Cancers are highly heterogeneous and typically contain a small subset of drug-resisting cells called tumor initiating cells or cancer stem cells (CSCs). CSCs can self-renew, divide asymmetrically, and often cause tumor invasion and metastasis. Therefore, treatments specifically targeting CSCs are critical to improve patient survival. Recently, we identified a highly specific peptidomimetic (peptoid – PCS2) that selectively binds to the CSC subpopulation of lung cancer over the remaining cancer cells (non-CSCs). Subsequently, we identified plectin as the target of PCS2. Plectin is an intracellular structural protein, which is involved in tumor invasion and metastasis when it appears on cell surface. While PCS2 monomer did not display any anti-cancer activity, we designed a series of homo-dimeric versions of PCS2, and identified PCS2D1.2 optimized homo-dimer that displayed highly specific cytotoxicity towards CSCs over non-CSCs. PCS2D1.2 effectively blocked the in vitro colony formation and cell migration, hallmarks of CSCs. Furthermore, PCS2D1.2 reduced the in vivo tumor formation. In both in vitro and in vivo studies, PCS2D1.2 effectively reduced plectin expression and/or plectin-rich CSCs, but had no effect on non-CSCs. Therefore, PCS2D1.2 has the potential to be developed as a highly CSC specific drug candidate, which can be used in combination with current anti-cancer drugs.

癌症具有高度异质性，通常包含一小部分称为肿瘤起始细胞或癌症干细胞 (CSC) 的抗药细胞。CSCs可以自我更新，不对称分裂，并且经常引起肿瘤侵袭和转移。因此，专门针对 CSC 的治疗对于提高患者的生存率至关重要。最近，我们发现了一种高度特异性的拟肽（类肽 – PCS2），它选择性地结合肺癌的 CSC 亚群，而不是剩余的癌细胞（非 CSC）。随后，我们将 plectin 确定为 PCS2 的目标。凝集素是一种细胞内结构蛋白，当它出现在细胞表面时就参与了肿瘤的侵袭和转移。虽然 PCS2 单体没有显示出任何抗癌活性，但我们设计了一系列 PCS2 的同源二聚体版本，并鉴定了 PCS2D1。2 优化的同源二聚体对 CSC 的细胞毒性优于对非 CSC 的特异性细胞毒性。PCS2D1.2有效阻断了体外集落形成和细胞迁移，CSCs 的标志。此外，PCS2D1.2 减少了体内肿瘤的形成。在体外和体内研究中，PCS2D1.2 有效降低了 plectin 表达和/或富含 plectin 的 CSC，但对非​​ CSC 没有影响。因此，PCS2D1.2 有可能被开发为一种高度 CSC 特异性的候选药物，可与当前的抗癌药物联合使用。