Department of Cell Biology, Annette G Strauss Center for Neuro-Oncology, University of Texas, Southwestern Medical Center, Dallas, Texas 75390-9039, USA.
Clin Cancer Res. 2010 Jan 1;16(1):154-63. doi: 10.1158/1078-0432.CCR-09-2850.
Telomerase activity is one of the hallmarks of cancer and is a highly relevant therapeutic target. The effects of a novel human telomerase antagonist, imetelstat, on primary human glioblastoma (GBM) tumor-initiating cells were investigated in vitro and in vivo.
Tumor-initiating cells were isolated from primary GBM tumors and expanded as neurospheres in vitro. The GBM tumor-initiating cells were treated with imetelstat and examined for the effects on telomerase activity levels, telomere length, proliferation, clonogenicity, and differentiation. Subsequently, mouse orthotopic and subcutaneous xenografts were used to assess the in vivo efficacy of imetelstat.
Imetelstat treatment produced a dose-dependent inhibition of telomerase (IC(50) 0.45 micromol/L). Long-term imetelstat treatment led to progressive telomere shortening, reduced rates of proliferation, and eventually cell death in GBM tumor-initiating cells. Imetelstat in combination with radiation and temozolomide had a dramatic effect on cell survival and activated the DNA damage response pathway. Imetelstat is able to cross the blood-brain barrier in orthotopic GBM xenograft tumors. Fluorescently labeled GBM tumor cells isolated from orthotopic tumors, following systemic administration of imetelstat (30 mg/kg every day for three days), showed approximately 70% inhibition of telomerase activity. Chronic systemic treatment produced a marked decrease in the rate of xenograft subcutaneous tumor growth.
This preclinical study supports the feasibility of testing imetelstat in the treatment of GBM patients, alone or in combination with standard therapies.
端粒酶活性是癌症的特征之一，是一个高度相关的治疗靶点。本研究旨在研究新型人端粒酶拮抗剂imetelstat 对原代人脑胶质瘤（GBM）肿瘤起始细胞的体内外作用。
从原发性 GBM 肿瘤中分离肿瘤起始细胞，在体外作为神经球进行扩增。用 imetelstat 处理 GBM 肿瘤起始细胞，检测其对端粒酶活性水平、端粒长度、增殖、克隆形成和分化的影响。随后，使用小鼠原位和皮下异种移植模型评估 imetelstat 的体内疗效。
imetelstat 治疗呈剂量依赖性抑制端粒酶（IC50 为 0.45 μmol/L）。长期 imetelstat 治疗导致端粒逐渐缩短，GBM 肿瘤起始细胞增殖率降低，最终导致细胞死亡。imetelstat 与放疗和替莫唑胺联合应用对细胞存活有显著影响，并激活了 DNA 损伤反应途径。imetelstat 能够穿过原位 GBM 异种移植肿瘤的血脑屏障。在给予 imetelstat（30 mg/kg，每天一次，连续 3 天）后，从原位肿瘤分离的荧光标记 GBM 肿瘤细胞，端粒酶活性约抑制 70%。慢性全身治疗显著降低了皮下异种移植肿瘤的生长速度。
这项临床前研究支持测试 imetelstat 单独或与标准疗法联合治疗 GBM 患者的可行性。
