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.
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DOI：
10.1158/1078-0432.ccr-13-3448
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发表时间：
2014-06-01
期刊：
影响因子：
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通讯作者：
Konecny GE
中科院分区：
文献类型：
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作者：
Beltran PJ;Calzone FJ;Mitchell P;Chung YA;Cajulis E;Moody G;Belmontes B;Li CM;Vonderfecht S;Velculescu VE;Yang G;Qi J;Slamon DJ;Konecny GE
胰岛素样生长因子1受体（IGF-IR）与卵巢癌的发病机制有关。Ganitumab是一种研究中的抗IGF-IR的全人源单克隆抗体。在此，我们探讨了Ganitumab治疗卵巢癌的治疗潜力。在体外测试了ganitumab对一组23种已建立的卵巢癌细胞系的作用。使用卵巢癌模型，在体外和肿瘤异种移植物中检查了ganitumab抑制IGF-I-、IGF-II-和胰岛素介导的信号传导的能力，卵巢癌模型显示IGF-IR/PI 3 K/AKT通路通过两种不同的机制（PTEN丢失和IGF-II过表达）激活。在体外和体内研究了ganitumab与顺铂、卡铂或紫杉醇之间的药物相互作用。在体外，生长抑制在个体卵巢癌细胞系之间变化显著。IGF-II mRNA和磷酸化-IGF-IR蛋白表达与对ganitumab的反应定量相关，并且PTEN突变赋予对ganitumab的抗性。Ganitumab在体外和体内有效抑制基线和IGF-I-、IGF-II-和胰岛素诱导的IGF-IR和IGF-IR/胰岛素杂合受体信号传导。在体外，观察到加尼妥单抗和卡铂或紫杉醇的协同和相加药物相互作用。此外，ganitumab在体内卵巢癌异种移植模型中显著增加顺铂的功效。这些观察结果为在卵巢癌患者中测试ganitumab作为单药或与卡铂/顺铂和紫杉醇联合治疗提供了生物学依据。此外，评估IGF-II、磷酸化IGF-IR或PTEN状态的肿瘤表达可能有助于选择最有可能从ganitumab获益的卵巢癌患者。
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.