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

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

Research output: Contribution to journalArticle

33 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2473-2482
Number of pages10
JournalMolecular Cancer Therapeutics
Volume11
Issue number11
DOIs
StatePublished - Nov 2012

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Platelet-Derived Growth Factor Receptors
Heterografts
Lung Neoplasms
Neoplasms
Therapeutics
Growth
Fibroblasts
Cell Line
Stromal Cells
Combination Drug Therapy
Vascular Endothelial Growth Factor A

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Stromal platelet-derived growth factor receptor α (PDGFRα) provides a therapeutic target independent of tumor cell PDGFRα expression in lung cancer xenografts. / Gerber, David E.; Gupta, Puja; Dellinger, Michael T.; Toombs, Jason E.; Peyton, Michael; Duignan, Inga; Malaby, Jennifer; Bailey, Timothy; Burns, Colleen; Brekken, Rolf A.; Loizos, Nick.

In: Molecular Cancer Therapeutics, Vol. 11, No. 11, 11.2012, p. 2473-2482.

Research output: Contribution to journalArticle

Gerber, David E. ; Gupta, Puja ; Dellinger, Michael T. ; Toombs, Jason E. ; Peyton, Michael ; Duignan, Inga ; Malaby, Jennifer ; Bailey, Timothy ; Burns, Colleen ; Brekken, Rolf A. ; Loizos, Nick. / Stromal platelet-derived growth factor receptor α (PDGFRα) provides a therapeutic target independent of tumor cell PDGFRα expression in lung cancer xenografts. In: Molecular Cancer Therapeutics. 2012 ; Vol. 11, No. 11. pp. 2473-2482.
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AU - Duignan, Inga

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