Abstract 1793: Platelet-derived growth factor receptor alpha blockade significantly enhances sensitization to docetaxel in ovarian carcinoma

Abstract

Abstract Objective: Platelet-derived growth factor receptor alpha (PDGFRα) is a member of class III receptor tyrosine kinase and is associated with cell survival. Here, we examined whether PDGFRα blockade enhances the anti-tumor activity of taxanes in ovarian carcinoma. Methods: PDGFRα expression was evaluated with RT-PCR and Western blot in multiple ovarian cancer cell lines. Human-specific monoclonal antibody to PDGFRα (IMC-3G3, ImClone Systems, NJ, USA) was used for in-vitro (cell viability assay, apoptosis assay) and in-vivo experiments with or without docetaxel. Results: All eleven tested ovarian cancer cell lines had variable expression of PDGFRα. OVCA433 cell line had the highest level of expression of PDGFRα. IMC-3G3 blocked PDGFRα phosphorylation in response to PDGF-AA stimulation. IMC-3G3 alone had no affect on cell viability in all tested cell lines. However, IMC-3G3 significantly enhanced sensitization to docetaxel: IC50 reduction rate, SKOV3-ip1, 25.5%; HeyA8-parental, 31.7%; OVCA433, 35.3%; and HeyA8-MDR, 44.2% (all, p<0.05). While treatment with IMC-3G3 alone did not increase apoptosis, concurrent use with docetaxel significantly enhanced docetaxel-mediated apoptosis (mean percentage of total apoptotic cells in SKOV3-ip1, untreated vs IMC-3G3 alone vs docetaxel alone vs docetaxel with IMC-3G3, 7.3% vs 7.1% vs 15.4% vs 22.2%, p<0.001). In the in-vivo experiment with SKOV3-ip1 bearing mice, administration of IMC-3G3 monotherapy had no significant anti-tumor effects compared to the control group (mean tumor weight, 2.5 ± 0.32 vs 2.9 ± 0.51 grams, p>0.05). Concurrent use of IMC-3G3 with docetaxel significantly reduced tumor weight compared to docetaxel alone (mean tumor weight, 0.22 ± 0.07 vs 0.63 ± 0.14 grams, tumor reduction rate 65.1%, p<0.05). Conclusion: IMC-3G3 significantly enhances the anti-tumor effects of docetaxel. Therefore, targeting PDGFRα may be an attractive approach for increasing the cytotoxic effects of chemotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1793.