Genetic and pharmacological targeting of activin receptor-like kinase 1 impairs tumor growth and angiogenesis

Abstract

Members of the transforming growth factor β (TGF-β) family have been genetically linked to vascular formation during embryogenesis. However, contradictory studies about the role of TGF-β and other family members with reported vascular functions, such as bone morphogenetic protein (BMP) 9, in physiological and pathological angiogenesis make the need for mechanistic studies apparent. We demonstrate, by genetic and pharmacological means, that the TGF-β and BMP9 receptor activin receptor-like kinase (ALK) 1 represents a new therapeutic target for tumor angiogenesis. Diminution of ALK1 gene dosage or systemic treatment with the ALK1-Fc fusion protein RAP-041 retarded tumor growth and progression by inhibition of angiogenesis in a transgenic mouse model of multistep tumorigenesis. Furthermore, RAP-041 significantly impaired the in vitro and in vivo angiogenic response toward vascular endothelial growth factor A and basic fibroblast growth factor. In seeking the mechanism for the observed effects, we uncovered an unexpected signaling synergy between TGF-β and BMP9, through which the combined action of the two factors augmented the endothelial cell response to angiogenic stimuli. We delineate a decisive role for signaling by TGF-β family members in tumor angiogenesis and offer mechanistic insight for the forthcoming clinical development of drugs blocking ALK1 in oncology.

ALK5 and ALK1 Play Antagonistic Roles in Transforming Growth Factor β-Induced Podosome Formation in Aortic Endothelial Cells

“…We went on to explore the consequences of triggering ALK5 and ALK1 by exposing cells to TGF-␤ plus BMP9. Synergy between the two ligands has been seen in which the combined action of the two proteins improved the endothelial response to angiogenic stimuli (29). In the BAE cell model, BMP9 produced a dose-dependent inhibition of the TGF-␤-induced podosome response ( Fig.…”

BMPS and Liver: More Questions than Answers

“…On the other hand, recent data support the opposite function for BMP9. Inhibition of ALK1 activity both by pharmacologic and genetic approaches inhibits angiogenesis in a mouse model of multistep tumorigenesis, therefore inhibition of the ALK1/BMP9 system impairs tumor growth and progression [151,152]. Consistent with these data, an ALK1-Fc-fusion protein that acts as a ligand trap for BMP9 is in clinical trial, and is expected to diminish angiogenesis and proliferation of solid tumors [143,153].…”

“…Another ALK1-Fc fusion protein (AC-041) is currently in clinical development by Acceleron Pharma (human counterpart of the mouse RAP-041, aminoacids 23-119 of mouse ALK1) and has been proved to be useful for impairing tumor growth and angiogenesis [151]. Pfizer has developed a fully human monoclonal antibody against ALK1 (PF-3446962), which showed great effectiveness for anti-angiogenic therapy of cancer [165].…”

Deficiency for endoglin in tumor vasculature weakens the endothelial barrier to metastatic dissemination

“…Recent work demonstrates that genetic or pharmacological blockade of the endothelial cell-restricted TGF- type I receptor ALK1 inhibits tumor angiogenesis and growth (Cunha et al, 2010;Mitchell et al, 2010;Hu-Lowe et al, 2011). No overt resistance to the blockade of ALK1 was reported in these studies, but long-term investigations are warranted to make conclusive statements.…”

“…Genetic targeting studies in mice provide ample evidence for a role of signaling by TGF- ligands, receptors, and downstream mediators during developmental angiogenesis, although the precise mechanism remains unclear (David et al, 2009;Cunha and Pietras, 2011;van Meeteren et al, 2011). Moreover, pharmacological blocking of signaling by the endothelial cell-restricted type I receptor activin receptor-like kinase 1 (ALK1) inhibits tumor growth by impairing pathological angiogenesis (Cunha et al, 2010;Mitchell et al, 2010;Hu-Lowe et al, 2011). Signaling by ALK1 is complemented by the TGF- co-receptor endoglin (ten Dijke et al, 2008;Pérez-Gómez et al, 2010;Nassiri et al, 2011).…”