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Merck
  • Ganitumab (AMG 479) inhibits IGF-II-dependent ovarian cancer growth and potentiates platinum-based chemotherapy.

Ganitumab (AMG 479) inhibits IGF-II-dependent ovarian cancer growth and potentiates platinum-based chemotherapy.

Clinical cancer research : an official journal of the American Association for Cancer Research (2014-04-15)
Pedro J Beltran, Frank J Calzone, Petia Mitchell, Young-Ah Chung, Elaina Cajulis, Gordon Moody, Brian Belmontes, Chi-Ming Li, Steven Vonderfecht, Victor E Velculescu, Guorong Yang, Jingwei Qi, Dennis J Slamon, Gottfried E Konecny
要旨

Insulin-like growth factor 1 receptor (IGF-IR) has been implicated in the pathogenesis of ovarian cancer. Ganitumab is an investigational, fully human monoclonal antibody against IGF-IR. Here, we explore the therapeutic potential of ganitumab for the treatment of ovarian cancer. The effects of ganitumab were tested in vitro against a panel of 23 established ovarian cancer cell lines. The ability of ganitumab to inhibit IGF-I-, IGF-II-, and insulin-mediated signaling was examined in vitro and in tumor xenografts using ovarian cancer models displaying IGF-IR/PI3K/AKT pathway activation by two distinct mechanisms, PTEN loss and IGF-II overexpression. Drug interactions between ganitumab and cisplatin, carboplatin, or paclitaxel were studied in vitro and in vivo. In vitro, growth inhibition varied significantly among individual ovarian cancer cell lines. IGF-II mRNA and phospho-IGF-IR protein expression were quantitatively correlated with response to ganitumab, and PTEN mutations conferred resistance to ganitumab. Ganitumab potently inhibited baseline and IGF-I-, IGF-II-, and insulin-induced IGF-IR and IGF-IR/insulin hybrid receptor signaling in vitro and in vivo. Synergistic and additive drug interactions were seen for ganitumab and carboplatin or paclitaxel in vitro. Furthermore, ganitumab significantly increased the efficacy of cisplatin in ovarian cancer xenograft models in vivo. These observations provide a biologic rationale to test ganitumab as a single agent or in combination with carboplatin/cisplatin and paclitaxel in patients with ovarian cancer. Moreover, assessment of tumor expression of IGF-II, phospho-IGF-IR, or PTEN status may help select patients with ovarian cancer who are most likely to benefit from ganitumab. Clin Cancer Res; 20(11); 2947-58. ©2014 AACR.

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Sigma-Aldrich
cis-ジアンミン白金(II) ジクロリド, crystalline
Sigma-Aldrich
カルボプラチン
Sigma-Aldrich
cis-ジアンミン白金(II)ジクロリド, ≥99.9% trace metals basis
Sigma-Aldrich
モノクロナール抗β-チューブリンI マウス宿主抗体, clone SAP.4G5, ascites fluid
Sigma-Aldrich
trans-白金(II)ジアンミンジクロリド
USP
trans-白金(II)ジアンミンジクロリド, United States Pharmacopeia (USP) Reference Standard
シスプラチン, European Pharmacopoeia (EP) Reference Standard
trans-白金(II)ジアンミンジクロリド, European Pharmacopoeia (EP) Reference Standard