Blood：CRM1抑制剂治疗急性白血病

近日，根据研究美国俄亥俄州立大学综合癌症中心的研究人员完成额一项研究证实：一种穿梭于细胞核内的蛋白质分子可能是治疗急性白血病患者新的作用靶标。

抑制这一蛋白质家族的药物叫KPT-SINEs，能靶向调控运输蛋白——CRM1。在急性髓细胞性白血病（AML）细胞和动物模型研究中，研究人员发现这些药物能抑制白血病细胞增殖，阻断细胞分裂并诱导细胞死亡和分化。

在AML动物模型中，与对照组相比，KPT-SINEs能延长动物46％的存活时间。

KPT-SINEs对有NPM1肿瘤抑制基因突变的白血病细胞特别有效，这类突变白血病患者占所有成人白血病患者的三分之一左右。

这项研究结果发表在Blood杂志上。

医学助理教授Ramiro Garzon称：我们的研究表明这些药物可能是一个有效的治疗药物，特别是对AML NPM1突变患者来说。

研究人员我们希望尽快将这些药物启动临床试验，并进一步研究其与目前其他化疗药物结合使用情况。

doi:10.1182/blood-2012-04-423160
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Pre-clinical activity of a novel CRM1 inhibitor in acute myeloid leukemia

Parvathi Ranganathan, Xueyan Yu, Caroline Na, Ramasamy Santhanam, Sharon Shacham, et al.

CRM1 is a nuclear export receptor involved in the active transport of tumor suppressors [e.g. p53 and nucleophosmin] whose function is altered in cancer due to increased expression and overactive transport. Blocking CRM1 mediated nuclear export of such proteins is a novel therapeutic strategy to restore tumor suppressor function. Orally bioavailable selective inhibitors of nuclear export (SINE) that irreversibly bind to CRM1 and block the function of this protein have been recently developed. Here, we investigated the anti-leukemic activity of KPT-SINE (KPT-185 and -276) in vitro and in vivo in acute myeloid leukemia (AML). KPT-185 displayed potent anti-proliferative properties at submicromolar concentrations (IC50 values; 100-500nM), induced apoptosis (average 5 fold increase), cell-cycle arrest and myeloid differentiation in AML cell lines and patient blasts. A strong down-regulation of the oncogene FLT3 after KPT treatment in both FLT3-ITD and wild type cell lines was observed. Finally, using the FLT3-ITD positive MV4-11 xenograft murine model, we show that treatment of mice with oral KPT-276 (analog of KPT-185 for in vivo studies) significantly prolongs survival of leukemic mice (P<0.01). In summary, KPT-SINEs are highly potent in vitro and in vivo in AML. The preclinical results reported here support clinical trials of KPT-SINE in AML.