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Clin Cancer Res. 2014 May 15;20(10):2740-50. doi: 10.1158/1078-0432.CCR-13-2507. Epub 2014 Mar 14.

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

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1
Authors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine and Cancer Biology, Center for RNA Interference and Non-Coding RNA, the University of Texas MD Anderson Cancer Center, Houston, Texas; University of Southern California, Los Angeles, California; Department of Obstetrics and Gynecology, Dongguk University; Departments of Systems Biology and Obstetrics and Gynecology, Konkuk University, Seoul, Korea; and Department of Obstetrics and Gynecology, Ramathibodi Hospital, Mahidol University, Bangkok, ThailandAuthors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine and Cancer Biology, Center for RNA Interference and Non-Coding RNA, the University of Texas MD Anderson Cancer Center, Houston, Texas; University of Southern California, Los Angeles, California; Department of Obstetrics and Gynecology, Dongguk University; Departments of Systems Biology and Obstetrics and Gynecology, Konkuk University, Seoul, Korea; and Department of Obstetrics and Gynecology, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
2
Authors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine and Cancer Biology, Center for RNA Interference and Non-Coding RNA, the University of Texas MD Anderson Cancer Center, Houston, Texas; University of Southern California, Los Angeles, California; Department of Obstetrics and Gynecology, Dongguk University; Departments of Systems Biology and Obstetrics and Gynecology, Konkuk University, Seoul, Korea; and Department of Obstetrics and Gynecology, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
3
Authors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine and Cancer Biology, Center for RNA Interference and Non-Coding RNA, the University of Texas MD Anderson Cancer Center, Houston, Texas; University of Southern California, Los Angeles, California; Department of Obstetrics and Gynecology, Dongguk University; Departments of Systems Biology and Obstetrics and Gynecology, Konkuk University, Seoul, Korea; and Department of Obstetrics and Gynecology, Ramathibodi Hospital, Mahidol University, Bangkok, ThailandAuthors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine and Cancer Biology, Center for RNA Interference and Non-Coding RNA, the University of Texas MD Anderson Cancer Center, Houston, Texas; University of Southern California, Los Angeles, California; Department of Obstetrics and Gynecology, Dongguk University; Departments of Systems Biology and Obstetrics and Gynecology, Konkuk University, Seoul, Korea; and Department of Obstetrics and Gynecology, Ramathibodi Hospital, Mahidol University, Bangkok, ThailandAuthors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine and Cancer Biology, Center for RNA Interference and Non-Coding RNA, the University of Texas MD Anderson Cancer Center, Houston, Texas; University of Southern California, Los Angeles, California; Department of Obstetrics and Gynecology, Dongguk University; Departments of Systems Biology and Obstetrics and Gynecology, Konkuk University, Seoul, Korea; and Department of Obstetrics and Gynecology, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand asood@mdanderson.org.

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.

PMID:
24634380
PMCID:
PMC4024372
DOI:
10.1158/1078-0432.CCR-13-2507
[Indexed for MEDLINE]
Free PMC Article

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