Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
Target Oncol. 2019 Aug;14(4):479-489. doi: 10.1007/s11523-019-00654-4.
High-grade meningiomas (HGMs; World Health Organization [WHO] classification grade II and III) have high relapse rates and poor clinical outcomes despite surgery and radiation treatments. No effective medical therapy currently exists for HGMs, and developing novel therapeutic strategies depends on the identification of molecular drivers. In cancer, β1 integrin enhances malignant characteristics, including proliferation, invasion, and drug resistance.
We conducted this study to investigate whether β1 integrin could be a therapeutic target in HGMs.
Expression of β1 integrin was examined in gene array datasets, with proteomics of clinical meningioma specimens, and in patient-derived HGM xenografts. Anti-tumor activity of OS2966, a first-in-class humanized antagonizing monoclonal antibody against β1 integrin, was tested in vitro and in vivo using an orthotopic mouse model of patient-derived malignant meningioma.
β1 integrin was expressed in meningiomas of all WHO grades and two xenografts tested. In vitro, OS2966 suppressed the viability of NF2-deficient MN3 sphere cells and NF2-wild-type IOMM-Lee malignant meningioma cells only when plated on laminin-coated plastic. While OS2966 decreased phosphorylation of ERK1/2 in both MN3 cells and laminin-grown IOMM-Lee cells, OS2966 only affected the phosphorylation of FAK (Tyr397) in MN3, and of Akt (Ser473) in IOMM-Lee cells, respectively, indicating differential pathway inhibition. Systemic administration of OS2966 in mice bearing orthotopic MN3 HGMs inhibited HGM cell proliferation and significantly extended overall survival of the treated mice.
β1 Integrin may be a therapeutic target in HGMs, and further preclinical and clinical development of OS2966 for HGM therapy is warranted.
高级别脑膜瘤（HGMs；世界卫生组织[WHO]分级 II 和 III）尽管进行了手术和放疗，但仍有很高的复发率和较差的临床结局。目前尚无针对 HGMs 的有效药物治疗方法，而开发新的治疗策略取决于对分子驱动因素的识别。在癌症中，β1 整合素增强了恶性特征，包括增殖、侵袭和耐药性。
我们进行这项研究旨在探讨β1 整合素是否可以成为 HGMs 的治疗靶点。
通过基因阵列数据集、临床脑膜瘤标本的蛋白质组学以及患者来源的 HGM 异种移植瘤检测β1 整合素的表达。使用患者来源的恶性脑膜瘤的原位小鼠模型，在体外和体内测试了针对β1 整合素的首创人源化拮抗单克隆抗体 OS2966 的抗肿瘤活性。
β1 整合素在所有 WHO 分级的脑膜瘤和两种测试的异种移植瘤中均有表达。在体外，当 NF2 缺陷型 MN3 球体细胞和 NF2 野生型 IOMM-Lee 恶性脑膜瘤细胞在涂有层粘连蛋白的塑料上培养时，OS2966 抑制了它们的活力。虽然 OS2966 降低了 MN3 细胞和层粘连蛋白培养的 IOMM-Lee 细胞中 ERK1/2 的磷酸化，但 OS2966 仅影响 MN3 中的 FAK（Tyr397）和 IOMM-Lee 细胞中的 Akt（Ser473）的磷酸化，分别表明差异的通路抑制。在携带原位 MN3 HGM 的小鼠中全身给予 OS2966 抑制了 HGM 细胞的增殖，并显著延长了治疗小鼠的总生存期。
β1 整合素可能是 HGMs 的治疗靶点，因此需要进一步进行 OS2966 用于 HGM 治疗的临床前和临床开发。
