Efficacy of Onalespib, a Long-Acting Second-Generation HSP90 Inhibitor, as a Single Agent and in Combination with Temozolomide against Malignant Gliomas.
Efficacy of Onalespib, a Long-Acting Second-Generation HSP90 Inhibitor, as a Single Agent and in Combination with Temozolomide against Malignant Gliomas.
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DOI：
10.1158/1078-0432.ccr-16-3151
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发表时间：
2017-10-15
期刊：
影响因子：
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通讯作者：
Puduvalli VK
中科院分区：
文献类型：
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作者：
Canella A;Welker AM;Yoo JY;Xu J;Abas FS;Kesanakurti D;Nagarajan P;Beattie CE;Sulman EP;Liu J;Gumin J;Lang FF;Gurcan MN;Kaur B;Sampath D;Puduvalli VK
HSP90是一种高度保守的分子伴侣，调节几种致癌客户蛋白的功能，在胶质母细胞瘤中发生改变。然而，目前在临床试验中的HSP90抑制剂是短效的，具有不可接受的毒性或不能穿过血脑屏障（BBB）。我们研究了onalb，一种有效的，长效的新型HSP90抑制剂作为单一药物和与替莫唑胺（TMZ）联合在体外和体内对胶质瘤的疗效。测定onalbib对HSP 90、其客户蛋白以及对神经胶质瘤细胞系和患者来源的神经胶质瘤起始细胞（GSC）的生物学的影响。在非荷瘤小鼠中评估onalb的脑和血浆药代动力学及其体内抑制HSP 90的能力。使用斑马鱼和患者来源的GSC异种移植小鼠胶质瘤模型在体外和体内评估其作为单一药剂或与TMZ组合的功效。Onalb介导的HSP90抑制耗尽了几种促进生存的客户蛋白，如EGFR、EGFRvIII和AKT，破坏了它们的下游信号传导，并降低了胶质瘤细胞系和GSC的增殖、迁移、血管生成和存活。Onalbib有效地穿过BBB以在体内抑制HSP 90，并且在斑马鱼异种移植物中作为单一药剂以及在斑马鱼和GSC小鼠异种移植物中与TMZ组合延长存活。我们的研究结果表明，onalb在体外和体内对胶质瘤的长效作用，结合其穿过BBB的能力，支持其作为与TMZ联合治疗胶质瘤的潜在治疗剂的发展。
HSP90, a highly conserved molecular chaperone that regulates the function of several oncogenic client proteins is altered in glioblastoma. However, HSP90 inhibitors currently in clinical trials are short-acting, have unacceptable toxicities or are unable to cross the blood brain barrier (BBB). We examined the efficacy of onalespib, a potent, long-acting novel HSP90 inhibitor as a single agent and in combination with temozolomide (TMZ) against gliomas in vitro and in vivo. The effect of onalespib on HSP90, its client proteins, and on the biology of glioma cell lines and patient-derived glioma-initiating cells (GSC) was determined. Brain and plasma pharmacokinetics of onalespib and its ability to inhibit HSP90 in vivo was assessed in non-tumor bearing mice. Its efficacy as a single agent or in combination with TMZ was assessed in vitro and in vivo using zebrafish and patient derived GSC xenograft mouse glioma models. Onalespib mediated HSP90 inhibition depleted several survival-promoting client proteins such as EGFR, EGFRvIII and AKT, disrupted their downstream signaling and decreased the proliferation, migration, angiogenesis and survival of glioma cell lines and GSCs. Onalespib effectively crossed the BBB to inhibit HSP90 in vivo and extended survival as a single agent in zebrafish xenografts and in combination with TMZ in both zebrafish and GSC mouse xenografts. Our results demonstrate the long-acting effects of onalespib against gliomas in vitro and in vivo which combined with its ability to cross the BBB support its development as a potential therapeutic agent in combination with TMZ against gliomas.