Synergistic activity of the Hsp90 inhibitor ganetespib with taxanes in non-small cell lung cancer models.
Synergistic activity of the Hsp90 inhibitor ganetespib with taxanes in non-small cell lung cancer models.
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DOI：
10.1007/s10637-011-9790-6
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发表时间：
2012-12
影响因子：
3.4
通讯作者：
Wada, Yumiko
中科院分区：
文献类型：
--
作者：
Proia, David A.;Sang, Jim;He, Suqin;Smith, Donald L.;Sequeira, Manuel;Zhang, Chaohua;Liu, Yuan;Ye, Shuxia;Zhou, Dan;Blackman, Ronald K.;Foley, Kevin P.;Koya, Keizo;Wada, Yumiko
以铂类为基础的双药系统化疗方案治疗晚期非小细胞肺癌（NSCLC）的有效性已基本达到平台期。因此，改善存活率和生活质量结果的努力最近集中在单独使用分子靶向剂或与标准护理疗法如紫杉烷组合使用分子靶向剂。分子伴侣热休克蛋白90（Hsp 90）代表了用于治疗干预的有吸引力的候选者，因为其抑制导致同时阻断多个致癌信号级联。Ganetespib是一种Hsp 90的非安莎霉素抑制剂，目前正在许多人类恶性肿瘤（包括NSCLC）中进行临床评价。在这里，我们表明，ganetespib增强紫杉烷类紫杉醇和多西他赛在NSCLC模型中的细胞毒活性。ganetespib与紫杉醇、多西他赛或另一种微管靶向药物长春新碱的组合在体外H1975细胞系中产生协同抗增殖作用。这些益处转化为体内H1975异种移植物中的疗效改善，与紫杉醇组合观察到显著增强的肿瘤生长抑制，与多西他赛组合观察到肿瘤消退。值得注意的是，同时暴露于ganetespib和多西他赛改善了检查的6个NSCLC异种移植模型中的5个的抗肿瘤活性。我们的数据表明，改善的治疗指数可能是机械多因素的，包括损失的促生存信号和直接细胞周期的影响所产生的热休克蛋白90的调节ganetespib。总之，这些发现为使用该组合治疗晚期NSCLC患者提供了临床前证据。本文的在线版本（doi：10.1007/s10637-011-9790-6）包含补充材料，可供授权用户使用。
Systemic chemotherapy using two-drug platinum-based regimens for the treatment of advanced stage non-small cell lung cancer (NSCLC) has largely reached a plateau of effectiveness. Accordingly, efforts to improve survival and quality of life outcomes have more recently focused on the use of molecularly targeted agents, either alone or in combination with standard of care therapies such as taxanes. The molecular chaperone heat shock protein 90 (Hsp90) represents an attractive candidate for therapeutic intervention, as its inhibition results in the simultaneous blockade of multiple oncogenic signaling cascades. Ganetespib is a non-ansamycin inhibitor of Hsp90 currently under clinical evaluation in a number of human malignancies, including NSCLC. Here we show that ganetespib potentiates the cytotoxic activity of the taxanes paclitaxel and docetaxel in NSCLC models. The combination of ganetespib with paclitaxel, docetaxel or another microtubule-targeted agent vincristine resulted in synergistic antiproliferative effects in the H1975 cell line in vitro. These benefits translated to improved efficacy in H1975 xenografts in vivo, with significantly enhanced tumor growth inhibition observed in combination with paclitaxel and tumor regressions seen with docetaxel. Notably, concurrent exposure to ganetespib and docetaxel improved antitumor activity in 5 of 6 NSCLC xenograft models examined. Our data suggest that the improved therapeutic indices are likely to be mechanistically multifactorial, including loss of pro-survival signaling and direct cell cycle effects resulting from Hsp90 modulation by ganetespib. Taken together, these findings provide preclinical evidence for the use of this combination to treat patients with advanced NSCLC. The online version of this article (doi:10.1007/s10637-011-9790-6) contains supplementary material, which is available to authorized users.
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影响因子：
11.4
作者：
Lange, BMH;Bachi, A;González, C
通讯作者：
González, C
影响因子：
3.7
作者：
Proia DA;Foley KP;Korbut T;Sang J;Smith D;Bates RC;Liu Y;Rosenberg AF;Zhou D;Koya K;Barsoum J;Blackman RK
通讯作者：
Blackman RK
影响因子：
11.2
作者：
de Cárcer, G
通讯作者：
de Cárcer, G
影响因子：
5.8
作者：
Ramalingam, Suresh;Belani, Chandra
通讯作者：
Belani, Chandra
影响因子：
11.2
作者：
Sawai, Ayana;Chandarlapaty, Sarat;Solit, David B.
通讯作者：
Solit, David B.