics approaches coupled with in vitro and in vivo studies, we have identified AURKB and its inhibitor Barasertib as a lead target and lead small molecule respectively for IPF.”
Madala’s team’s findings were presented at the February 2020 Keystone Symposia on Fibrosis and Tissue Repair held in Victoria, British Columbia.
