ALK1 as an emerging target for antiangiogenic therapy of cancer

Abstract

IntroductionThe introduction of antiangiogenic therapies into oncologic practice has been highly anticipated because of the success of extensive preclinical testing. However, the initial clinical experience with this new class of anticancer drugs has been sobering, with a measurable therapeutic benefit of a few months observed and very little effect on overall patient survival. To fully realize the potential of therapies inhibiting neoangiogenesis, it is likely that drugs impinging on multiple regulatory pathways must be combined, and thus we must learn more about the biology of various signaling factors affecting endothelial cell (EC) growth and function. Activin receptor-like kinase 1 (ALK1) is an EC-restricted receptor of the large TGF-␤ family. 1 Herein, we will review our current understanding of ALK1 signaling and the potential of ALK1 to serve as a drug target for antiangiogenic therapy for cancer. Signaling by ALK1 in ECsThe large family of TGF-␤ extracellular ligands consists of Ͼ 30 cytokines that exert influence on several cellular compartments, notably epithelial cells, fibroblasts, immune cells, and endothelial and perivascular cells. TGF-␤, the prototypical member of the family, elicits a diverse set of cellular responses, such as growth arrest, immune suppression, differentiation, apoptosis, and specification of developmental cell fate during embryogenesis and pathogenesis, in species ranging from flies and worms to mammals. 2,3 On secretion and subsequent activation, the mature TGF-␤ ligand initiates signaling by inducing specific serine/threonine kinase type I and type II receptor heterotetrameric complexes. 4 Ligand binding results in signal propagation inside the cell by phosphorylation of specific effector proteins, so-called Smads, which translocate to the nucleus and activate transcription of target genes. 2,5 In ECs, TGF-␤ has been shown to signal via both the ubiquitously expressed type I receptor ALK5 and through the predominantly EC restricted receptor ALK1 (Figure 1). Depending on which type I receptor is recruited, different Smad signaling cascades are activated; ALK1 activation induces phosphorylation of Smad1/5/8, whereas ALK5 leads to Smad 2/3 activation. [6][7][8][9] Consequent to engagement of either Smad pathway, the receptoractivated Smads further form a heteromeric complex with a common and related partner molecule, Smad4, which translocates the complexes into the nucleus, where cell type-specific transcriptional modulators collaborate to activate or repress transcription of specific target genes in the angiogenic response. 10,11 In addition to the canonical signaling through Smad activation, TGF-␤ stimulation may lead to Smad-independent regulation of cellular outcomes, such as apoptosis and cell-cycle progression, through the direct modulation of prototypical signaling mediators, including MAP kinases and p21. 12 Furthermore, a third type of TGF-␤ receptor, the type III receptors, is represented by betaglycan and endoglin. Endoglin, primarily a vascular marker, is an auxilia...

BMPS and Liver: More Questions than Answers

“…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]. The reasons underneath the anti-versus pro-angiogenic function remain to be elucidated.…”

“…Dorsomorphin was proved to inhibit BMP-induced expression of hepcidin in vitro and maintained iron-hepcidin homeostasis in vivo [98] LDN-193189 attenuates anemia associated with inflammation due to its capacity to inhibit hepcidin expression [101,163] The use of biological compounds, such as antibodies or soluble extracellular inhibitors (traps) might allow for more specific inhibition of ALK1 activity, although caution must be taken to minimize crosstalk between different signaling pathways. The development of different biological ALK1 inhibitors for use in vivo has been reported [153]. An ALK1-Fc fusion protein (aminoacids 23-119 of mouse ALK1) was developed by Genentech to study whether ALK1 signaling controls lymphatic vessel formation [164].…”

Bone morphogenetic protein-9 inhibits lymphatic vessel formation via activin receptor-like kinase 1 during development and cancer progression

“…It will be of great interest to study whether LV density differs among tumor specimens that express different levels of BMP-9. Recently, BMP-9/ALK-1 signals have been attracting attention as a target of cancer therapy, as the inhibition of ALK-1 signaling interferes with tumor angiogenesis, which may inhibit tumor growth (24,34). Because the formation of LVs in tumors is associated with lymph node metastases in cancer, it is of interest to know whether blocking ALK-1 signals might influence tumor lymphangiogenesis.…”

Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of Dalantercept, an Activin Receptor–like Kinase-1 Ligand Trap, in Patients with Advanced Cancer

“…Diverse agents are under clinical evaluation as modulators of the BMP9/BMP10/ALK1 pathway, an emerging target for antiangiogenic therapy of cancer (41,42). As described here, dalantercept is a first-in-class soluble receptor fusion protein designed to sequester and inactivate the high-affinity ALK1 ligands BMP9 and BMP10.…”