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A Powerful Imaging-Based Translational Biomarker for Development of Novel Anti-Fibrotic Therapies

PET snapshot

Idiopathic pulmonary fibrosis (IPF) is a life-threatening lung disease caused by relentless destruction and scarring of lung tissue leading to respiratory failure. Current treatments for IPF slow disease progression but do not reverse lung fibrosis, so there is a clinical need for improved therapies. In addition, diagnosis and treatment of IPF patients is challenging because prognostic methods are generally non-specific or invasive. However, advanced imaging techniques such as positron emission tomography (PET) have demonstrated that uptake of 18F-Fluorodeoxyglucose, or 18F-FDG, is correlated with disease severity in IPF patients (Justet et al., 2017) suggesting PET imaging will be a valuable clinical tool for disease diagnosis and management.

IPF is widely modelled in animals following the administration of the anticancer agent bleomycin directly to the lungs; bleomycin damages lung epithelial cells, activating fibroblasts leading to lung fibrosis/scarring. Charles River has developed a rat model of bleomycin-induced pulmonary fibrosis and demonstrated that the model is reproducible and sensitive to the anti-fibrotic activity of nintedanib (currently used in IPF patients to slow disease progression) (McElroy et al, 2019)(Figure 1).

Medicines Discovery Catapult (MDC) and Charles River formed a collaboration to evaluate PET using 18F-FGF in the rat model of pulmonary fibrosis and initial data are very promising (Maynard et al, 2019). Fibrosis was induced in rats according to our standard protocol and the animals were transported to MDC for image analysis. PET data demonstrated significant uptake of the 18F-FDG probe in fibrotic lungs compared with vehicle controls (Figure 2, Figure 3). 18F-FDG uptake was not increased in non-fibrotic organs relative to vehicle controls demonstrating the selectivity of the 18F-FDG lung signal (data not shown). Therefore, these studies demonstrate that 18F-FDG is a promising biomarker to bridge the translational gap between preclinical models and efficacy evaluation in IPF patients.

Figure 1. Rat model of pulmonary fibrosis.
Figure 1: Rat Model of Pulmonary Fibrosis. Image shows areas of lung fibrosis (dotted green line) following bleomycin challenge.

Figure 2. 18 F-FDG update
Figure 2: 18F-FDG update is significantly increased in fibrotic (bleomycin challenged) lungs compared with vehicle controls. SUV = Standard Uptake Values.

Figure 3. Representative imaging data demonstrating increased 18 F-FDG in fibrotic lung following bleomycin treatment
Figure 3: Representative imaging data demonstrating increased 18F-FDG in the fibrotic lungs following bleomycin treatment (white circle, sagittal view) compared with vehicle treated lungs (white circle, sagittal view).

 

 

References

Justet A, Laurent-Bellue A, Thabut G, Dieudonné A, Debray MP, Borie R, Aubier M, Lebtahi R, Crestani B. [18F]FDG PET/CT Predicts Progression-Free Survival in Patients with Idiopathic Pulmonary Fibrosis. Respir Res. 2017 Apr 27;18(1):74.

McElroy MC, Baily J , Peris Serrano O , Marsden M , Briggs M, Love L , Madden S , Gandi S , M Whitmarsh M, Young A, Pharmacokinetics and Efficacy of Nintedanib in a Repetitive Bleomycin Challenge Model of Rat Lung Fibrosis., American Journal of Respiratory and Critical Care Medicine 2019;199:A5424

Maynard J, Price S, McElroy M, Simpson P. Validation of 18F-fluorodeoxyglucose Positron Emission Tomography (18F-FDG PET) as a Translational Biomarker to Support Development of Novel Anti-fibrotic Drug Therapies.