HSP 90 抑制剂：另一个EGFR抑制剂耐药后的合理选择

这是Johnson医生今天的新文章。Johnson医生的研究领域是靶向药，她的特殊兴趣在genetic mutations that may contribute to racial variations in lung cancer risk.

http://cancergrace.org/lung/2011/10/28/auy922-hsp90/

http://cancergrace.org/faculty/melissa-johnson-md/

谢谢分享！！

这个很早就在关注了 之前很关注STA9090的 ， HSP 90 抑制剂  

考虑到是静脉注射，自己也搞不到啊..而且目前试验组是对ALK 阳性的人效果较好（之前是一切肺癌都有有效率）

痛恨癌症能给多给些信息么？

又一个新的希望，请爱姐姐、痛恨癌症以及其他了解的朋友给予具体的信息，多谢。

痛恨癌症 发表于 2011-10-29 09:54

                               
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这个很早就在关注了 之前很关注STA9090的 ， HSP 90 抑制剂  

考虑到是静脉注射，自己也搞不到啊..而且目 ...

你可能没读内容。这是个完全新的临床，刚刚开始，是在特耐药后，加上AUY922. 一期试验的目的是找到“最好”的剂量。希望明年能进入二期。AUY922曾经用于ALK+的临床，这个是针对EGFR+且Tarceva耐药后的临床。就像Johnson医生说的，时间会告诉这些药的最好位置在哪里。

我的消息的确是之前的 ， 我当时关注的是STA9090， 也是HSP90抑制剂， 2期临床已经结束了

5：STA-9090( Hsp90 抑制剂）
——Synta Pharmaceuticals公司表示STA-9090在一项用于晚期非小细胞肺癌的2 期试验中获得了肯定性结果，显示出了该药缩小肿瘤与延缓疾病进程的作用。目前STA-9090正在进行8项临床试验，包括用于非小细胞肺癌、胃肠道间质瘤、结肠癌、胃癌、急性淋巴性白血病的2期试验，有望于 2011年开始1项以上的3期临床试验。 ——这个是之前找到的，老资料
另一项研究显示联合阿瓦有综合性效果，优点：耐忍受
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因为一些突变的激酶虽然对一些相应的药物 耐药了， 但HSP90抑制剂 仍然有可能有效，因为这些激酶的活性仍然依赖于HSP90 ；  简单的可以理解为 HSP90 （热休克蛋白酶90）这种东西可以帮助癌细胞生长。

这个药物之前的 理论是说即使一些激酶抑制剂已经耐药，比如特罗凯耐药， 那么Hsp 90抑制剂依然会有作用 （我这里加个有可能，因为还没找到有力的数据支持）

除此之外，HSP90 抑制剂还有很多，比如IPI-504 和 17-AAG， 据说这种抑制剂对于 EGFR耐药后的细胞有特别的作用 ， EGFR耐药的原因目前认为最多的是MET扩增（广省临床组有30%属于这类），另外一种就是T790M突变（当然除这两种之外还有其他原因）， HSP90就是从这点下手的

这种药品注射的就算了，大家估计都很难弄到，还是从粉末下手吧.

我有ASCO2011 STA9090的资料，

An open-label phase II study of the Hsp90 inhibitor ganetespib (STA-9090) in
patients (pts) with metastatic and/or unresectable GIST.

Background: Ganetespib, a potent, synthetic small-molecule inhibitor of Hsp90, has shown an improved
safety profile relative to 1st -generation agents as well as promising signals of antitumor activity in early
clinical studies, including one pt with PDGFRA D842V mutant GIST. Preclinical studies have shown that
human GIST cells with primary or secondary TKI-resistance mutations are highly sensitive to ganetespib,
justifying this phase 2 trial in GIST.

Methods: Pts with advanced GIST following failure of prior therapy
(tx) received ganetespib (200 mg/m 2) as a 1 hour IV infusion qw for 3 wks of a 28 day cycle. GIST status
was assessed q8 wks per RECIST, until progression. In this Simon’s 2 stage study design, if 4/23 pts in
Stage 1 had clinical benefit (CRPRSD  16 wks) enrolment would continue with Stage 2. Hsp90 client
protein levels were analyzed in biopsies pre-tx and 24-48 h post-ganetespib in a subset of pts.

