Abstract
Purpose: Platelet-derived growth factor receptor a (PDGFR alpha) expression is frequently observed in many kinds of cancer and is a candidate for therapeutic targeting. This preclinical study evaluated the biologic significance of PDGFR alpha and PDGFR alpha 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 PDGFR alpha-positive models (Hec-1A, Ishikawa, Spec-2) but not in the PDGFR alpha-negative model (OVCA432). Greater therapeutic effects were observed for 3G3 in combination with chemotherapy than for either drug alone in the PDGFR alpha-positive models. The antitumor effects of therapy were related to increased apoptosis and decreased proliferation and angiogenesis.
Conclusions: These findings identify PDGFR alpha as an attractive target for therapeutic development in uterine cancer.