Activin Receptor Inhibitors—Dalantercept

  title={Activin Receptor Inhibitors—Dalantercept},
  author={Shilpa Gupta and David M. Gill and Sumanta Kumar Pal and Neeraj Agarwal},
  journal={Current Oncology Reports},
Development of anti-angiogenic therapy including the vascular endothelial growth factor (VEGF) antibodies and VEGF-tyrosine kinase receptors has been a major landmark in cancer therapy leading improvement in survival in several cancers. While anti-angiogenic therapy is effective in some settings, resistance often develops owing to evasive, alternative pathways. Novel targets for anti-angiogenic therapy are urgently required to provide treatment alternatives in patients whose tumors are… 

Targeting tumour vasculature by inhibiting activin receptor-like kinase (ALK)1 function.

The role of ALK1 in blood vessel formation and the current status of the preclinical and clinical studies on inhibition of ALk1 signalling as an anti-angiogenic strategy are recapitulate.

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

The addition of ALK1-Fc to the cisplatin treatment was able to enhance the cytotoxic effect of the chemotherapy, providing strong rationale to explore combined targeting of ALk1 with chemotherapy in a clinical setting.

Regulation of the ALK1 ligands, BMP9 and BMP10.

Understanding the regulation of BMP9 and BMP10, at both gene and protein levels, under physiological and pathological conditions, will reveal essential information and potential novel prognostic markers for the B MP9/BMP10-targeted therapies.

Activin receptor-like kinases: a diverse family playing an important role in cancer.

This review focuses on the characteristic function of the individual receptors within each subfamily and their recognized roles in cancer, and the clinical utility of therapeutically targeting ALKs as some have shown partial responses in Phase I clinical trials but disappointing outcomes when used in Phase II studies.

Dual targeting of vascular endothelial growth factor and bone morphogenetic protein‐9/10 impairs tumor growth through inhibition of angiogenesis

It is suggested that simultaneous blockade of VEGF and BMP‐9/10 signals is a promising therapeutic strategy for the cancers that are resistant to anti‐VEGF and B MP‐ 9/10 therapies.

Advances in treatment of metastatic renal cell carcinoma

This work focuses on nivolumab, cabozantinib, and lenvatinib plus everolimus, agents that have recently emerged with positive clinical data leading to Food and Drug Administration approval or pending approval in mRCC.

BMP9 signaling promotes the normalization of tumor blood vessels

It is shown that BMP9 promotes vascular normalization in LLC tumors that leads to changes in the microenvironment that resulted in significant alterations of the tumor microenvironment, characterized by a decrease in hypoxia and an increase in immune infiltration.

Selective BMP-9 Inhibition Partially Protects Against Experimental Pulmonary Hypertension

The data obtained in human pulmonary endothelial cells derived from controls and pulmonary arterial hypertension patients indicate that BMP9 can affect the balance between endothelin-1, apelin, and adrenomedullin, and that the loss of B MP9, by deletion or inhibition, has beneficial effects against pulmonary hypertension onset and progression.

Bone Morphogenetic Proteins in Vascular Homeostasis and Disease.

This review emphasizes the pivotal role of BMPs in the vascular system, based on studies of mouse models and human vascular disorders, and confirms the importance of signaling by bone morphogenetic proteins in vascular function.

BMP signaling and its paradoxical effects in tumorigenesis and dissemination

The paradoxical effects of BMPs on various aspects of carcinogenesis, including epithelial–mesenchymal transition (EMT), cancer stem cells (CSCs), and angiogenesis are emphasized as well as potential therapeutic targets against B MPs that might be valuable in preventing tumor growth and invasion.



Targeting activin receptor-like kinase 1 inhibits angiogenesis and tumorigenesis through a mechanism of action complementary to anti-VEGF therapies.

Given the observation of its expression in the vasculature of many human tumor types and in circulating ECs from patients with advanced cancers, ALK1 blockade may represent an effective therapeutic opportunity complementary to the current antiangiogenic modalities in the clinic.

ALK1-Fc Inhibits Multiple Mediators of Angiogenesis and Suppresses Tumor Growth

Data show the efficacy of chimeric ALK1-Fc proteins in mitigating vessel formation and support the view that ALK 1-fc is a powerful antiangiogenic agent capable of blocking vascularization.

Tumor angiogenesis.

The current era of research in antiangiogenic therapy for cancer began in earnest in 1971 with the publication of Folkman's imaginative hypothesis,1 but 33 years would elapse before the first drug

Phase II evaluation of dalantercept, a soluble recombinant activin receptor-like kinase 1 (ALK1) receptor-fusion protein, for treatment of recurrent/persistent endometrial cancer: GOG-0229N.

A 2-stage design was used to estimate number of pts with persistent/recurrent EC who survived progression-free without receiving non-protocol therapy (TPFS) for at least 6 mos and number of points who had objective tumor response (ORR) and determine toxicity of Dal 1.2 mg/kg SC Q3W.

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

It is demonstrated, 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 and offers mechanistic insight for the forthcoming clinical development of drugs blocking ALK1 in oncology.

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

Dalantercept was well-tolerated at doses up to 1.6 mg/kg, with a safety profile distinct from inhibitors of the VEGF pathway, and displayed promising antitumor activity in patients with advanced refractory cancer, and multiple phase II studies are underway.

A Phase I First-in-Human Study of TRC105 (Anti-Endoglin Antibody) in Patients with Advanced Cancer

This first-in-human, phase I, open-label study assessed safety, pharmacokinetics, and antitumor activity of TRC105 in patients with advanced refractory solid tumors, finding a safety profile that was distinct from that of VEGF inhibitors.

ALK1 signaling regulates early postnatal lymphatic vessel development.

This study finds that ALK1 signaling regulates the differentiation of lymphatic endothelial cells to influence the lymphatic vascular development and remodeling, and suggests that targetingALK1 pathway might provide additional control of lymphangiogenesis in human diseases.

Context-dependent signaling defines roles of BMP9 and BMP10 in embryonic and postnatal development

Surprisingly, analysis of Bmp109/9 mice demonstrated that BMP10 has an exclusive function in cardiac development, which cannot be substituted by BMP9, and reveals context-dependent significance in having multiple ligands in a signaling pathway.