Platelet-derived Growth Factor Receptor Alpha (PDGFRα) Targeting and Relevant Biomarkers in Ovarian Carcinoma (IMC-3G3)

abstract

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Highlights

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Targeting PDGFRα with monoclonal antibody (IMC-3G3) significantly enhanced the efficacy of chemotherapy in ovarian cancer cells both in-vitro and in-vivo.

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Ovarian cancer cells with high-PDGFRα expression showed significant antitumor effects with IMC-3G3 monotherapy, whereas those expressing low-PDGFRα did not.

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MAPK and CCNB1 were associated with response to IMC-3G3 in high-PDGFRα cells that showed antitumor effects with IMC-3G3 monotherapy.

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Objective

Platelet-derived growth factor receptor alpha (PDGFRα) is believed to be associated with cell survival. We examined (i) whether PDGFRα blockade enhances the antitumor activity of taxanes in ovarian carcinoma and (ii) potential biomarkers of response to anti-PDGFRα therapy.

Methods

PDGFRα expression in 176 ovarian carcinomas was evaluated with tissue microarray and correlated to survival outcome. Human-specific monoclonal antibody to PDGFRα (IMC-3G3) was used for in vitro and in vivo experiments with or without docetaxel. Gene microarrays and reverse-phase protein arrays with pathway analyses were performed to identify potential predictive biomarkers.

Results

When compared to low or no PDGFRα expression, increased PDGFRα expression was associated with significantly poorer overall survival of patients with ovarian cancer (P = 0.014). Although treatment with IMC-3G3 alone did not affect cell viability or increase apoptosis, concurrent use of IMC-3G3 with docetaxel significantly enhanced sensitization to docetaxel and apoptosis. In an orthotopic mouse model, IMC-3G3 monotherapy had no significant antitumor effects in SKOV3-ip1 (low PDGFRα expression), but showed significant antitumor effects in HeyA8-MDR (high PDGFRα expression). Concurrent use of IMC-3G3 with docetaxel, compared with use of docetaxel alone, significantly reduced tumor weight in all tested cell lines. In protein ontology, the EGFR and AKT pathways were downregulated by IMC-3G3 therapy. MAPK and CCNB1 were downregulated only in the HeyA8-MDR model.

Conclusion

These data identify IMC-3G3 as an attractive therapeutic strategy and identify potential predictive markers for further development.