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Biologic effects of platelet-derived growth factor receptor α blockade in uterine cancer
Ju-Won Roh1, Jie Huang2, Wei Hu2
1Authors' 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.
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.
Insights
Platelet-derived growth factor receptor α (PDGFRα) is highly expressed in uterine cancer. Blocking PDGFRα with antibody 3G3 showed significant antitumor effects, especially when combined with chemotherapy, identifying it as a promising therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Platelet-derived growth factor receptor α (PDGFRα) is implicated in various cancers and represents a potential therapeutic target.
- Uterine cancer is a significant health concern, necessitating novel treatment strategies.
Purpose of the Study:
- To investigate the biological role of PDGFRα in uterine cancer.
- To evaluate the efficacy of PDGFRα blockade using the monoclonal antibody 3G3 in preclinical uterine cancer models.
Main Methods:
- PDGFRα expression was analyzed in clinical uterine cancer samples and cell lines.
- In vitro assays assessed cell viability, apoptosis, and invasion upon PDGFRα inhibition.
- In vivo studies utilized orthotopic mouse models of uterine cancer to evaluate antitumor effects of 3G3, alone and in combination with chemotherapy.
Main Results:
- PDGFRα was highly expressed and activated in uterine cancer.
- 3G3 treatment inhibited PDGFRα phosphorylation and downstream signaling (AKT, MAPK).
- 3G3 demonstrated significant antitumor activity in PDGFRα-positive uterine cancer models, reducing viability and invasion, and enhancing effects with chemotherapy.
Conclusions:
- PDGFRα is a validated therapeutic target in uterine cancer.
- Antibody-mediated PDGFRα blockade shows promise for uterine cancer treatment.
- Combination therapy with 3G3 and chemotherapy offers enhanced therapeutic potential.
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