Initial testing of the aurora kinase A inhibitor MLN8237 by the Pediatric Preclinical Testing Program (PPTP).
Initial testing of the aurora kinase A inhibitor MLN8237 by the Pediatric Preclinical Testing Program (PPTP).
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DOI：
10.1002/pbc.22430
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发表时间：
2010-07-15
影响因子：
3.2
通讯作者：
Houghton, Peter J.
中科院分区：
文献类型：
--
作者：
Maris, John M.;Morton, Christopher L.;Gorlick, Richard;Kolb, E. Anders;Lock, Richard;Carol, Hernan;Keir, Stephen T.;Reynolds, C. Patrick;Kang, Min H.;Wu, Jianrong;Smith, Malcolm A.;Houghton, Peter J.
MLN 8237是一种极光激酶A（AURKA）的小分子抑制剂，目前正处于早期临床试验阶段。AURKA在有丝分裂过程中中心体成熟和纺锤体形成中起着关键作用。MLN 8237在1.0 nM-10 μM浓度范围内根据儿科临床前试验项目（PPTP）体外样本组进行检测，并在20 mg/kg剂量下每日两次经口给药× 5天根据PPTP体内样本组进行检测。实体瘤异种移植物的治疗持续时间为6周，ALL异种移植物的治疗持续时间为3周。MLN 8237对PPTP的中位IC 50为61 nM。ALL细胞系更敏感，横纹肌肉瘤细胞系敏感性低于其余PPTP细胞系。在体内，MLN 8237在32/40（80%）实体瘤模型和所有（6/6）ALL模型中诱导的无事件生存期（EFS）分布与对照组相比存在显著差异。在7例神经母细胞瘤异种移植物中的3例中观察到维持完全缓解（CR），所有6例可评价的ALL异种移植物均达到CR（n=4）或维持CR（n=2）状态。在其他组的单个异种移植物中观察到维持CR，包括Wilms肿瘤、横纹肌样肿瘤、横纹肌肉瘤、尤文肉瘤、骨肉瘤和髓母细胞瘤。观察到的针对神经母细胞瘤组的体内活性远远超过PPTP针对该组评价的标准药物观察到的活性。还观察到针对ALL异种移植物组的高水平体内活性。这些数据支持加快MLN 8237在儿童癌症中的临床开发。
MLN8237 is a small molecule inhibitor of Aurora Kinase A (AURKA) that is currently in early phase clinical testing. AURKA plays a pivotal role in centrosome maturation and spindle formation during mitosis. MLN8237 was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro panel at concentrations ranging from 1.0 nM to 10 μM and was tested against the PPTP in vivo panels at a dose of 20 mg/kg administered orally twice daily × 5 days. Treatment duration was 6 weeks for solid tumor xenografts and 3 weeks for ALL xenografts. MLN8237 had a median IC50 of 61 nM against the PPTP in vitro panel. The ALL cell lines were more sensitive and the rhabdomyosarcoma cell lines less sensitive than the remaining PPTP cell lines. In vivo, MLN8237 induced significant differences in event-free survival (EFS) distributions compared to controls in 32/40 (80%) solid tumor models and all (6/6) ALL models. Maintained complete responses (CRs) were observed in 3 of 7 neuroblastoma xenografts, and all 6 evaluable ALL xenografts achieved CR (n=4) or maintained CR (n=2) status. Maintained CRs were observed among single xenografts in other panels, including the Wilms tumor, rhabdoid tumor, rhabdomyosarcoma, Ewing sarcoma, osteosarcoma, and medulloblastoma. The in vivo activity observed against the neuroblastoma panel far exceeds that observed for standard agents evaluated against the panel by the PPTP. High levels of in vivo activity were also observed against the ALL xenograft panel. These data support expedited clinical development of MLN8237 in childhood cancer.
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影响因子：
5.7
作者：
Henderson MC;Shaw YJ;Wang H;Han H;Hurley LH;Flynn G;Dorr RT;Von Hoff DD
通讯作者：
Von Hoff DD
影响因子：
3.2
作者：
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通讯作者：
Smith, Malcolm A.
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通讯作者：
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影响因子：
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作者：
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通讯作者：
Reynolds, C. Patrick