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Research ArticleArticle

Inhibition of Platelet-Derived Growth Factor Receptor α by MEDI-575 Reduces Tumor Growth and Stromal Fibroblast Content in a Model of Non-Small Cell Lung Cancer

Naomi Laing, Brenda McDermott, Shenghua Wen, David Yang, Deborah Lawson, Mike Collins, Corinne Reimer, Peter A. Hall, Harriet Andersén, Michael Snaith, Xin Wang, Vahe Bedian, Zhu A. Cao and David Blakey
Molecular Pharmacology June 2013, 83 (6) 1247-1256; DOI: https://doi.org/10.1124/mol.112.084079
Naomi Laing
AstraZeneca R&D Boston, Waltham, Massachusetts (N.L., B.M., S.W., D.Y., D.L., M.C., C.R., X.W., V.B., Z.A.C.); AstraZeneca R&D Alderley Park, Manchester, United Kingdom (P.A.H., D.B.); and AstraZeneca R&D Mölndal, Mölndal, Sweden (H.A., M.S.)
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Brenda McDermott
AstraZeneca R&D Boston, Waltham, Massachusetts (N.L., B.M., S.W., D.Y., D.L., M.C., C.R., X.W., V.B., Z.A.C.); AstraZeneca R&D Alderley Park, Manchester, United Kingdom (P.A.H., D.B.); and AstraZeneca R&D Mölndal, Mölndal, Sweden (H.A., M.S.)
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Shenghua Wen
AstraZeneca R&D Boston, Waltham, Massachusetts (N.L., B.M., S.W., D.Y., D.L., M.C., C.R., X.W., V.B., Z.A.C.); AstraZeneca R&D Alderley Park, Manchester, United Kingdom (P.A.H., D.B.); and AstraZeneca R&D Mölndal, Mölndal, Sweden (H.A., M.S.)
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David Yang
AstraZeneca R&D Boston, Waltham, Massachusetts (N.L., B.M., S.W., D.Y., D.L., M.C., C.R., X.W., V.B., Z.A.C.); AstraZeneca R&D Alderley Park, Manchester, United Kingdom (P.A.H., D.B.); and AstraZeneca R&D Mölndal, Mölndal, Sweden (H.A., M.S.)
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Deborah Lawson
AstraZeneca R&D Boston, Waltham, Massachusetts (N.L., B.M., S.W., D.Y., D.L., M.C., C.R., X.W., V.B., Z.A.C.); AstraZeneca R&D Alderley Park, Manchester, United Kingdom (P.A.H., D.B.); and AstraZeneca R&D Mölndal, Mölndal, Sweden (H.A., M.S.)
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Mike Collins
AstraZeneca R&D Boston, Waltham, Massachusetts (N.L., B.M., S.W., D.Y., D.L., M.C., C.R., X.W., V.B., Z.A.C.); AstraZeneca R&D Alderley Park, Manchester, United Kingdom (P.A.H., D.B.); and AstraZeneca R&D Mölndal, Mölndal, Sweden (H.A., M.S.)
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Corinne Reimer
AstraZeneca R&D Boston, Waltham, Massachusetts (N.L., B.M., S.W., D.Y., D.L., M.C., C.R., X.W., V.B., Z.A.C.); AstraZeneca R&D Alderley Park, Manchester, United Kingdom (P.A.H., D.B.); and AstraZeneca R&D Mölndal, Mölndal, Sweden (H.A., M.S.)
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Peter A. Hall
AstraZeneca R&D Boston, Waltham, Massachusetts (N.L., B.M., S.W., D.Y., D.L., M.C., C.R., X.W., V.B., Z.A.C.); AstraZeneca R&D Alderley Park, Manchester, United Kingdom (P.A.H., D.B.); and AstraZeneca R&D Mölndal, Mölndal, Sweden (H.A., M.S.)
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Harriet Andersén
AstraZeneca R&D Boston, Waltham, Massachusetts (N.L., B.M., S.W., D.Y., D.L., M.C., C.R., X.W., V.B., Z.A.C.); AstraZeneca R&D Alderley Park, Manchester, United Kingdom (P.A.H., D.B.); and AstraZeneca R&D Mölndal, Mölndal, Sweden (H.A., M.S.)
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Michael Snaith
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Xin Wang
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Vahe Bedian
AstraZeneca R&D Boston, Waltham, Massachusetts (N.L., B.M., S.W., D.Y., D.L., M.C., C.R., X.W., V.B., Z.A.C.); AstraZeneca R&D Alderley Park, Manchester, United Kingdom (P.A.H., D.B.); and AstraZeneca R&D Mölndal, Mölndal, Sweden (H.A., M.S.)
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Zhu A. Cao
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David Blakey
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Abstract

Platelet-derived growth factor receptor α (PDGFRα) is a receptor tyrosine kinase that promotes cell survival and is expressed in both the tumor and the stromal components of human cancers. We have developed a fully human monoclonal antibody, MEDI-575, that selectively binds to human PDGFRα with high affinity, with no observable affinity for murine PDGFRα. To more fully characterize the role of PDGFRα in the regulation of tumor stroma, we evaluated the in vivo antitumor effects of MEDI-575 in tumor-bearing severe combined immunodeficient (SCID) mice and in genetically altered SCID mice expressing human PDGFRα in place of murine PDGFRα. We used the Calu-6 non-small cell lung cancer model because it lacks an in vitro proliferative response to PDGFRα activation. Antitumor activity was observed when the study was performed in mice expressing the human receptor, but no activity was observed in the mice expressing the murine receptor. Immunohistologic analysis of the tumors from mice expressing human PDGFRα showed a highly significant reduction in stromal fibroblast content and only minor changes in tumor proliferative index in tumors exposed to MEDI-575 compared with the results seen in vehicle-treated tumors or in tumors from mice expressing murine PDGFRα. Additional in vitro studies indicated that exposure of primary cancer-associated fibroblasts to MEDI-575 can directly affect proliferation and key signaling pathways in these cells. These results highlight the potential for observing antitumor activity with MEDI-575 through modulation of the stromal component of tumors and confirm that the PDGFRα pathway can play a role in maintaining a tumor microenvironment conducive to tumor growth.

Footnotes

    • Received March 19, 2013.
    • Accepted April 4, 2013.
  • ↵1 Current affiliation: Novartis, Cambridge, Massachusetts.

  • ↵2 Current affiliation: MedImmune, Cambridge, United Kingdom.

  • This work was supported by AstraZeneca, LLC.

  • dx.doi.org/10.1124/mol.112.084079.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 83 (6)
Molecular Pharmacology
Vol. 83, Issue 6
1 Jun 2013
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Research ArticleArticle

Modulation of Tumor Stroma by MEDI-575

Naomi Laing, Brenda McDermott, Shenghua Wen, David Yang, Deborah Lawson, Mike Collins, Corinne Reimer, Peter A. Hall, Harriet Andersén, Michael Snaith, Xin Wang, Vahe Bedian, Zhu A. Cao and David Blakey
Molecular Pharmacology June 1, 2013, 83 (6) 1247-1256; DOI: https://doi.org/10.1124/mol.112.084079

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Research ArticleArticle

Modulation of Tumor Stroma by MEDI-575

Naomi Laing, Brenda McDermott, Shenghua Wen, David Yang, Deborah Lawson, Mike Collins, Corinne Reimer, Peter A. Hall, Harriet Andersén, Michael Snaith, Xin Wang, Vahe Bedian, Zhu A. Cao and David Blakey
Molecular Pharmacology June 1, 2013, 83 (6) 1247-1256; DOI: https://doi.org/10.1124/mol.112.084079
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