Targeting the insulin growth factor and the vascular endothelial growth factor pathways in ovarian cancer.

Antiangiogenic therapy is emerging as a highly promising strategy for the treatment of ovarian cancer, but the clinical benefits are usually transitory. The purpose of this study was to identify and target alternative angiogenic pathways that are upregulated in ovarian xenografts during treatment with bevacizumab. For this, angiogenesis-focused gene expression arrays were used to measure gene expression levels in SKOV3 and A2780 serous ovarian xenografts treated with bevacizumab or control. Reverse transcription-PCR was used for results validation. The insulin growth factor 1 (IGF-1) was found upregulated in tumor and stromal cells in the two ovarian xenograft models treated with bevacizumab. Cixutumumab was used to block IGF-1 signaling in vivo. Dual anti-VEGF and IGF blockade with bevacizumab and cixutumumab resulted in increased inhibition of tumor growth. Immunohistochemistry measured multivessel density, Akt activation, and cell proliferation, whereas terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay measured apoptosis in ovarian cancer xenografts. Bevacizumab and cixutumumab combination increased tumor cell apoptosis in vivo compared with therapy targeting either individual pathway. The combination blocked angiogenesis and cell proliferation but not more significantly than each antibody alone. In summary, IGF-1 activation represents an important mechanism of adaptive escape during anti-VEGF therapy in ovarian cancer. This study provides the rationale for designing bevacizumab-based combination regimens to enhance antitumor activity.

Shao M ，Hollar S ，Chambliss D ，Schmitt J ，Emerson R ，Chelladurai B ，Perkins S ，Ivan M ，Matei D ... -  《-》

Proteasome inhibition with bortezomib induces cell death in GBM stem-like cells and temozolomide-resistant glioma cell lines, but stimulates GBM stem-like cells' VEGF production and angiogenesis.

Bota DA ，Alexandru D ，Keir ST ，Bigner D ，Vredenburgh J ，Friedman HS ... -  《-》

Combined anti-angiogenic therapy against VEGF and integrin alphaVbeta3 in an orthotopic model of ovarian cancer.

Kim TJ ，Landen CN ，Lin YG ，Mangala LS ，Lu C ，Nick AM ，Stone RL ，Merritt WM ，Armaiz-Pena G ，Jennings NB ，Coleman RL ，Tice DA ，Sood AK ... -  《-》

Maintenance treatment with bevacizumab prolongs survival in an in vivo ovarian cancer model.

Mabuchi S ，Terai Y ，Morishige K ，Tanabe-Kimura A ，Sasaki H ，Kanemura M ，Tsunetoh S ，Tanaka Y ，Sakata M ，Burger RA ，Kimura T ，Ohmichi M ... -  《CLINICAL CANCER RESEARCH》

Effect of MDM2 and vascular endothelial growth factor inhibition on tumor angiogenesis and metastasis in neuroblastoma.

Patterson DM ，Gao D ，Trahan DN ，Johnson BA ，Ludwig A ，Barbieri E ，Chen Z ，Diaz-Miron J ，Vassilev L ，Shohet JM ，Kim ES ... -  《-》