title: 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.
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.
authors.affiliation: AstraZeneca R&D Boston, Waltham, MA 02451, USA. Naomi.laing@astrazeneca.com
authors.forename: Naomi
authors.initials: N
authors.lastname: Laing
authors.forename: Brenda
authors.initials: B
authors.lastname: McDermott
authors.forename: Shenghua
authors.initials: S
authors.lastname: Wen
authors.forename: David
authors.initials: D
authors.lastname: Yang
authors.forename: Deborah
authors.initials: D
authors.lastname: Lawson
authors.forename: Mike
authors.initials: M
authors.lastname: Collins
authors.forename: Corinne
authors.initials: C
authors.lastname: Reimer
authors.forename: Peter A
authors.initials: PA
authors.lastname: Hall
authors.forename: Harriet
authors.initials: H
authors.lastname: Andersén
authors.forename: Michael
authors.initials: M
authors.lastname: Snaith
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Vahe
authors.initials: V
authors.lastname: Bedian
authors.forename: Zhu A
authors.initials: ZA
authors.lastname: Cao
authors.forename: David
authors.initials: D
authors.lastname: Blakey
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D041681:NIH 3T3 Cells; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors* / Q000235:genetics; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014183:Transplantation, Heterologous
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D020796:Receptor, Platelet-Derived Growth Factor alpha