Activin receptor-like kinase 1 as a target for anti-angiogenesis therapy

Hawinkels, Lukas J.A.C.; Vinuesa, Amaya García de; Dijke, Peter ten

doi:10.1517/13543784.2013.837884

Cited by 31 publications

(26 citation statements)

References 86 publications

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“…33 Interestingly, low BMP9 concentrations were reported to have pro-angiogenic properties 55 and inhibiting BMP9 levels using an ALK1-Fc ligand trap was shown to inhibit tumour angiogenesis. 56,57 In addition, other BMPs, including BMP2, BMP4, BMP6, and BMP7, have been shown to induce endothelial cell proliferation, migration, and formation of tube-like structures, and to promote angiogenesis in vitro and in vivo in mouse models. 58 The induction of inhibitor of DNA binding protein (Id) expression by BMP contributes to its pro-angiogenic response.…”

Section: H1 Bmps and The Cardiovascular Systemmentioning

confidence: 99%

Targeting BMP signalling in cardiovascular disease and anaemia

et al. 2015

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Bone morphogenetic proteins (BMPs) and their receptors, known to be essential regulators of embryonal patterning and organogenesis, are also critical for the regulation of cardiovascular structure and function. In addition to their contributions to syndromic disorders of heart and vascular development, BMP signalling is increasingly recognized for its influence on endocrine-like functions in postnatal cardiovascular and metabolic homeostasis. In this Review, we discuss several critical and novel aspects of BMP signalling in cardiovascular health and disease, which highlight the cell- and context-specific nature of BMP signalling. Based on advancing knowledge of the physiological roles and regulation of BMP signaling, we indicate opportunities for therapeutic intervention in a range of cardiovascular conditions including atherosclerosis and pulmonary arterial hypertension, and well as for anaemia of chronic disease. Depending on the context and the repertoire of ligands and receptors involved in specific disease processes, the selective inhibition or enhancement of signaling via particular BMP ligands (such as in atherosclerosis and pulmonary arterial hypertension, respectively) might be beneficial. The development of selective small molecule antagonists of BMP receptors, and the identification of ligands selective for BMP receptor complexes expressed in the vasculature provide the most immediate opportunities for new therapies.

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Section: H1 Bmps and The Cardiovascular Systemmentioning

confidence: 99%

Targeting BMP signalling in cardiovascular disease and anaemia

et al. 2015

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“…ALK1 forms part of a TGFb receptor signaling complex on endothelial cells and plays an important role in regulating angiogenesis (13,14). Bone morphogenetic protein (BMP)9 and BMP10 bind directly to ALK1 (15,16).…”

Section: Introductionmentioning

confidence: 99%

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

Hawinkels

Vinuesa

Paauwe

et al. 2016

Clinical Cancer Research

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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.

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“…Recent literature has emphasized on the importance of angiogenesis in the progression of cancer development and use of antiangiogenic agents as crucial therapeutic agents in cancer therapy (19,37). Interestingly, P7170, in addition to potently inhibiting the mTORC1/C2 pathway, also effectively inhibits ALK1 activity (IC 50 47 nmol/L).…”

Section: Discussionmentioning

confidence: 99%

“…Media were replaced with PBS containing 1 mg/mL Acridine Orange (AO) solution and incubated at 37 C for an additional 15 minutes. Cells were harvested, resuspended in PBS, and analyzed for autophagy using a flow cytometer (BD FACS Calibur).…”

Section: Autophagy Analysismentioning

confidence: 99%

“…Fine 1.0-mm aorta rings were prepared from aorta using scalpel blade, and these rings were washed in ice cold PBS. In a 24-well plate, 200 mL of Matrigel (BD Sciences) premixed with 1:1 RPMI was coated and incubated at 37 C for 1 hour. Rings were carefully arranged in every well and prediluted Matrigel (50 mL) supplemented with VEGF (40 ng/mL) was added to immerse rings.…”

Section: Rat Aorta Ring Assaymentioning

confidence: 99%

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P7170: A Novel Molecule with Unique Profile of mTORC1/C2 and Activin Receptor-like Kinase 1 Inhibition Leading to Antitumor and Antiangiogenic Activity

Jalota‐Badhwar

Bhatia

Boreddy

et al. 2015

Molecular Cancer Therapeutics

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The mTOR pathway is often upregulated in cancer and thus intensively pursued as a target to design novel anticancer therapies. Approved and emerging drugs targeting the mTOR pathway have positively affected the clinical landscape. Recently, activin receptor-like kinase 1 (ALK1), belonging to the TGFb receptor family, has been reported as an emerging target for antiangiogenic cancer therapy. Here, we describe a novel orally efficacious compound, P7170, that inhibits mTORC1/mTORC2/ALK1 activity with a potent cell growth inhibition. In cell-based assays, P7170 strongly inhibited (IC 50 < 10 nmol/L) the phosphorylation of p70S6K (T389) and pAKT (S473). In many cancer cell lines, such as prostate, ovarian, colon, and renal, P7170 treatment resulted in marked cell growth inhibition. Furthermore, it induced G 1 -S cellcycle arrest and autophagy. In vitro HUVEC tube formation, in vivo Matrigel plug, and rat aorta ring assays demonstrated that P7170 exhibited significant antiangiogenic activity. In addition, ALK1 knockdown studies in HUVEC confirmed that the antiangiogenic activity of P7170 was primarily due to ALK1 inhibition. Strong inhibition of ALK1 in addition to mTORC1/mTORC2 differentiates P7170 in its mechanism of action in comparison with existing inhibitors. In vivo mouse xenograft studies revealed P7170 to exhibit a significant dose-dependent tumor growth inhibition in a broad range of human tumor types when administered orally at 10 to 20 mg/kg doses. The distinctive pharmacological profile with favorable pharmacokinetic parameters and in vivo efficacy makes P7170 an attractive candidate for clinical development. It is currently being tested in phase I clinical studies.

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Activin receptor-like kinase 1 as a target for anti-angiogenesis therapy

Cited by 31 publications

References 86 publications

Targeting BMP signalling in cardiovascular disease and anaemia

Targeting BMP signalling in cardiovascular disease and anaemia

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

P7170: A Novel Molecule with Unique Profile of mTORC1/C2 and Activin Receptor-like Kinase 1 Inhibition Leading to Antitumor and Antiangiogenic Activity

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