Role of the transforming growth factor (TGF)-β signal pathway in haematopoiesis and studies of new inhibitors of this pathway in the treatment of lower-risk myelodysplastic syndrome
Authors:
O. Fuchs; R. Bokorová
Authors‘ workplace:
Ústav hematologie a krevní transfuze, Praha
Published in:
Transfuze Hematol. dnes,25, 2019, No. 4, p. 310-318.
Category:
Review/Educational Papers
Overview
Transforming growth factor (TGF)-β is a cytokine originally named for its ability to transform normal fibroblasts in culture. TGF-β was subsequently found to inhibit growth of epithelial and lymphoid cells. The cellular response to TGF-β depends on the cell type and cell microenvironment. The TGF-β family includes TGF-β1, TGF-β2, TGF TGF-β3, activins A and B, nodal, myostatin, different growth differentiation factors (GDFs), the bone morphogenetic proteins (BMPs) and the anti-Műllerian hormone (AMH). More than thirty of these ligands use a far smaller number of receptors and down-stream intracellular signalling molecules. TGF-β receptor activation and phosphorylation is associated with the myelosuppression and ineffective erythropoiesis in myelodysplastic syndrome (MDS). Anaemia is the predominant cause of poor quality of life and morbidity in patients with lower-risk MDS (LR-MDS). Lenalidomide was approved only for the treatment of del(5q) MDS after failure of erythropoiesis stimulating agents (ESAs), also known as erythropoiesis stimulating proteins (ESPs). Other patients with LR-MDS have very limited therapy options after failure of ESPs and are dependent on red blood cell transfusions. Targeted inhibition of the TGF-β signalling pathway in preclinical and clinical studies showed promising results. Sotatercept and its later analogue luspatercept stimulated erythropoiesis in postmenopausal women with osteoporosis and were also efficient in a specific group of MDS patients with ring sideroblasts who had lost their response to ESPs. Luspatercept is the first TGF-β pathway inhibitor intended for the stimulation of late stage of erythroid differentiation and for the treatment of anaemia awaiting approval on the basis of promising results of phase III studies, namely MEDALIST in RL-MDS and BELIEVE in transfusion-dependent β-thalassemia.
Keywords:
erythropoietin – myelodysplastic syndrome – ring sideroblasts – anaemia – TGF-β signal pathway – growth differentiation factor 11 – sotatercept – luspatercept – galunisertib – vactosertib
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