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WZ4002,延缓因T790M突变导致易、特、2992的耐药及耐药后的选择

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271616 359 又一个五年 发表于 2012-12-2 10:56:35 | 精华 |
又一个五年  高中一年级 发表于 2012-12-14 12:27:11 | 显示全部楼层 来自: 山东烟台
本帖最后由 又一个五年 于 2012-12-14 12:34 编辑

WZ4002 inhibits EGFR phosphorylation and induces significant tumor regression in murine models of EGFR T790M

Our studies identify a novel structural class of EGFR kinase inhibitors which are effective in vitro and in vivo models harboring the EGFR T790M mutation. Given the dramatic activity in models with established EGFR T790M, we determined whether WZ4002 treatment could also prevent the development of EGFR T790M using in vitro models harboring EGFR activating mutations. Unlike with gefitinib or HKI-272, which when used at their achievable plasma concentrations lead to development of EGFR T790M in vitro13,21,22, we were unable to isolate any EGFR T790M containing clones from WZ4002 treated Ba/F3 or PC9 NSCLC cells (Table S9). These findings suggest that WZ4002 could also be used as initial therapy for EGFR mutant NSCLC patients and may ultimately lead to a longer time to disease progression than currently achieved with gefitinib1.

Figure 4
nihms183745f4.jpg
又一个五年  高中一年级 发表于 2012-12-14 12:36:15 | 显示全部楼层 来自: 山东烟台
Mutations, including at the gatekeeper residue, are a common mechanism of drug resistance to kinase inhibitors. The current approach, using a cellular screen expressing the mutant kinase of interest, can be applied to identify novel agents specifically against drug resistance or oncogenic mutations implicated in human cancers. Such agents may truly be cancer selective and clinically more potent and less toxic than those that also concurrently inhibit the wild type kinase. The agents described here are unique in that they inhibit both the drug sensitizing and resistance mutations but are selective against WT EGFR23,24,25. Further studies are needed to determine whether this class of EGFR inhibitors will be clinically effective in patients with EGFR mutant cancers harboring EGFR T790M mediated acquired drug resistance.

又一个五年  高中一年级 发表于 2012-12-14 21:44:10 | 显示全部楼层 来自: 山东烟台
新药CO-1686研究报告(摘选)

Results: In vitro and in vivo pharmacology studies were conducted to evaluate CO-1686 potency in four EGFR
mutations common in NSCLC patients: L858R, delE746-A750, L858R/T790M and delE746-A750/T790M. CO-1686
was shown to be active against all four EGFR mutants. Effects of CO-1686 on cell proliferation and EGFR signaling
were evaluated in HCC827 cells (delE746-A750) and its erlotinib-resistant clone, HCC827-EPR harboring the second
site mutation T790M (delE746-A750/T790M). CO-1686 inhibited cell proliferation in both cell lines equally. In mouse
xenograft studies, oral dosing of CO-1686 in double mutant (L858R/T790M) and in single mutant (delE746-A750)
models caused tumor shrinkage as a single agent in a dose-dependent manner. Different dosing schedules were
explored.

Conclusions: Our results establish CO-1686 as a potent, mutant-selective EGFR inhibitor with excellent in vivo
activity in mice bearing tumors with activating EGFR mutations as well as the resistance mutation T790M. These data
suggest that treatment with CO-1686 as a single agent may overcome T790M-mediated drug resistance in NSCLC.
Initially, clinical development will focus on NSCLC patients with mutant EGFR.
天空的颜色  初中二年级 发表于 2012-12-18 16:40:16 | 显示全部楼层 来自: 新疆乌鲁木齐

请问有哪些抗血管生成药?谢谢

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小美无限  高中三年级 发表于 2012-12-18 17:03:59 | 显示全部楼层 来自: 广西梧州
米,你研究wz4002好深入啊,尽管上面的图和英文我什么也看不明白,我真心祝愿向你致敬!希望像你这样的前行者能给我们带来更多的福音!
谁能用眼泪换取幸福~~

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天空的颜色  初中二年级 发表于 2012-12-18 17:46:36 | 显示全部楼层 来自: 新疆乌鲁木齐
真是给患者带来一个好消息。感谢!

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keenman  超级版主 发表于 2012-12-19 08:19:33 | 显示全部楼层 来自: 北京朝阳
天空的颜色 发表于 2012-12-18 16:40
请问有哪些抗血管生成药?谢谢

目前我所了解的抗血管生成药,使用较多的有凡德他尼、阿西替尼,另外还有最新的Tivozanib药
本人不是医生,发帖内容是根据自身所掌握知识和以往的经验所建议,不构成治疗建议,请以医嘱为准

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lliyany  高中一年级 发表于 2012-12-19 19:35:51 | 显示全部楼层 来自: 清华大学紫荆公寓
谢谢“又一个五年”,刚刚在Q上向你学了很多,也更加迷惑了。唉

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rebirth99  小学六年级 发表于 2012-12-19 22:13:38 | 显示全部楼层 来自: 中国


标记个,母亲易耐药中

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weiyi1900897111  初中三年级 发表于 2012-12-20 11:26:27 | 显示全部楼层 来自: 江西九江
我也希望早一点试用WZ4002!!!

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