Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Expert Opin Ther Targets. 2022 Jun;26(6):547-556. doi: 10.1080/14728222.2022.2083957. Epub 2022 Jun 2.
Despite advances in the treatment of acute myeloid leukemia (AML), long-term survival remains low. In 1994, it was proposed that leukemic stem cells (LSCs) played a key role in relapsed and refractory disease. LSCs are capable of self-renewal, proliferation, differentiation, immune evasion, and drug resistance through several unique mechanisms. More recent leukemia drug development initiatives have included efforts to target LSCs. With LSCs, the challenge with such drug design is finding a way to selectively target LSCs while sparing normal hematopoietic stem cells (HSCs).
In this review, we explore the evolving knowledge of the unique LSC biology and physiology in the scientific literature, while noting the several agents that have been designed throughout the years to target this subgroup of leukemic cells. Our review includes discussion on chimeric antigen receptor T cells, monoclonal antibodies, antibody-drug conjugates against cell surface markers, signaling pathway targets, pro-apoptotic agents, epigenetic regulators, and more.
As our understanding of the intricate pathophysiology of LSCs continues to grow, it is clear that targeting such heterogenous cells successfully will require a thoughtful and multi-modal approach.
尽管急性髓系白血病（AML）的治疗取得了进展，但长期生存率仍然较低。1994 年，有人提出白血病干细胞（LSCs）在复发和难治性疾病中发挥关键作用。LSCs 通过几种独特的机制具有自我更新、增殖、分化、免疫逃避和耐药性的能力。最近的白血病药物开发计划包括努力针对 LSCs。对于 LSCs，此类药物设计的挑战在于找到一种方法来选择性地靶向 LSCs，同时保留正常造血干细胞（HSCs）。
在这篇综述中，我们探讨了科学界文献中 LSC 生物学和生理学的不断发展的知识，同时注意到多年来为靶向这组白血病细胞而设计的几种药物。我们的综述包括嵌合抗原受体 T 细胞、单克隆抗体、针对细胞表面标志物的抗体药物偶联物、信号通路靶点、促凋亡剂、表观遗传调节剂等的讨论。
随着我们对 LSCs 复杂病理生理学的理解不断加深，很明显，要成功靶向这种异质细胞，需要一种深思熟虑的多模式方法。
