RT Journal Article
SR Electronic
T1 Inhibition of PDGFRα by MEDI-575 Reduces Tumor Growth and Stromal Fibroblast Content in a Model of Non-Small Cell Lung Cancer
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.112.084079
DO 10.1124/mol.112.084079
A1 Naomi Laing
A1 Brenda McDermott
A1 Shenghua Wen
A1 David Yang
A1 Deborah Lawson
A1 Mike Collins
A1 Corinne Reimer
A1 Peter A. Hall
A1 Harriet Andersen
A1 Michael Snaith
A1 Xin Wang
A1 Vahe Bedian
A1 Zhu A. Cao
A1 David Blakey
YR 2013
UL http://molpharm.aspetjournals.org/content/early/2013/04/04/mol.112.084079.abstract
AB Platelet-derived growth factor receptor alpha (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 SCID mice and in genetically altered SCID mice expressing human PDGFRα in place of murine PDGFRα. We utilized 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. Immunohistological analysis of 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 to the results seen in vehicle-treated tumors or 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.