Biologic effects of platelet-derived growth factor receptor α blockade in uterine cancer.

Abstract

PURPOSE:

Platelet-derived growth factor receptor α (PDGFRα) expression is frequently observed in many kinds of cancer and is a candidate for therapeutic targeting. This preclinical study evaluated the biologic significance of PDGFRα and PDGFRα blockade (using a fully humanized monoclonal antibody, 3G3) in uterine cancer.

EXPERIMENTAL DESIGN:

Expression of PDGFRα was examined in uterine cancer clinical samples and cell lines, and biologic effects of PDGFRα inhibition were evaluated using in vitro (cell viability, apoptosis, and invasion) and in vivo (orthotopic) models of uterine cancer.

RESULTS:

PDGFRα was highly expressed and activated in uterine cancer samples and cell lines. Treatment with 3G3 resulted in substantial inhibition of PDGFRα phosphorylation and of downstream signaling molecules AKT and mitogen-activated protein kinase (MAPK). Cell viability and invasive potential of uterine cancer cells were also inhibited by 3G3 treatment. In orthotopic mouse models of uterine cancer, 3G3 monotherapy had significant antitumor effects in the PDGFRα-positive models (Hec-1A, Ishikawa, Spec-2) but not in the PDGFRα-negative model (OVCA432). Greater therapeutic effects were observed for 3G3 in combination with chemotherapy than for either drug alone in the PDGFRα-positive models. The antitumor effects of therapy were related to increased apoptosis and decreased proliferation and angiogenesis.

CONCLUSIONS:

These findings identify PDGFRα as an attractive target for therapeutic development in uterine cancer.

• Authors: Ju-Won Roh, Jie Huang, Wei Hu, XiaoYun Yang, Nicholas B Jennings, Vasudha Sehgal, Bo Hwa Sohn, Hee Dong Han, Sun Joo Lee, Duangmani Thanapprapasr, Justin Bottsford-Miller, Behrouz Zand, Heather J Dalton, Rebecca A Previs, Ashley N Davis, Koji Matsuo, Ju-Seog Lee, Prahlad Ram, Robert L Coleman, Anil K Sood
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 20 Issue 10 Pg. 2740-50 (May 15 2014) ISSN: 1557-3265 [Electronic] United States
• PMID: 24634380 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents
• Receptor, Platelet-Derived Growth Factor alpha
• Proto-Oncogene Proteins c-akt
• Mitogen-Activated Protein Kinases

Topics

• Animals
• Antibodies, Monoclonal (immunology, pharmacology)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Drug Synergism
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Immunohistochemistry
• Mice, Nude
• Mitogen-Activated Protein Kinases (metabolism)
• Neovascularization, Pathologic (metabolism, pathology, prevention & control)
• Oligonucleotide Array Sequence Analysis
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptor, Platelet-Derived Growth Factor alpha (antagonists & inhibitors, immunology, metabolism)
• Signal Transduction (drug effects)
• Transcriptome (drug effects)
• Uterine Neoplasms (drug therapy, genetics, metabolism)
• Xenograft Model Antitumor Assays