TY - JOUR
T1 - Foretinib (GSK1363089), an orally available multikinase inhibitor of c-Met and VEGFR-2, blocks proliferation, induces anoikis, and impairs ovarian cancer metastasis
AU - Zillhardt, Marion
AU - Park, Sun Mi
AU - Romero, Iris L.
AU - Sawada, Kenjiro
AU - Montag, Anthony
AU - Krausz, Thomas
AU - Yamada, S. Diane
AU - Peter, Marcus E.
AU - Lengyel, Ernst
PY - 2011/6/15
Y1 - 2011/6/15
N2 - Purpose: Currently, there are no approved targeted therapies for the treatment of ovarian cancer, despite the fact that it is the most lethal gynecological malignancy. One proposed target is c-Met, which has been shown to be an important prognostic indicator in a number of malignancies, including ovarian cancer. The objective of this study was to determine whether an orally available multikinase inhibitor of c-Met and vascular endothelial growth factor receptor-2 (foretinib, GSK1363089) blocks ovarian cancer growth. Experimental Design: The effect of foretinib was tested in a genetic mouse model of endometrioid ovarian cancer, several ovarian cancer cell lines, and an organotypic 3D model of the human omentum. Results: In the genetic mouse model, treatment with foretinib prevented the progression of primary tumors to invasive adenocarcinoma. Invasion through the basement membrane was completely blocked in treated mice, whereas in control mice, invasive tumors entirely replaced the normal ovary. In 2 xenograft mouse models using human ovarian cancer cell lines, the inhibitor reduced overall tumor burden (86% inhibition, P < 0.0001) and metastasis (67% inhibition, P < 0.0001). The mechanism of inhibition by foretinib involved (a) inhibition of c-Met activation and downstream signaling, (b) reduction of ovarian cancer cell adhesion, (c) a block in migration and invasion, (d) reduced proliferation mediated by a G2-M cell-cycle arrest, and (e) induction of anoikis. Conclusions: This study shows that foretinib blocks tumorigenesis and reduces invasive tumor growth in different models of ovarian cancer by affecting several critical tumor functions. We believe that it provides a rationale for the further clinical development of foretinib for the treatment of ovarian cancer.
AB - Purpose: Currently, there are no approved targeted therapies for the treatment of ovarian cancer, despite the fact that it is the most lethal gynecological malignancy. One proposed target is c-Met, which has been shown to be an important prognostic indicator in a number of malignancies, including ovarian cancer. The objective of this study was to determine whether an orally available multikinase inhibitor of c-Met and vascular endothelial growth factor receptor-2 (foretinib, GSK1363089) blocks ovarian cancer growth. Experimental Design: The effect of foretinib was tested in a genetic mouse model of endometrioid ovarian cancer, several ovarian cancer cell lines, and an organotypic 3D model of the human omentum. Results: In the genetic mouse model, treatment with foretinib prevented the progression of primary tumors to invasive adenocarcinoma. Invasion through the basement membrane was completely blocked in treated mice, whereas in control mice, invasive tumors entirely replaced the normal ovary. In 2 xenograft mouse models using human ovarian cancer cell lines, the inhibitor reduced overall tumor burden (86% inhibition, P < 0.0001) and metastasis (67% inhibition, P < 0.0001). The mechanism of inhibition by foretinib involved (a) inhibition of c-Met activation and downstream signaling, (b) reduction of ovarian cancer cell adhesion, (c) a block in migration and invasion, (d) reduced proliferation mediated by a G2-M cell-cycle arrest, and (e) induction of anoikis. Conclusions: This study shows that foretinib blocks tumorigenesis and reduces invasive tumor growth in different models of ovarian cancer by affecting several critical tumor functions. We believe that it provides a rationale for the further clinical development of foretinib for the treatment of ovarian cancer.
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U2 - 10.1158/1078-0432.CCR-10-3387
DO - 10.1158/1078-0432.CCR-10-3387
M3 - Article
C2 - 21551255
AN - SCOPUS:79959215032
SN - 1078-0432
VL - 17
SP - 4042
EP - 4051
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 12
ER -