Targeting FgfR2b for the Treatment of Adult Lung Injury
National Jewish Health
The epithelial cells that line the airways are constantly exposed to potential toxic agents and pathogens in the environment, and they must therefore be able to respond quickly and effectively to both cellular damage and local inflammation. The cellular hallmark of lung repair after injury of lung epithelial cells is a rapid proliferative response ultimately leading to restoration of the airway epithelium and function. Remodeling of the airway epithelium is a common pathological feature in chronic lung disease and a predisposing factor in the development of lung cancer. In young animals, tissue damage can usually be repaired quickly, but this natural capacity may fail after persistent injury and with age. Diseases such as cancer exploit the mechanisms by which the body normally rebuilds itself.
Dr. De Langhe, Assistant Professor for National Jewish Health has shown the importance of Fibroblast Growth Factor 10 (FGF10) signaling though FGFR2b for lung regeneration, lung tumor formation as well as globet/mucus cell differentiation. His group has identified FGFR2b as a marker for lung stem cells. This discovery creates an enormous potential for diagnostic and treatment of several of the most critical lung diseases.
Diagnostic: The ex-vivo detection of lung stem cells on histological samples using monoclonal antibodies (mAb) against FGFR2b. The presence of these stem cells is an indicator of lung injury and/or tumor development. This diagnostic approach could also prove useful to establish which subgroup of patients will benefit from anti-FGFR2b drugs.
Therapeutic: The isolation of live lung airway stem cells from a biopsy sample using mAb against FGFR2b. These cells can be amplified ex-vivo and intratracheally instill back to the same patient to repair injured lungs or treatment of fibrosis. Also an aerosolized mAb that blocks FGFR2b could be used to inhibit the proliferation of airway stem cells in the case of lung cancer or their transdifferentiation into goblet cells/mucous producing cells in the case of asthma. Alternatively, agonist FGFR2b antibodies could be used to increase proliferation of airway stem cells after a lung injury and to protect against and/or cure lung fibrosis.
State of Development
Proof of concept that FGFR2b can be used to isolate lung stem cells and that FGFR2b signaling is important for lung stem cell activation and therefore epithelial regeneration, tumor development as well as mucous cell hyperplasia.
Parabronchial smooth muscle constitutes an airway epithelial stem cell niche in the mouse lung after injury. Thomas Volckaert, Erik Dill, Alice Campbell, Caterina Tiozzo, Susan Majka, Saverio Bellusci, Stijn P. De Langhe. J Clin Invest. 2011; doi:10.1172/JCI58097.
US patent pending. International Patent Publication #WO/2011/025814.
Stijn De Langhe, Ph.D.