gsk-1363089 and Ovarian-Neoplasms

Chemotherapeutic drug testing of SCCOHT-1 and BIN-67 tumor cells revealed synergistic growth-inhibition of >95% in vitro with a combination of foretinib and FK228. Application of this drug combination in vivo in NODscid mice-induced SCCOHT-1GFP tumors was associated with ~6-fold reduction in tumor mass within 10 days, whereby synergistic effects of the two compounds remained undetectable compared to previous results with foretinib treatment alone. Histopathologic evaluation revealed a reduced vascularization and a lower amount of proliferating cells in the treated tumors. Surprisingly, a simultaneous significant accumulation of extracellular matrix structures with positive elastin-van Gieson staining was observed following foretinib/FK228 exposure. Expression analysis of treated animal tumors exhibited various changes including increased mouse transcript levels of elastin, laminin, and fibronectin. In parallel, markers for mesenchymal stroma/stem cells (MSC) including CD73 and CD90 were detectable in all mouse tumors suggesting a possible involvement of these cells in extracellular matrix restructure. Indeed, incubation of MSC with FK228 or foretinib/FK228 demonstrated morphologic alterations and enhanced expression of laminin and fibronectin. Moreover, a co-culture of MSC with lentiviral-labeled SCCOHT-1GFP cells contributed to protection of the tumor cells against FK228-mediated cytotoxicity. Furthermore, explant cultures of SCCOHT-1GFP-induced tumors acquired an increased resistance to FK228 and a combination of foretinib/FK228 in contrast to foretinib alone. Together, these data suggested that FK228-mediated extracellular matrix protein expression by MSC contributes to increased protection and enhanced resistance of SCCOHT tumors which could represent a more general mechanism of MSC during drug-induced alterations of a tumor microenvironment.

Topics: 5'-Nucleotidase; Anilides; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Depsipeptides; Drug Resistance, Neoplasm; Elastin; Extracellular Matrix; Female; Fibronectins; Humans; Laminin; Mesenchymal Stem Cells; Mice; Mice, Inbred NOD; Mice, SCID; Ovarian Neoplasms; Quinolines; Thy-1 Antigens; Tumor Microenvironment; Xenograft Model Antitumor Assays

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.. 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.. 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 G(2)-M cell-cycle arrest, and (e) induction of anoikis.. 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.

Topics: Administration, Oral; Anilides; Animals; Anoikis; Antineoplastic Agents; Cell Cycle; Cell Death; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Female; Humans; Mice; Mice, Nude; Mice, Transgenic; Neoplasm Invasiveness; Ovarian Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Quinolines; Tumor Burden; Vascular Endothelial Growth Factor Receptor-2; Xenograft Model Antitumor Assays