Analysis and basic research of targeted therapy for CML stem cells

几个数学模型和离体检查表明，伊马替尼（IM）治疗不能根除BCR-ABL阳性白血病干细胞（LSC）。在IM治疗的最佳应答者中，HSC人群中的BCR-ABL转录本倾向于比其他人群更具保留性。即使在HSC人群中，第二代ABL-酪氨酸激酶抑制剂（2nd TKI）治疗也能诱导BCR-ABL转录物更快地减少。将Ph^+白血病细胞连续异种移植到免疫缺陷NOG小鼠体内，慢循环的CD 34 ^+细胞对IM不敏感。从使用这种共培养系统对其他小化合物进行的全面药物筛选中，我们发现PI 3 K/AKT/mTOR轴信号传导的抑制剂，包括雷帕霉素，是有希望的候选物。在体外和体内实验中，IM和雷帕霉素类似物依维莫司（RAD 001）联合治疗可诱导慢循环CD 34 ^+细胞群中大量细胞死亡，并伴有p70-S6 K去磷酸化。双重PI 3 K/mTOR抑制剂NVP-BEZ 235（BEZ）在较低剂量下也诱导了大量细胞死亡，包括慢循环CD 34 ^+细胞。

Several mathematical models and ex-vivo examinations suggested that imatinib(IM) therapy does not eradicate BCR-ABL-positive leukemia stem cells(LSCs). In optimal responders to IM therapy, BCR-ABL transcripts in the HSC population tended to be more retentive than other populations. Treatment with the second-generation of ABL-tyrosine kinase inhibitors(2nd TKIs) induced more rapid reduction of BCR-ABL transcripts even in the HSC population. In Ph^+leukemia cells serially xenotransplanted into immunodeficient NOG mice, slow-cycling CD34^+cells were insensitive to IM. From comprehensive drug screening of other small compounds using this co-culturing system, we found that inhibitors of PI3K/AKT/mTOR-axis signaling, including rapamycin, were promising candidates. In vitro and in vivo, combination treatment with IM and rapamycin analogue, everolimus(RAD001), induced substantial cell death in the slow-cycling CD34^+population with p70-S6K dephosphorylation. The dual PI3K/mTOR inhibitor, NVP-BEZ235(BEZ), also induced substantial cell death including slow-cycling CD34^+cells at lower doses.