Targeting activin receptor-like kinase 1 inhibits angiogenesis and tumorigenesis through a mechanism of action complementary to anti-VEGF therapies
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Abstract
Genetic and molecular studies suggest that activin receptor-like kinase 1 (ALK1) plays an important role in vascular development, remodeling, and pathologic angiogenesis. Here we investigated the role of ALK1 in angiogenesis in the context of common proangiogenic factors [PAF; VEGF-A and basic fibroblast growth factor (bFGF)]. We observed that PAFs stimulated ALK1-mediated signaling, including Smad1/5/8 phosphorylation, nuclear translocation and Id-1 expression, cell spreading, and tubulogenesis of endothelial cells (EC). An antibody specifically targeting ALK1 (anti-ALK1) markedly inhibited these events. In mice, anti-ALK1 suppressed Matrigel angiogenesis stimulated by PAFs and inhibited xenograft tumor growth by attenuating both blood and lymphatic vessel angiogenesis. In a human melanoma model with acquired resistance to a VEGF receptor kinase inhibitor, anti-ALK1 also delayed tumor growth and disturbed vascular normalization associated with VEGF receptor inhibition. In a human/mouse chimera tumor model, targeting human ALK1 decreased human vessel density and improved antitumor efficacy when combined with bevacizumab (anti-VEGF). Antiangiogenesis and antitumor efficacy were associated with disrupted co-localization of ECs with desmin+ perivascular cells, and reduction of blood flow primarily in large/mature vessels as assessed by contrast-enhanced ultrasonography. Thus, ALK1 may play a role in stabilizing angiogenic vessels and contribute to resistance to anti-VEGF therapies. Given our 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. Cancer Res; 71(4); 1362–73. ©2011 AACR.
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PF-03446962 has been shown in preclinical studies to reverse the sensitivity of tumors to antiangiogenic therapy.
“PF-03446962 has been shown in preclinical studies to reverse the sensitivity of tumors to antiangiogenic therapy [38].”
From Drug Resistance in Colorectal Cancer: From Mechanism to Clinic (2022) · cites this paper as [38]
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- Authors
- Hu-Lowe, D. D., Chen, E., Zhang, L., Watson, K. D., Mancuso, P., Lappin, P., Wickman, G., Chen, J. H., Wang, J., Jiang, X., Amundson, K., Simon, R., Erbersdobler, A., Bergqvist, S., Feng, Z., Swanson, T. A., Simmons, B. H., Lippincott, J., Casperson, G. F., Levin, W. J., Stampino, C. G., Shalinsky, D. R., Ferrara, K. W., Fiedler, W., & Bertolini, F.
- Affiliations
- Authors' Affiliations: 1Oncology Research Unit, 2Drug Safety, Research, and Development, and 3Translational Oncology, Pfizer Inc., San Diego, California; 4Molecular and Cellular Integrative Physiology and 5Department of Biomedical Engineering, University of California at Davis, Davis, California; 6Laboratory Unit of Clinical Haematology-Oncology, European Institute of Oncology and 7Clinical Oncology, Pfizer Italia Srl, Milan, Italy; 8Institute of Pathology, and 9Department of Oncology, Hematology, BMT with section pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 10Institute of Pathology, University of Rostock, Rostock, Germany; 11Comparative Medicine, Pfizer Inc., Groton, Connecticut; and 12Biotherapeutics Pharmaceutical Sciences, Pfizer Inc., St. Louis, Missouri.
- Pfizer (United States) (US)
- ORCID
- Venue
- Cancer Research
- Published
- 2011-02-14
- Volume
- 71
- Issue
- 4
- Pages
- 1362-1373
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC3269003
- OpenAlex
- W2113980589
- Cited by
- 130
- References
- 46
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 4 · 2023: 7 · 2022: 6 · 2021: 6 · 2020: 8 · 2019: 7 · 2018: 6 · 2017: 7 · 2016: 11 · 2015: 15 · 2014: 11 · 2013: 14 · 2012: 14
- FWCI
- 6.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Pfizer
- National Cancer Institute (R01CA134659, R01CA103828, R01CA112356)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
- Keywords
- ALK1, angiogenesis, carcinogenesis, anti-VEGF therapy resistance, Smad1/5/8 signaling, Id1, endothelial cells, tubulogenesis, vascular normalization, melanoma, perivascular cells, anti-angiogenic therapy
- MeSH terms
- Animals, Antineoplastic Combined Chemotherapy Protocols, Cells, Cultured, Drug Synergism, Humans, Neoplasms, Neovascularization, Pathologic, Signal Transduction, Down-Regulation, Mice, SCID, Drug Resistance, Neoplasm, Angiogenesis Inhibitors, Xenograft Model Antitumor Assays, Activin Receptors, Type II, Vascular Endothelial Growth Factor A, Mice, Molecular Targeted Therapy
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