Stromal platelet-derived growth factor receptor α (PDGFRα) provides a therapeutic target independent of tumor cell PDGFRα expression in lung cancer xenografts.

Abstract

In lung cancer, platelet-derived growth factor receptor α (PDGFRα) is expressed frequently by tumor-associated stromal cells and by cancer cells in a subset of tumors. We sought to determine the effect of targeting stromal PDGFRα in preclinical lung tumor xenograft models (human tumor, mouse stroma). Effects of anti-human (IMC-3G3) and anti-mouse (1E10) PDGFRα monoclonal antibodies (mAb) on proliferation and PDGFRα signaling were evaluated in lung cancer cell lines and mouse fibroblasts. Therapy studies were conducted using established PDGFRα-positive H1703 cells and PDGFRα-negative Calu-6, H1993, and A549 subcutaneous tumors in immunocompromised mice treated with vehicle, anti-PDGFRα mAbs, chemotherapy, or combination therapy. Tumors were analyzed for growth and levels of growth factors. IMC-3G3 inhibited PDGFRα activation and the growth of H1703 cells in vitro and tumor growth in vivo, but had no effect on PDGFRα-negative cell lines or mouse fibroblasts. 1E10 inhibited growth and PDGFRα activation of mouse fibroblasts, but had no effect on human cancer cell lines in vitro. In vivo, 1E10-targeted inhibition of murine PDGFRα reduced tumor growth as single-agent therapy in Calu-6 cells and enhanced the effect of chemotherapy in xenografts derived from A549 cells. We also identified that low expression cancer cell expression of VEGF-A and elevated expression of PDGF-AA were associated with response to stromal PDGFRα targeting. We conclude that stromal PDGFRα inhibition represents a means for enhancing control of lung cancer growth in some cases, independent of tumor cell PDGFRα expression.

• Authors: David E Gerber, Puja Gupta, Michael T Dellinger, Jason E Toombs, Michael Peyton, Inga Duignan, Jennifer Malaby, Timothy Bailey, Colleen Burns, Rolf A Brekken, Nick Loizos
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 11 Issue 11 Pg. 2473-82 (Nov 2012) ISSN: 1538-8514 [Electronic] United States
• PMID: 22933705 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2012 AACR.

Chemical References

• Antibodies, Monoclonal
• Platelet-Derived Growth Factor
• Vascular Endothelial Growth Factor A
• platelet-derived growth factor A
• Receptor, Platelet-Derived Growth Factor alpha

Topics

• Animals
• Antibodies, Monoclonal (pharmacology, therapeutic use)
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Female
• Humans
• Lung Neoplasms (drug therapy, metabolism, pathology)
• Mice
• Molecular Targeted Therapy
• Platelet-Derived Growth Factor (metabolism)
• Receptor, Platelet-Derived Growth Factor alpha (antagonists & inhibitors, metabolism)
• Species Specificity
• Stromal Cells (drug effects, metabolism, pathology)
• Vascular Endothelial Growth Factor A (metabolism)
• Xenograft Model Antitumor Assays