Androgen deprivation therapy and second-generation androgen receptor signaling inhibitors such as enzalutamide are standard treatments for advanced/metastatic prostate cancer. Unfortunately, most men develop resistance and relapse; signaling via insulin-like growth factor (IGF) has been implicated in castration-resistant prostate cancer. We evaluated the antitumor activity of xentuzumab (IGF ligand–neutralizing antibody), alone and in combination with enzalutamide, in prostate cancer cell lines (VCaP, DuCaP, MDA PCa 2b, LNCaP, and PC-3) using established in vitro assays, and in vivo, using LuCaP 96CR, a prostate cancer patient-derived xenograft (PDX) model. Xentuzumab + enzalutamide reduced the viability of phosphatase and tensin homolog (PTEN)-expressing VCaP, DuCaP, and MDA PCa 2b cells more than either single agent, and increased antiproliferative activity and apoptosis induction in VCaP. Xentuzumab or xentuzumab + enzalutamide inhibited IGF type 1 receptor and AKT serine/threonine kinase (AKT) phosphorylation in VCaP, DuCaP, and MDA PCa 2b cells; xentuzumab had no effect on AKT phosphorylation and proliferation in PTEN-null LNCaP or PC-3 cells. Knockdown of PTEN led to loss of antiproliferative activity of xentuzumab and reduced activity of xentuzumab + enzalutamide in VCaP cells. Xentuzumab + enzalutamide inhibited the growth of castration-resistant LuCaP 96CR PDX with acquired resistance to enzalutamide, and improved survival in vivo. The data suggest that xentuzumab + enzalutamide combination therapy may overcome castration resistance and could be effective in patients who are resistant to enzalutamide alone. PTEN status as a biomarker of responsiveness to combination therapy needs further investigation.

中文翻译：

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IGF-1/IGF-2 中和抗体 Xentuzumab (BI 836845) 联合恩杂鲁胺在前列腺癌模型中的抗肿瘤活性


雄激素剥夺疗法和第二代雄激素受体信号抑制剂（例如恩杂鲁胺）是晚期/转移性前列腺癌的标准治疗方法。不幸的是，大多数男性都会产生耐药性并复发。通过胰岛素样生长因子（IGF）发出的信号与去势抵抗性前列腺癌有关。我们使用已建立的体外测定法评估了 Xentuzumab（IGF 配体中和抗体）单独使用以及与恩杂鲁胺联合使用在前列腺癌细胞系（VCaP、DuCaP、MDA PCa 2b、LNCaP 和 PC-3）中的抗肿瘤活性，并在体内，使用 LuCaP 96CR，一种前列腺癌患者来源的异种移植 (PDX) 模型。 Xentuzumab + enzalutamide 比任一单一药物更能降低表达磷酸酶和张力蛋白同源物 (PTEN) 的 VCaP、DuCaP 和 MDA PCa 2b 细胞的活力，并增加 VCaP 的抗增殖活性和凋亡诱导。 Xentuzumab 或 Xentuzumab + enzalutamide 抑制 VCaP、DuCaP 和 MDA PCa 2b 细胞中 IGF 1 型受体和 AKT 丝氨酸/苏氨酸激酶 (AKT) 磷酸化； xentuzumab 对 PTEN 缺失的 LNCaP 或 PC-3 细胞中的 AKT 磷酸化和增殖没有影响。 PTEN 的敲低导致 Xentuzumab 抗增殖活性丧失，并降低 VCaP 细胞中 Xentuzumab + 恩杂鲁胺的活性。 Xentuzumab + enzalutamide 可抑制具有恩杂鲁胺获得性耐药性的去势抗性 LuCaP 96CR PDX 的生长，并提高体内存活率。数据表明，xentuzumab + 恩杂鲁胺联合疗法可以克服去势抵抗，并且对单独对恩杂鲁胺耐药的患者可能有效。 PTEN 作为联合治疗反应性生物标志物的状态需要进一步研究。