文章：

端粒酶和癌症治疗

Telomerase and cancer therapeutics

原文发布日期：2008-03-01

DOI: 10.1038/nrc2275

类型: Review Article

开放获取: 否

要点：

1. Telomerase is an important drug target for cancer. It is expressed in most tumours from virtually all types of cancers and is required for long-term maintenance of telomeres, which in turn is crucial for the long-term survival of tumour cells.
2. Telomerase is a relatively specific cancer target as normal body cells express little or no telomerase for most of their lifespan and generally have longer telomeres than those in tumour cells.
3. Two major approaches to killing telomerase-positive tumour cells are in clinical trials. A direct telomerase inhibitor, GRN163L, is in trials in chronic lymphocytic leukaemia, multiple myeloma, solid tumours and non-small-cell lung cancer. Several therapeutic vaccines directed against the crucial telomerase protein TERT are in or have completed trials in leukaemia and renal, prostate, lung, skin, pancreatic and breast cancer.
4. Telomerase inhibitors can have fast-acting single-agent activity in certain cancers with short telomeres and rapid turnover, but this should not be the expectation in most patients.
5. Putative cancer stem cells are telomerase-positive and thus telomerase inhibitors, in combination with effective tumour de-bulking agents, might help meet a major unmet need: durability of response.
6. Telomerase vaccines offer the potential to stimulate the rapid killing of tumour cells by enhancing the activity of telomerase-specific cytotoxic (CD8⁺) and/or helper (CD4⁺) T cells. No significant toxicity to normal tissues has been seen in any of animal studies or clinical trials to date.
7. Potential challenges in the clinical development of telomerase-based cancer therapies include selection of the best patient population, good pharmacodynamic or biological markers to assess early activity, and optimal dose and schedule for combination therapies.

要点翻译：

1. 端粒酶是癌症的一个重要药物靶点。它在几乎所有类型癌症的大多数肿瘤中均有表达，是维持端粒长期稳定所必需的，而端粒的长期稳定对肿瘤细胞的长期存活至关重要。
2. 端粒酶是一个相对特异性的癌症靶点，因为正常体细胞在大部分生命周期中很少或不表达端粒酶，且通常比肿瘤细胞具有更长的端粒。
3. 目前有两大杀伤端粒酶阳性肿瘤细胞的方法正处于临床试验阶段。直接端粒酶抑制剂GRN163L正在慢性淋巴细胞白血病、多发性骨髓瘤、实体瘤和非小细胞肺癌中进行试验。针对关键端粒酶蛋白TERT的多种治疗性疫苗已在白血病、肾癌、前列腺癌、肺癌、皮肤癌、胰腺癌和乳腺癌中开展或完成试验。
4. 端粒酶抑制剂在端粒较短且更新迅速的部分癌症中可能具有快速起效的单药活性，但在大多数患者中不应抱有此预期。
5. 推定的癌症干细胞呈端粒酶阳性，因此端粒酶抑制剂与有效的肿瘤减灭剂联用，可能有助于满足当前未被满足的重大需求：持续应答。
6. 端粒酶疫苗通过增强端粒酶特异性细胞毒性（CD8+）和/或辅助性（CD4+）T细胞的活性，为快速杀伤肿瘤细胞提供了潜力。迄今为止的所有动物研究或临床试验中，均未观察到对正常组织的显著毒性。
7. 基于端粒酶的癌症疗法在临床开发中面临的潜在挑战包括：最佳患者人群的选择、用于评估早期活性的良好药效学或生物学标志物，以及联合疗法的最佳剂量和治疗方案。

英文摘要：

Telomerase is an attractive cancer target as it appears to be required in essentially all tumours for immortalization of a subset of cells, including cancer stem cells. Moreover, differences in telomerase expression, telomere length and cell kinetics between normal and tumour tissues suggest that targeting telomerase would be relatively safe. Clinical trials are ongoing with a potent and specific telomerase inhibitor, GRN163L, and with several versions of telomerase therapeutic vaccines. The prospect of adding telomerase-based therapies to the growing list of new anticancer products is promising, but what are the advantages and limitations of different approaches, and which patients are the most likely to respond?

摘要翻译： 

端粒酶是一个有吸引力的癌症靶点，因为它似乎在所有肿瘤中都是必需的，用于包括癌症干细胞在内的一部分细胞的永生化。此外，正常组织与肿瘤组织之间在端粒酶表达、端粒长度和细胞动力学上的差异表明，靶向端粒酶可能是相对安全的。目前，临床试验正在进行中，使用一种强效且特异性的端粒酶抑制剂GRN163L，以及几种版本的端粒酶治疗性疫苗。将基于端粒酶的治疗添加到日益增多的新型抗癌产品中的前景是令人鼓舞的，但不同方法的优势和局限性是什么，哪些患者最有可能产生应答？

原文链接：

Telomerase and cancer therapeutics