Efficacy of ALK5 inhibition in myelofibrosis

Yue, Lanzhu; Bartenstein, Matthias; Zhao, Wanke; Ho, Wan‐Ting; Han, Ying; Murdun, Cem; Mailloux, Adam W.; Zhang, Ling; Wang, Xuefeng; Budhathoki, Anjali; Pradhan, Kith; Rapaport, Franck; Wang, Huaquan; Shao, Zonghong; Ren, Xiubao; Steidl, Ulrich; Levine, Ross L.; Zhao, Zhizhuang Joe; Verma, Amit; Epling-Burnette, Pearlie K.

doi:10.1172/jci.insight.90932

Cited by 42 publications

(40 citation statements)

References 71 publications

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“…Median overall survival is only six years using current standards of care ruxolitinib, hydroxyurea, or bone marrow transplantation 42 – 44 . PGDHi may hold significant promise for PMF therapy, as inhibition of the TGFβ signaling axis has demonstrated efficacy in preclinical PMF models 45 , 46 . TGFβ transformation of fibroblasts plays a significant role in additional fibrotic diseases including hepatic, skin, and post-radiation induced fibrosis of multiple organs 47 , as well.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic targeting of 15-PGDH in murine pulmonary fibrosis

Smith

Witkin

Jogasuria

et al. 2020

Sci Rep

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Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by interstitial remodeling and pulmonary dysfunction. The etiology of IPF is not completely understood but involves pathologic inflammation and subsequent failure to resolve fibrosis in response to epithelial injury. Treatments for IPF are limited to anti-inflammatory and immunomodulatory agents, which are only partially effective. Prostaglandin E2 (PGE2) disrupts TGFβ signaling and suppresses myofibroblast differentiation, however practical strategies to raise tissue PGE2 during IPF have been limited. We previously described the discovery of a small molecule, (+)SW033291, that binds with high affinity to the PGE2-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and increases PGE2 levels. Here we evaluated pulmonary 15-PGDH expression and activity and tested whether pharmacologic 15-PGDH inhibition (PGDHi) is protective in a mouse model of bleomycin-induced pulmonary fibrosis (PF). Long-term PGDHi was well-tolerated, reduced the severity of pulmonary fibrotic lesions and extracellular matrix remodeling, and improved pulmonary function in bleomycintreated mice. Moreover, PGDHi attenuated both acute inflammation and weight loss, and decreased mortality. Endothelial cells and macrophages are likely targets as these cell types highly expressed 15-PGDH. In conclusion, PGDHi ameliorates inflammatory pathology and fibrosis in murine PF, and may have clinical utility to treat human disease.

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Section: Discussionmentioning

confidence: 99%

Therapeutic targeting of 15-PGDH in murine pulmonary fibrosis

Smith

Witkin

Jogasuria

et al. 2020

Sci Rep

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“…Finally, in order to further confirm the involvement of the axis TGF-b1/miR-382-5p/SOD2 in PMF pathogenesis, we inhibited TGF-b1 pathway in PMF CD34+ cells using the TGF-b-receptor I kinase inhibitor galunisertib. Among the TGF-b inhibitors, galunisertib preclinical efficacy has been already tested in different mouse models (Yue et al, 2017), demonstrating a strong effect in reversing or reducing BM fibrosis. Moreover, it has been demonstrated that galunisertib is a strong inhibitor of TGF-b signaling in hematopoietic cells (Zhou et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Role of TGF‐β1/miR‐382‐5p/SOD2 axis in the induction of oxidative stress in CD34+ cells from primary myelofibrosis

