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Title: Biologic effects of platelet-derived growth factor receptor a blockade in uterine cancer
Authors: Ju Won Roh
Jie Huang
Wei Hu
Xiaoyun Yang
Nicholas B. Jennings
Vasudha Sehgal
Bo HwaSohn
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
University of Texas MD Anderson Cancer Center
Departments of Cancer Biology
University of Southern California
Dongguk University
Systems Biology
Konkuk University
Mahidol University
Keywords: Biochemistry, Genetics and Molecular Biology;Medicine
Issue Date: 15-May-2014
Citation: Clinical Cancer Research. Vol.20, No.10 (2014), 2740-2750
Abstract: Purpose: Platelet-derived growth factor receptor a (PDGFRa) expression is frequently observed in many kinds of cancer and is a candidate for therapeutic targeting. This preclinical study evaluated the biologic significance of PDGFRa and PDGFRa blockade (using a fully humanized monoclonal antibody, 3G3) in uterine cancer. Experimental Design: Expression of PDGFRa was examined in uterine cancer clinical samples and cell lines, and biologic effects of PDGFRa inhibition were evaluated using in vitro (cell viability, apoptosis, and invasion) and in vivo (orthotopic) models of uterine cancer. Results: PDGFRa was highly expressed and activated in uterine cancer samples and cell lines. Treatment with 3G3 resulted in substantial inhibition of PDGFRa 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 PDGFRa-positive models (Hec-1A, Ishikawa, Spec-2) but not in the PDGFRa-negative model (OVCA432). Greater therapeutic effects were observed for 3G3 in combination with chemotherapy than for either drug alone in the PDGFRa-positive models. The antitumor effects of therapy were related to increased apoptosis and decreased proliferation and angiogenesis. Conclusions: These findings identify PDGFRa as an attractive target for therapeutic development in uterine cancer. Clin Cancer Res © 2014 American Association for Cancer Research.
ISSN: 15573265
Appears in Collections:Scopus 2011-2015

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