Cell Biology Program and James Burrell Laboratories, The Hospital for Sick Children, Toronto, Canada.
EMBO Mol Med. 2010 Sep;2(9):371-84. doi: 10.1002/emmm.201000093.
Neuroblastoma (NB) is the most deadly extra-cranial solid tumour in children necessitating an urgent need for effective and less toxic treatments. One reason for the lack of efficacious treatments may be the inability of existing drugs to target the tumour-initiating or cancer stem cell population responsible for sustaining tumour growth, metastases and relapse. Here, we describe a strategy to identify compounds that selectively target patient-derived cancer stem cell-like tumour-initiating cells (TICs) while sparing normal paediatric stem cells (skin-derived precursors, SKPs) and characterize two therapeutic candidates. DECA-14 and rapamycin were identified as NB TIC-selective agents. Both compounds induced TIC death at nanomolar concentrations in vitro, significantly reduced NB xenograft tumour weight in vivo, and dramatically decreased self-renewal or tumour-initiation capacity in treated tumours. These results demonstrate that differential drug sensitivities between TICs and normal paediatric stem cells can be exploited to identify novel, patient-specific and potentially less toxic therapies.
神经母细胞瘤（NB）是儿童最致命的颅外实体瘤，因此迫切需要有效的、毒性更小的治疗方法。目前治疗方法效果不佳的原因之一可能是，现有的药物无法针对肿瘤起始或癌症干细胞群进行靶向治疗，而这些细胞群正是维持肿瘤生长、转移和复发的罪魁祸首。在这里，我们描述了一种鉴定化合物的策略，该策略可以选择性地针对源自患者的癌症干细胞样肿瘤起始细胞（TIC），同时对正常儿科干细胞（皮肤衍生前体细胞，SKP）具有选择性，并对两种治疗候选药物进行了特征描述。DECA-14 和雷帕霉素被鉴定为 NB TIC 选择性药物。这两种化合物在体外以纳摩尔浓度诱导 TIC 死亡，显著减少了体内 NB 异种移植肿瘤的重量，并显著降低了治疗肿瘤中的自我更新或肿瘤起始能力。这些结果表明，TIC 与正常儿科干细胞之间的药物敏感性差异可用于鉴定新的、针对患者的、潜在毒性更小的治疗方法。
