Targeting the α Receptor for Platelet-Derived Growth Factor as a Primary or Combination Therapy in a Preclinical Model of Prostate Cancer Skeletal Metastasis

Purpose: Platelet-derived growth factor a (PDGFR alpha) is highly expressed in primary prostate cancer and associated skeletal metastases. Here, we tested whether targeting this receptor could impair metastatic colonization and progression, as well as prolong survival, either as primary or as combination therapy. Experimental Design: We used a preclinical animal model of metastasis in which PC3-ML human prostate cancer cells are inoculated directly in the blood circulation. First, the humanized, monoclonal antibody IMC-3G3 was administered to mice bearing established skeletal metastases. Second, we targeted the stromal PDGFR alpha with IMC-1E10, an antibody specific for the murine receptor. Third, IMC-3G3 and the bisphosphonate zoledronic acid (ZA), administered separately or in combination, were tested on the progression of skeletal lesions and overall survival. In addition, the ability of IMC-3G3 and ZA to impair initial colonization of the bone marrow by prostate cancer cells was investigated. Results: The blockade of PDGFR alpha on prostate cancer cells by IMC-3G3 reduces the size of established skeletal metastases, whereas the IMC-1E10 antibody directed against the stromal PDGFR alpha fails to inhibit metastatic progression. IMC-3G3 and ZA, either separately or in combination, significantly slow tumor growth and seem to prolong survival. Lastly, the blockade of PDGFR alpha by IMC-3G3 inhibits the initial phase of bone colonization, whereas ZA is ineffective at this stage. Conclusion: This study presents compelling evidence that targeting PDGFR alpha with IMC-3G3 delays the progression of early metastatic foci and reduces the size of more established lesions. In addition, IMC-3G3, either alone or in combination with ZA, prolongs survival in animal models. Clin Cancer Res; 16(20); 5002-10. (C) 2010 AACR.