靶向端粒:端粒维持的机制特异性癌症治疗的研究进展

SCI

21 July 2022

Targeting telomeres: advances in telomere maintenance mechanism-specific cancer therapies

(Nat Rev Cancer ;IF: 69.8)

• Gao J, Pickett HA. Targeting telomeres: advances in telomere maintenance mechanism-specific cancer therapies. Nat Rev Cancer 2022. DOI: 10.1038/s41568-022-00490-1

• Correspondence to：hpickett@cmri.org.au

Abstract | 

Cancer cells establish replicative immortality by activating a telomere- maintenance mechanism (TMM), be it telomerase or the alternative lengthening of telomeres (ALT) pathway. Targeting telomere maintenance represents an intriguing opportunity to treat the vast majority of all cancer types. Whilst telomerase inhibitors have historically been heralded as promising anticancer agents, the reality has been more challenging, and there are currently no therapeutic options for cancer types that use ALT despite their aggressive nature and poor prognosis. In this Review, we discuss the mechanistic differences between telomere maintenance by telomerase and ALT, the current methods used to detect each mechanism, the utility of these tests for clinical diagnosis, and recent developments in the therapeutic strategies being employed to target both telomerase and ALT. We present notable developments in repurposing established therapeutic agents and new avenues that are emerging to target cancer types according to which TMM they employ. These opportunities extend beyond inhibition of telomere maintenance, by finding and exploiting inherent weaknesses in the telomeres themselves to trigger rapid cellular effects that lead to cell death.

癌细胞通过激活端粒维持机制(TMM)形成无限复制模式，该机制可能是端粒酶或端粒替代延长(ALT)途径。靶向端粒维持是治疗绝大多数癌症的一个有趣的机会。虽然端粒酶抑制剂在历史上一直被认为是很有前途的抗癌药物，但现实情况却更具挑战性，尽管ALT具有侵袭性和不良的预后，但目前还没有针对癌症类型的治疗选择。在这篇综述中，我们讨论了端粒酶和谷丙转氨酶维持端粒的机制差异，目前用于检测每种机制的方法，这些方法在临床诊断中的应用，以及针对端粒酶和谷丙转氨酶的治疗策略的最新进展。我们介绍了在重新利用现有的治疗药物方面的显著进展，以及根据其使用的TMM来针对癌症类型的新途径。这些机会不仅仅局限于抑制端粒维持，通过发现和利用端粒本身的固有弱点来触发导致细胞死亡的快速细胞效应。