PAIRS: Validating telomerase reverse transcriptase (TERT) as an intrinsic vulnerability toward sensitizing cancer to radiation

总结 放射合成组合的一个有利靶点将是癌细胞的一个特征， 参与生长，信号传导，修复或存活，可以用无毒药物阻断， 肿瘤易受辐射而对正常组织无不良影响。该项目旨在验证 抑制端粒酶逆转录酶（TERT）作为提高放射治疗指数的手段 并在将这一战略转化为临床方面取得了关键进展。虽然在大多数肿瘤细胞中不表达TERT， 在正常细胞中，大约90%的癌症显示出TERT表达的重新激活，支持了催化的 端粒酶的活性，以维持端粒的完整性，尽管失控的增长。靶向TERT的药物 已经在患者中显示出足够的安全性来评估阻断端粒重复序列合成的效果，这已经 在实体瘤中失败，因为端粒侵蚀太慢而不影响肿瘤进展。除了在以下方面发挥重要作用之外， 癌细胞永生，TERT也有助于支持多种癌症标志的途径。通过限制 氧化应激，加速双链断裂修复和支持细胞存活， 癌细胞可赋予临床上显著的对辐射的抗性。这就提出了一个问题， 在放射治疗期间靶向TERT以增强所产生的DNA损伤对癌细胞的毒性 可显著提高放射治疗指数。 在最近发表的工作中，我们的团队描述了一类新的TERT抑制剂，其灵感来自于 抗生素色乳霉素。像天然产品一样，我们的流线型天然产品类似物与活性物质反应， 在TERT逆转录酶活性位点的半胱氨酸。优化的抑制剂NU-1在其他方面无毒 但在低微摩尔浓度下抑制端粒酶活性。NU-1赋予敏感性， 辐射对表达TERT的癌细胞的影响。我们的数据表明，TERT可能促进非同源末端- 连接修复，从而影响修复途径的选择。最后，使用BALB/c小鼠中的同基因肿瘤模型， 我们已经证明了体内对辐射的明显敏感性，显然是由持久的DNA介导的， 损伤和增加抗肿瘤免疫应答。有了这些初步研究，我们建议：1） 探讨TERT在双链断裂修复和免疫逃避中的作用; 2）改善药物样 NU-1的性质，并使用这些新化合物来了解如何最好地获得辐射敏化 和有效的抗肿瘤免疫应答。

Summary A favorable target for radiation synthetic combinations would be a feature of cancer cells critically involved in growth, signaling, repair, or survival that can be blocked with an otherwise non-toxic drug, leaving tumors vulnerable to radiation without adverse effects on normal tissue. This project is directed at validating inhibition of telomerase reverse transcriptase (TERT) as a means to enhance the therapeutic index of radiation and achieving key progress toward translating this strategy to the clinic. While TERT is not expressed in most normal cells, approximately 90% of cancers display reactivation of TERT expression, supporting the catalytic activity of telomerase to maintain telomere integrity despite deregulated growth. While drugs targeting TERT have displayed sufficient safety in patients to evaluate effects of blocking telomere repeat synthesis, this has failed in solid tumors, as telomere erosion is too slow to affect tumor progression. Beyond its essential role in cancer cell immortality, TERT also contributes to pathways that support multiple cancer hallmarks. By limiting oxidative stress, accelerating double strand break repair and supporting cell survival, TERT expression in cancer cells may confer clinically significant resistance to radiation. This raises the question whether transiently targeting TERT during radiotherapy to enhance the toxicity of the resulting DNA damage to the cancer cells might significantly improve the therapeutic index of radiation. In recently published work, our groups described a novel class of TERT inhibitors inspired by the antibiotic chrolactomycin. Like the natural product, our streamlined natural product analogs react with an active site cysteine in the TERT reverse transcriptase active site. The optimized inhibitor, NU-1, is otherwise nontoxic in vitro or in vivo, but inhibits telomerase activity at low micromolar concentrations. NU-1 confers sensitivity to radiation to TERT-expressing cancer cells. Our data suggest that TERT may promote non-homologous end- joining repair, thereby affecting repair pathway choice. Finally, using a syngeneic tumor model in BALB/c mice, we have demonstrated marked sensitization to radiation in vivo, apparently mediated by persistent DNA damage and increased anti-tumor immune response. With these preliminary studies in hand, we propose to 1) Dissect the roles of TERT in double strand break repair and immune evasion, and 2) Improve the drug-like properties of NU-1 and use these novel compounds to understand how best to obtain radiation sensitization and an effective anti-tumor immune response.