et al. 2018

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Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by an excessive production of pro‐inflammatory cytokines resulting in chronic inflammation and genomic instability. Besides the driver mutations in JAK2,MPL, and CALR genes, the deregulation of miRNA expression may also contribute to the pathogenesis of PMF. To this end, we recently reported the upregulation of miR‐382‐5p in PMF CD34+ cells. In order to unveil the mechanistic details of the role of miR‐382‐5p in pathogenesis of PMF, we performed gene expression profiling of CD34+ cells overexpressing miR‐382‐5p. Among the downregulated genes, we identified superoxide dismutase 2 (SOD2), which is a predicted target of miR‐382‐5p. Subsequently, we confirmed miR‐382‐5p/SOD2 interaction by luciferase assay and we showed that miR‐382‐5p overexpression in CD34+ cells causes the decrease in SOD2 activity leading to reactive oxygen species (ROS) accumulation and oxidative DNA damage. In addition, our data indicate that inhibition of miR‐382‐5p in PMF CD34+ cells restores SOD2 function, induces ROS disposal, and reduces DNA oxidation. Since the pro‐inflammatory cytokine transforming growth factor‐β1 (TGF‐β1) is a key player in PMF pathogenesis, we further investigated the effect of TGF‐β1 on ROS and miR‐382‐5p levels. Our data showed that TGF‐β1 treatment enhances miR‐382‐5p expression and reduces SOD2 activity leading to ROS accumulation. Finally, inhibition of TGF‐β1 signaling in PMF CD34+ cells by galunisertib significantly reduced miR‐382‐5p expression and ROS accumulation and restored SOD2 activity. As a whole, this study reports that TGF‐β1/miR‐382‐5p/SOD2 axis deregulation in PMF cells is linked to ROS overproduction that may contribute to enhanced oxidative stress and inflammation. Our results suggest that galunisertib may represent an effective drug reducing abnormal oxidative stress induced by TGF‐β1 in PMF patients.Database linkingGEO: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE103464.

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“…There is ample experimental evidence to support the role of the ALK5/Smad3 axis in the pathogenesis of fibrosis in many different tissues. In animal models, pharmacologic inhibition of ALK5 attenuated fibrotic remodeling of the lung ( Bonniaud et al, 2005 ), liver ( de Gouville et al, 2005 ), kidney ( Moon et al, 2006 ), heart ( Engebretsen et al, 2014 ), intestine ( Medina et al, 2011 ), vasculature ( Fu et al, 2008 ), and bone marrow ( Yue et al, 2017 ). In fibroblasts, the potent fibrogenic actions of TGF-β/ALK5 signaling are predominantly mediated through activation of Smad3 ( Zhao et al, 2002 ; Flanders et al, 2002 ; Sato et al, 2003 ; Bujak et al, 2007 ; Dobaczewski et al, 2010 ; Khalil et al, 2017 ).…”

Section: The Molecular Signals Involved In Tgf-β–mediated Fibrosismentioning

confidence: 99%

Transforming growth factor–β in tissue fibrosis

Frangogiannis

2020

Journal of Experimental Medicine

748

454

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TGF-β is extensively implicated in the pathogenesis of fibrosis. In fibrotic lesions, spatially restricted generation of bioactive TGF-β from latent stores requires the cooperation of proteases, integrins, and specialized extracellular matrix molecules. Although fibroblasts are major targets of TGF-β, some fibrogenic actions may reflect activation of other cell types, including macrophages, epithelial cells, and vascular cells. TGF-β–driven fibrosis is mediated through Smad-dependent or non-Smad pathways and is modulated by coreceptors and by interacting networks. This review discusses the role of TGF-β in fibrosis, highlighting mechanisms of TGF-β activation and signaling, the cellular targets of TGF-β actions, and the challenges of therapeutic translation.

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Efficacy of ALK5 inhibition in myelofibrosis

Cited by 42 publications

References 71 publications

Therapeutic targeting of 15-PGDH in murine pulmonary fibrosis

Therapeutic targeting of 15-PGDH in murine pulmonary fibrosis

Role of TGF‐β1/miR‐382‐5p/SOD2 axis in the induction of oxidative stress in CD34+ cells from primary myelofibrosis

Transforming growth factor–β in tissue fibrosis

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