In Vivo Nuclear Imaging of Hypoxia as Predictive Biomarkers and follow up the Response to Anti-VEGF Therapies in Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and fatal disease of unknown origin. In France, it is one of the most common interstitial pathologies (IP) and affects 4,400 new people each year. IPF is characterized by dysregulated healing mechanisms that lead to the accumulation of large amounts of collagen in the lung tissue and cause disorganization of the alveolar architecture. It results in progressive deterioration of the respiratory function, leading in a few years to chronic respiratory failure and then to death. Idiopathic pulmonary fibrosis has a lower survival rate than many cancers with a median survival of 2 to 5 years from diagnosis. This pathology whose main risk factor, in addition to genetic and environmental factors (cigarettes, pollution, etc.), remains age, rarely occurs before the age of 60. Despite the therapeutic advances made in recent years in the field of fibrosis, IPF remains an incurable and lethal disease. The late management of patients, the complexity of the diagnosis and the lack of therapeutic solutions or early diagnosis strategies are all issues that explain the mortality associated with this pathology. Today, the identification of signaling pathways and key cellular actors involved in IPF development remains crucial in order, on the one hand, to develop new treatments and, on the other hand, to identify new tools for earlier diagnoses. In this context, the study of the roles of heat shock proteins HSPB5 and HSP90 in idiopathic pulmonary fibrosis as well as markers of hypoxia could provide new therapeutic and diagnostic targets. IPF imaging is in practice limited to high-resolution computed tomography (HRCT). This examination is often insufficient for a definitive diagnosis of the disease and has a limited impact on the therapeutic decision and management of IPF patients. Pulmonary hypoxia is an important feature of IPF, but its role in disease progression remains unknown. Thus, using a preclinical model of bleomycin-induced pulmonary fibrosis, we have determined in vivo that hypoxia imaging with ¹⁸F-FMISO could constitute a predictive biomarker of disease progression and treatment efficacy compared to another clinically used marker ¹⁸F-FDG. We have also shown in vivo in our mouse model that inhibition of HSPB5, a low molecular weight heat shock protein known to be involved in the development of fibrosis, using NCI-41356 allows to reduce fibrosis by modulating the expression of several pro-fibrotic factors including TGF-β. In addition, we have also demonstrated that targeting the extracellular HSP90 protein overexpressed in plasma as well as in fibrotic tissues of IPF patients could constitute a potential theranostic tool for fibrosis. In conclusion, this thesis work has made it possible to characterize a potential early and predictive radiopharmaceutical tracer of the evolution of pulmonary fibrosis as well as the anti-fibrotic role of a chemical inhibitor of the canonical TGF-β pathway. Furthermore, we hope that our results concerning the HSP90 protein will make it possible to envisage the theranostic use of recombinant antibodies against HSP90 in the context of IPF. (author)