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.