Platelet-derived growth factor receptor alpha (PDGFR?) targeting and relevant biomarkers in ovarian carcinoma.

ABSTRACT: Platelet-derived growth factor receptor alpha (PDGFR?) is believed to be associated with cell survival. We examined (i) whether PDGFR? blockade enhances the antitumor activity of taxanes in ovarian carcinoma and (ii) potential biomarkers of response to anti-PDGFR? therapy.PDGFR? expression in 176 ovarian carcinomas was evaluated with tissue microarray and correlated to survival outcome. Human-specific monoclonal antibody to PDGFR? (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.When compared to low or no PDGFR? expression, increased PDGFR? 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 PDGFR? expression), but showed significant antitumor effects in HeyA8-MDR (high PDGFR? 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.These data identify IMC-3G3 as an attractive therapeutic strategy and identify potential predictive markers for further development.

SUBMITTER: Matsuo K 

PROVIDER: S-EPMC3946949 | biostudies-other | 2014 Jan

REPOSITORIES: biostudies-other