Results: 26 pts (15 M, 11 F; median age 53 yrs, range 33-67; ECOG status 0-1; median 5 prior tx regimens, range 3-12,
wild-type PDGFRA) received a median of 2 cycles of ganetespib (range 1-8). AEs reported in 20% of pts
were generally NCI CTC grade 1-2 and included diarrhea, fatigue, nausea, vomiting, increased alkaline
phosphatase, headache, insomnia, and abdominal pain. 12/23 evaluable pts had SD (4 SD 16 wks, 8 SD
8 wks), meeting formal criteria to enroll Stage 2. However, analysis of client proteins in paired tumor
biopsies from 4 pts did not show prolonged inhibition of activated KIT or its downstream pathways. These
data suggest the once-weekly tx schedule is likely not optimal for inhibition of KIT. At this time, accrual
has been limited to pts with PDGFRA mutations to allow further preclinical development of alternative
schedules and combinations.

Conclusions: Ganetespib given by once-weekly dosing was well tolerated in
pts with heavily pre-treated advanced GIST, with no evidence of severe liver, ocular, cardiac or renal
toxicity. Disease stabilization was seen in a subset of pts. Advanced preclinical modeling is ongoing to
optimize the impact of ganetespib on mutant KIT in GIST.

An open-label phase II study of the Hsp90 inhibitor ganetespib (STA-9090) as
monotherapy in patients with advanced non-small cell lung cancer (NSCLC).



Background: Ganetespib is a potent, next-generation Hsp90 inhibitor that is structurally unrelated to the
first-generation ansamycin class of Hsp90 inhibitors and has shown superior activity to these agents in
preclinical studies. Ganetespib has been well tolerated and has shown promising antitumor activity in early
trials in multiple cancers.

Methods: Patients (pts) with advanced NSCLC who failed prior treatments
received 200 mg/m  ganetespib as a 1-hr infusion once weekly for 3 of a 4-wk cycle in a Simon two-stage
study design assessing primary endpoint of PFS rate at 16 wks. Initial cohorts were defined by mutation
status: A) EGFR B) KRAS C) EGFR and KRAS wild type (WT). If 2/14 pts in A, B or C were
progression-free at 16 wks, enrollment increased to 23 pts for that cohort. Tumor response was assessed
every 8 wks. Cohort D was added to include 35 additional EGFR and KRAS WT pts with adenocarcinoma
histology. Additional mutational analysis of BRAF, PIK3CA, ERBB2 and MET, as well as FISH analysis for
ALK translocation, were performed for Cohorts C and D.

Results: 73 pts (31 M, 42 F; median age 62 yrs,
range 28-82; ECOG 0-1; prior therapies range 1-10) received a median of 2 cycles (range 1-12) of
ganetespib in cohorts A (14), B (17), and CD (42). AEs reported in 20% of pts included diarrhea,
fatigue, nausea, anorexia, constipation, and dyspnea and were generally grade 1-2. Expansion criteria were
achieved for cohort C, including a durable partial response (PR) and seven pts with prolonged stable disease
(16 wks). Cohort D continues recruitment. Mutational analyses of Cohort C and D samples will be
presented.

Conclusions: Ganetespib administered as a single-agent is well-tolerated in pts with NSCLC at
200 mg/m2 once weekly without severe liver, ocular, cardiovascular or renal toxicity. Clinical activity has
been observed in pts with advanced NSCLC tumors harboring wild-type EGFR and KRAS.

爱姐姐 发表于 2011-10-30 03:40

                               
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你可能没读内容。这是个完全新的临床，刚刚开始，是在特耐药后，加上AUY922. 一期试验的目的是找到“最 ...

这个研究还是存在问题的ALK+病人治疗克里错替尼的作用不可替代，HSP90的机制主要集中在调节EGFR、AKT、HER2这些激酶分子的构象与稳定性的调节，因此是一个相当下游的调节，当然EGFR耐药后构象是有所改变的，但是这些改变对于增殖、凋亡等下游信号通路只是其中一条。因此将来可能作为联合治疗的成员之一，就像贝伐单抗。