Format

Send to

Choose Destination
Gynecol Oncol. 2014 Jan;132(1):166-75. doi: 10.1016/j.ygyno.2013.10.027. Epub 2013 Oct 29.

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

Author information

1
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA; Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
2
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
3
Department of System Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
4
Department of Pathology, Wayne State University, Detroit, MI, USA.
5
Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
6
ImClone Systems Inc., New York, NY, USA.
7
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Center for RNA Interference and Non-Coding RNA, University of Texas, Houston, TX, USA.
8
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Center for RNA Interference and Non-Coding RNA, University of Texas, Houston, TX, USA; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: asood@mdanderson.org.

Abstract

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.

KEYWORDS:

EGFR; IMC-3G3; MAPK; Ovarian cancer; Platelet-derived growth factor receptor alpha

PMID:
24183729
PMCID:
PMC3946949
DOI:
10.1016/j.ygyno.2013.10.027
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center