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

Platelet-derived growth factor receptor a (PDGFRa) 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, MEDI575, that selectively binds to human PDGFRa with high affinity, with no observable affinity for murine PDGFRa. To more fully characterize the role of PDGFRa 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 PDGFRa in place of murine PDGFRa. We used the Calu-6 non-small cell lung cancer model because it lacks an in vitro proliferative response to PDGFRa activation. Antitumor activity was observed when the study was performed in mice expressing the human receptor, but no activity was observed in themice expressing the murine receptor. Immunohistologic analysis of the tumors from mice expressing human PDGFRa 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 frommice expressing murine PDGFRa. 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 PDGFRa pathway can play a role in maintaining a tumor microenvironment conducive to tumor growth.