Activin Receptor-like Kinase 1 Ligand Trap Reduces Microvascular Density and Improves Chemotherapy Efficiency to Various Solid Tumors

Abstract

Purpose: Antiangiogenic therapy, mostly targeting VEGF, has been applied in cancer patients for the last decade. However, resistance to anti-VEGF therapy and/or no significant benefit as monotherapeutic agent is often observed. Therefore, new antiangiogenic strategies are needed. In the current study, we investigated the therapeutic effect of interfering with the bone morphogenetic protein (BMP)9/activin receptor-like kinase (ALK)1 signaling pathway by using an ALK1-Fc ligand trap.Experimental Design: We analyzed the potential antiangiogenic and antitumor effects of ALK1-Fc protein as monotherapy and in combination with chemotherapy in vivo in mouse models of melanoma, head and neck cancer, and invasive lobular breast carcinomas. ALK1-Fc sequesters BMP9 and 10 and prevents binding of these ligands to endothelial ALK1, which regulates angiogenesis.Results: Treatment of mice with ALK1-Fc strongly decreased the tumors' microvascular density in the three different mouse cancer models. However, this effect was not accompanied by a reduction in tumor volume. An immunohistochemical analysis of the tumor samples revealed that ALK1-Fc treatment increased the pericyte coverage of the remaining tumor vessels and decreased the hypoxia within the tumor. Next, we observed that combining ALK1-Fc with cisplatin inhibited tumor growth in the breast and head and neck cancer models more efficiently than chemotherapy alone.Conclusions: The addition of ALK1-Fc to the cisplatin treatment was able to enhance the cytotoxic effect of the chemotherapy. Our results provide strong rationale to explore combined targeting of ALK1 with chemotherapy in a clinical setting, especially in the ongoing phase II clinical trials with ALK1-Fc.

BMP-9 interferes with liver regeneration and promotes liver fibrosis

“…Plates were blocked with 5% Tween-20, 0.05% sodium azide in PBS for 1 hour, followed by incubation with plasma samples (50 μL diluted with 1% bovine serum albumin (BSA) (PAA, Germany)/PBS) or a standard (recombinant mouse BMP-9, R&D Systems) for 2 hours at room temperature (RT). Detection was performed with biotinylated goat anti-human BMP-9 antibodies (0.2 μg/mL in 1% BSA/PBS 2 hours, RT), streptavidin-horse radish peroxidase and a substrate reagent pack (all R&D Systems) as described previously 36 37…”

Reduced activin receptor-like kinase 1 activity promotes cardiac fibrosis in heart failure

“…In vitro and in vivo studies of ALK1 inhibition have consistently shown a profound effect on endothelial homeostasis and attenuation of neoangiogenesis in solid tumor animal models and thus generated interest in targeting ALK1 signaling as a new therapeutic approach for malignancies characterized by neoangiogenesis [16]. An anti-human ALK1 antibody (PF-3446962) and a ligand trap (ALK1-Fc; Dalantercept) designed to disrupt ligand-receptor interaction have been developed and are currently under clinical investigation [15, 17].…”

“…Recently, several reports have implicated a role for ALK1 as a negative regulator of fibrosis in vascular tissue, cartilage, the liver and the kidney [9, 16–19]. From these observations, we hypothesized that reduced ALK1 activity promotes cardiac fibrosis in HF by limiting SMAD1 activation.…”

ALK1 signaling in development and disease: new paradigms

“…Given the important role of ALK1 signaling in blood vessel development, this pathway has more recently emerged as a possible target for anti-tumor angiogenesis. In mouse models of pancreatic cancer, breast cancer, melanoma, and head and neck cancer, immunological sequestration of ALK1 ligands (using ALK1-F c ) or antibody targeting of ALK1 inhibits tumor angiogenesis and tumor growth [111, 235–237]. These promising results led to the development of dalantercept, a human ALK1-F c fusion.…”