Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	22	1	2016 Jan 01	96-106	Clin Cancer Res

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	1	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Dalantercept		ACE-041\|ALK1-Fc	ALK Inhibitor 32	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, PMID: 30951193).

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	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	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	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