Ganitumab (AMG 479) Inhibits IGF-2-dependent Ovarian Cancer Growth and Potentiates Platinum-based Chemotherapy
Menée sur des lignées cellulaires et à l'aide de xénogreffes de cancer de l'ovaire, cette étude évalue l'activité antitumorale du ganitumab, un anticorps anti IGF1R, seul ou en combinaison avec une chimiothérapie à base de sels de platine
Résumé en anglais
Purpose:: Insulin-like growth factor 1 receptor (IGF1R) has been implicated in the pathogenesis of ovarian cancer. Ganitumab is an investigational, fully human monoclonal antibody against IGF1R. Here, we explore the therapeutic potential of ganitumab for the treatment of ovarian cancer.
Experimental Design:Ganitumab's effects were tested in vitro against a panel of 23 established ovarian cancer cell lines. The ability of ganitumab to inhibit IGF-1-, IGF-2-, and insulin-mediated signaling was examined in vitro and in tumor xenografts using ovarian cancer models displaying IGF1R/PI3K/AKT pathway activation by two distinct mechanisms, PTEN loss and IGF-2 overexpression. Drug interactions between ganitumab and cisplatin, carboplatin, or paclitaxel were studied in vitro and in vivo.
Results:: In vitro, growth inhibition varied significantly among individual ovarian cancer cell lines. IGF-2 mRNA and phospho-IGF1R protein expression were quantitatively correlated with response to ganitumab, and PTEN mutations conferred resistance to ganitumab. Ganitumab potently inhibited baseline and IGF-1-, IGF-2-, and insulin-induced IGF1R and IGF1R/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.
Conclusions:These observations provide a biological 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-2, phospho-IGF1R, or PTEN status may help select patients with ovarian cancer who are most likely to benefit from ganitumab.
