Induction of cancer cell death by selective DNA misincorporation

描述(申请人提供)：端粒覆盖并保护所有人类染色体的末端。在健康的成人组织中，端粒随着每一轮细胞分裂而缩短，这是正常衰老过程的一部分。在诱导细胞程序性死亡之前，这种机制将人类细胞限制在有限数量的细胞分裂中，因此起到了肿瘤抑制的作用。然而，在癌细胞中，一种名为端粒酶的酶被上调，以使有限数量的细胞分裂无效。因此，癌细胞能够无限分裂，这使得~90%的恶性肿瘤得以增殖。由于端粒酶在癌症生物学中的这种独特而关键的作用，它为创新的治疗提供了一个新的靶点。本提案的目的是探索一种利用端粒酶作为抗癌靶点的新机制。在我们的方法中，我们将设计非天然的核苷酸类似物，使其优先和选择性地被端粒酶结合到端粒DNA中。一旦被掺入，非天然核苷酸将取消与端粒DNA序列高度特异的端粒保护1(POT1)等重要端粒末端结合蛋白的结合。POT1结合的取消通过一系列DNA损伤事件诱导细胞死亡。这些非天然核苷酸化合物的细胞杀伤潜力将通过测量它们对端粒酶阳性癌细胞株和异种移植小鼠模型的效力和选择性来验证。我们预测，我们的策略将提供一种选择性机制，潜在地治疗广泛的人类癌症。

DESCRIPTION (provided by applicant): Telomeres cap and protect the ends of all human chromosomes. In healthy adult tissue, telomeres shorten with each round of cell division as part of the normal aging process. This mechanism limits human cells to a finite number of cell divisions before induction of programmed cell death and therefore serves as a tumor suppressor. In cancer cells, however, an enzyme called telomerase is upregulated to nullify the limited number of cell divisions. As such, cancer cells are capable of infinite division, which allows proliferation of ~90% of all malignant tumors. Due to this unique and critical role in cancer biology, telomerase provides a novel target for innovative therapeutics. The purpose of the present proposal is to explore a novel mechanism toward using telomerase as an anti-cancer target. In our approach, we will design non-native nucleotide analogs to be preferentially and selectively incorporated by telomerase into telomere DNA. Once incorporated, the non-native nucleotides should abrogate binding of essential telomere-end binding proteins such as the Protection of Telomeres 1 (POT1), which is highly specific for telomere DNA sequence. Abrogation of POT1 binding induces cell death through a cascade of DNA damage events. The cell-killing potential of these non-native nucleotide compounds will be validated by measuring their potency and selectivity against telomerase-positive cancer cell lines as well as xenograft mouse models. We predict that our strategy will provide a selective mechanism to potentially treat a wide range of human cancers.