Ganetespib对ALK驱动型NSCLC有效

据3月26日在线发表于《癌症研究》的一篇报告，Ganetespib或可成为抑制间变型淋巴瘤激酶（ALK）的一种替代或是补充策略，而据估计，7%的非小细胞肺癌(NSCLC)是由ALK驱动发生的。研究者为麻省莱克星顿市Synta制药公司的Jim Sang医生等人。

据主要研究者、麻省莱克星顿市Synta制药公司的Jim Sang介绍，迄今为止，此药已经在体内外动物研究中初显成效，并且在1例ALK引起的NSCLC患者中进行了检验。该患者为男性，24岁，对克唑替尼的初始治疗有应答，不过1年后对该药产生耐药性并复发，而单个疗程的ganetespib治疗即产生了显著的抗肿瘤效应，使肺部病灶明显萎缩，这凸显出该药对这个难治群体的治疗潜能(Cancer Res. 2013 March 26 [doi:10.1158/2159-8290.CD-12-0440])。克唑替尼是目前经FDA批准治疗该病的惟一靶向治疗药物，但几乎所有接受克唑替尼治疗的NSCLC患者都会对其产生耐药性。若ganetespib在临床试验中被证明有效，可能会给克唑替尼耐药患者带来福音。

Ganetespib可抑制Hsp90(热休克蛋白90)，Hsp90是在调节许多“客户蛋白”的正确折叠、稳定性和功能方面起着核心作用的分子伴侣，其中包括ALK。据了解，抑制Hsp90可阻断多个对肿瘤细胞增殖和生存必不可少的致癌信号途径。因此，就ALK驱动型癌症而言，靶向作用于Hsp90的伴侣功能代表着一条通过直接抑制激酶进行治疗干预的替代途径。药物阻断Hsp90也或许会克服许多癌症中常见的耐药性机制。

研究者们首先在一个ALK阳性的NSCLC培养细胞系中对ganetespib进行了检验。结果显示，该药的抗癌效力较克唑替尼高30倍以上，能使体外ALK表达完全消失，也显示出针对对克唑替尼产生耐药性的ALK阳性NSCLC细胞系的强大活性。随后，研究者利用ALK阳性NSCLC癌细胞异种移植的小鼠，对ganetespib与克唑替尼进行了比较，结果显示，与克唑替尼相比，genetespib显示出较强的抗肿瘤活性，并明显延长了动物的生存时间。进一步的实验研究显示，ganetespib联合其他靶向ALK药物在体内外实验中均很有效。

研究者表示，就ALK驱动的多种恶性肿瘤的治疗干预而言，使用ganetespib靶向作用于Hsp90伴侣途径代表着一种潜在有效的治疗策略，尤其是NSCLC。与直接抑制激酶相比，Hsp90对ALK本身及其他客户蛋白的多向作用能够产生更多完全及持久的应答效应。

本研究由Synta制药公司资助。Sang的合作者报告与许多业内人士有其他联系。

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By: MARY ANN MOON, Oncology Practice

Ganetespib may be an alternative or possibly a complementary strategy for inhibiting anaplastic lymphoma kinase, the protein that drives tumorigenesis in an estimated 7% of non–small cell lung carcincomas, according to a report published online March 26 in Cancer Research.

So far the drug has shown promise in vitro and in animal studies and has been tested in a single patient with ALK-driven NSCLC.

The 24-year-old man had initially responded to crizotinib, but after 1 year he developed resistance to the drug and relapsed. "A single cycle of ganetespib treatment resulted in marked tumor response and discernible shrinkage of lung lesions, highlighting the therapeutic potential of the drug within this refractory population," Dr. Jim Sang and his associates wrote (Cancer Res. 2013 March 26 [doi:10.1158/2159-8290.CD-12-0440]).

If ganetespib proves effective in clinical trials, the drug may become especially helpful for patients who develop resistance to crizotinib, the only targeted therapy for the disease that currently has FDA approval, said Dr. Sang of Synta Pharmaceuticals, Lexington, Mass. and his associates. Almost all NSCLC patients who receive crizotinib acquire resistance to it, they noted.

Ganetespib inhibits Hsp90 (heat shock protein 90), "a molecular chaperone that plays a central role in regulating the correct folding, stability, and function of numerous ‘client proteins,’ " including ALK, they said. Inhibition of Hsp90 is known to disrupt several oncogenic signaling pathways that are crucial to tumor cell proliferation and survival.

"Targeting the chaperone function of Hsp90, therefore, represents an alternative approach to direct kinase inhibition for therapeutic intervention in ALK-driven cancer," Dr. Sang and his colleagues said. Pharmacologic blockade of Hsp90 also may overcome drug resistance mechanisms commonly seen in many cancers.

The researchers first tested ganetespib in a cultured, ALK-positive NSCLC cell line. The drug was 30 times more potent than crizotinib against the carcinoma, causing the complete loss of ALK expression in vitro. Ganetespib also demonstrated strong activity against ALK-positive NSCLC cell lines that were resistant to crizotinib.

The investigators then compared ganetespib with crizotinib in mice that were xenografted with ALK-positive NSCLC cancer cells. Ganetespib showed greater antitumor activity and actually prolonged the survival of the animals, compared with crizotinib.

In further experiments, ganetespib was effective both in vitro and in vivo when combined with other targeted ALK agents.

"Targeting the Hsp90 chaperone pathway with ganetespib represents a potentially effective strategy for therapeutic intervention in multiple ALK-driven malignancies – in particular, NSCLC. The pleiotropic effects of Hsp90 inhibition on both ALLK itself and other client proteins provide more complete and durable responses, compared with direct kinase inhibition," Dr. Sang and his associates wrote.

This study was funded by Synta Pharmaceuticals. Dr. Sang’s associates reported additional ties to numerous industry sources.