Brain tumors remain the leading cause of cancer-related deaths in children and often are associated with long-term sequelae among survivors of current therapies. Hence, there is an urgent need to identify actionable targets and to develop more effective therapies. Telomerase and telomeres play important roles in cancer, representing attractive therapeutic targets to treat children with poor-prognosis brain tumors such as diffuse intrinsic pontine glioma (DIPG), high-grade glioma (HGG), and high-risk medulloblastoma. We have previously shown that DIPG, HGG, and medulloblastoma frequently express telomerase activity. Here, we show that the telomerase-dependent incorporation of 6-thio-2′deoxyguanosine (6-thio-dG), a telomerase substrate precursor analogue, into telomeres leads to telomere dysfunction–induced foci (TIF) along with extensive genomic DNA damage, cell growth inhibition, and cell death of primary stem-like cells derived from patients with DIPG, HGG, and medulloblastoma. Importantly, the effect of 6-thio-dG is persistent even after drug withdrawal. Treatment with 6-thio-dG elicits a sequential activation of ATR and ATM pathways and induces G2–M arrest. In vivo treatment of mice bearing medulloblastoma xenografts with 6-thio-dG delays tumor growth and increases in-tumor TIFs and apoptosis. Furthermore, 6-thio-dG crosses the blood–brain barrier and specifically targets tumor cells in an orthotopic mouse model of DIPG. Together, our findings suggest that 6-thio-dG is a promising novel approach to treat therapy-resistant telomerase-positive pediatric brain tumors. Mol Cancer Ther; 17(7); 1504–14. ©2018 AACR.

中文翻译：

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诱导端粒损伤治疗表达端粒酶的抗药性小儿脑肿瘤

脑肿瘤仍然是儿童癌症相关死亡的主要原因，并且通常与当前疗法幸存者的长期后遗症有关。因此，迫切需要确定可操作的目标并开发更有效的疗法。端粒酶和端粒在癌症中发挥重要作用，代表了治疗预后不良脑肿瘤儿童的有吸引力的治疗靶点，例如弥漫性内源性脑桥胶质瘤 (DIPG)、高级别胶质瘤 (HGG) 和高危髓母细胞瘤。我们之前已经表明 DIPG、HGG 和成神经管细胞瘤经常表达端粒酶活性。在这里，我们展示了端粒酶依赖性掺入 6-硫代-2'脱氧鸟苷（6-硫代-dG），一种端粒酶底物前体类似物，进入端粒导致端粒功能障碍诱导的病灶 (TIF) 以及来自 DIPG、HGG 和成神经管细胞瘤患者的原代干细胞样细胞的广泛基因组 DNA 损伤、细胞生长抑制和细胞死亡。重要的是，6-thio-dG 的作用即使在停药后也能持续存在。用 6-thio-dG 处理引起 ATR 和 ATM 通路的顺序激活并诱导 G2-M 阻滞。用 6-硫代-dG 体内治疗携带髓母细胞瘤异种移植物的小鼠可延迟肿瘤生长并增加肿瘤内 TIF 和细胞凋亡。此外，6-硫代-dG 穿过血脑屏障并特异性靶向 DIPG 原位小鼠模型中的肿瘤细胞。总之，我们的研究结果表明 6-thio-dG 是一种有前景的新方法，用于治疗对治疗耐药的端粒酶阳性小儿脑肿瘤。摩尔癌症治疗; 17(7); 1504-14。©2018 AACR。