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

• DOI: 10.1124/mol.112.084079
• Publication Date: 2013-04-05T03:34:58Z
• Authors: 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; David Blakey
• Keywords: 0301 basic medicine; Lung Neoplasms; Receptor, Platelet-Derived Growth Factor alpha; Transplantation, Heterologous; Antibodies, Monoclonal; Mice, Nude; Antineoplastic Agents; Mice, SCID; Fibroblasts; 3. Good health; Mice; 03 medical and health sciences; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; NIH 3T3 Cells; Animals; Humans; Phosphorylation; Stromal Cells; Neoplasm Transplantation; Cell Proliferation

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