Title: Evaluation of the efficacy of the tyrosine kinase inhibitor Nintedanib and characterization of the role of the tyrosine-phosphatase SHP2 in preclinical models of Systemic Sclerosis
Abstract: Systemic sclerosis (SSc) is a complex heterogeneous autoimmune disease with unknown etiology. It has three major pathologic hallmarks: vasculopathy, immune activation and extensive fibrosis that is an excessive accumulation of extracellular matrix proteins released from activated fibroblasts and destroys the physiological tissue architecture and function of the involved organs. Particularly, diffuse cutaneous SSc (dcSSc) has a highly increased risk of morbidity and mortality. Unfortunately, no targeted treatment is approved for fibrosis in SSc. Therefore, there is a great medical need for new anti-fibrotic therapies for SSc. In this thesis, we evaluated the anti-fibrotic effects of nintedanib that target several receptor tyrosine kinases (PDGF receptors, VEGF receptors and FGF receptors) and evaluated the tyrosine phosphatase SHP2 as a potential target for the treatment of fibrosis in SSc.
In the first part of this thesis, we evaluated the effect of nintedanib, an inhibitor of the tyrosine kinase activity of PDGF receptors, VEGF receptors and FGF receptors that has been approved for the treatment of idiopathic pulmonary fibrosis recently, in preclinical models of SSc. We showed that nintedanib effectively inhibits migration, proliferation and activation of cultured fibroblasts. Nintedanib reduces PDGF- and TGFβ-induced expression of extracellular matrix components such as collagens and fibronectin. Furthermore, nintedanib ameliorated fibrosis in several complementary mouse models of SSc. In addition to improvement of fibrotic readouts, nintedanib also reduced vascular manifestations such as thickening of the pulmonary arteries in the lung and loss of capillaries in the skin in the Fra2 transgenic mouse model of SSc.
In the second part of this thesis, we investigated the role of SHP2 in the pathogenesis of SSc. We demonstrated that SHP2 regulates TGFβ signaling which is the core pathway in fibrotic diseases. Inactivation of SHP2 signaling reduced the TGFβ mediated activation of JAK2/STAT3 signaling in dermal fibroblasts, thereby inhibiting myofibroblast differentiation and collagen release. Moreover, fibroblast-specific knockout of SHP2 inhibited the activation of JAK2/ STAT3 and ameliorated fibrosis in several mouse models. Pharmacological inhibition of SHP2 was well tolerated and also demonstrated potent anti-fibrotic effects in experimental pulmonary and dermal fibrosis.
The results of the both parts of the thesis might have clinical implications. The potent anti-fibrotic effects of nintedanib in several in vitro and in vivo model systems together with findings from clinical trials in idiopathic pulmonary fibrosis stimulated the initiation of an international clinical study to evaluate the efficacy of nintedanib in SSc patients. In the second part, we characterize SHP2 as a novel regulator of TGFβ signaling and as a potential target for anti-fibrotic therapies in SSc. As inhibitors of SHP2 are currently in development, they might be available for clinical trials in SSc as well.
Publication Year: 2016
Publication Date: 2016-01-01
Language: en
Type: article
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