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Ref Type Journal Article
PMID (26373572)
Authors Hawinkels LJ, de Vinuesa AG, Paauwe M, Kruithof-de Julio M, Wiercinska E, Pardali E, Mezzanotte L, Keereweer S, Braumuller TM, Heijkants RC, Jonkers J, Löwik CW, Goumans MJ, ten Hagen TL, ten Dijke P
Title Activin Receptor-like Kinase 1 Ligand Trap Reduces Microvascular Density and Improves Chemotherapy Efficiency to Various Solid Tumors.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 22
Issue 1
Date 2016 Jan 01
URL
Abstract Text 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.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.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.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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Dalantercept Dalantercept 2 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
Dalantercept ACE-041|ALK1-Fc ALK Inhibitor 23 Dalantercept (ACE-041) is an ALK1 ligand trap composed of the ALK1 extracellular domain linked to the IgG Fc region, which binds to ALK1 ligands and prevents binding to the receptor, potentially leading to decreased tumor angiogenesis and growth and increased sensitivity to chemotherapeutic agents (PMID: 25708802, PMID: 26373572, PMID: 20124460).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ALK wild-type breast cancer predicted - sensitive Cisplatin + Dalantercept Preclinical - Cell line xenograft Actionable In a preclinical study, Dalantercept (ACE-041) in combination with Platinol (cisplatin) resulted in decreased tumor growth in cell line xenograft models of breast cancer (PMID: 26373572). 26373572
ALK wild-type head and neck cancer predicted - sensitive Cisplatin + Dalantercept Preclinical - Cell line xenograft Actionable In a preclinical study, the addition of Dalantercept (ACE-041) to Platinol (cisplatin) treatment resulted in increased cytoxicity and decreased tumor growth in cell line xenograft models of head and neck cancer (PMID: 26373572). 26373572
ALK wild-type melanoma sensitive Dalantercept + Doxorubicin Preclinical - Cell line xenograft Actionable In a preclinical study, Dalantercept (ACE-041) in combination with Adria (doxorubicin) resulted in decreased tumor growth in cell line xenograft models of melanoma, with increased efficacy over either agent alone (PMID: 26373572). 26373572