I agree this is a very promising target, but has been marred by toxicity problems with many inhibitor candidates. If you are looking into the various competitors, here is the run-down:
Single-agent responses have been reported ganetespib aka STA-9090 from SNTA - phase 2b data 2q2012 retaspamycin HCl aka IPI-504 from INFI - in phase 2 but no data in 2012
Phase 1 results coming by ASCO 2012 - claims of good safety and PRs have been made AT13387 from ASTX Debio0932 from CRIS/DebioPharm
Phase 1 reported with ocular toxicity issues or otherwise abandoned MPC-3100 from MYRX AUY922 from NVS/Vernalis BIIB021 and BIIB028 from BIIB SNX5422 from PFE XL888 from EXEL
I started to assemble info on these programs here...you'll find trial info and some abstracts, but it is admittedly incomplete: http://goo.gl/tGXuV
I'm also convinced HSP90 is a very promising target, but my concern is that its activity may not properly emerge as a single agent. If this is correct, it makes development much harder, and means that any promising candidate really belongs in a big pharma program rather than in a small company program.
Is the MOA is something along the lines of: if hsp90 allows genotypic variation in a protein to exist, it could mask oncogenic mutations from immune survelance.
Inhibit HSP90 and the protein resulting from an oncogenic mutation is either exposed to immune survelance, or may become nonfunctional due to misfolding?
This might interest you. I know Exelixis was very high on this early asset before Cabo prioritization. Just mouse studies, but looks pretty interesting. Someone posted on yahoo EXEL mb
Purpose: The clinical use of BRAF inhibitors is being hampered by the acquisition of drug resistance. This study demonstrates the potential therapeutic utility of the HSP90 inhibitor (XL888) in 6 different models of vemurafenib resistance. Experimental design: The ability of XL888 to inhibit growth and to induce apoptosis and tumor regression of vemurafenib-resistant melanoma cell lines was demonstrated in vitro and in vivo. A novel mass spectrometry-based pharmacodynamic assay was developed to measure intratumoral HSP70 levels following HSP90 inhibition in melanoma cell lines, xenografts and melanoma biopsies. Mechanistic studies were performed to determine the mechanism of XL888-induced apoptosis. Results: XL888 potently inhibited cell growth, induced apoptosis and prevented the growth of vemurafenib resistant melanoma cell lines in 3D cell culture, long-term colony formation assays and human melanoma mouse xenografts. The reversal of the resistance phenotype was associated with the degradation of PDGFR beta, COT, IGFR1, CRAF, ARAF, S6, cyclin D1 and AKT, which in turn led to the nuclear accumulation of FOXO3a, an increase in BIM expression and the downregulation of Mcl-1. In most resistance models, XL888 treatment increased BIM expression, decreased Mcl-1 expression, and induced apoptosis more effectively than dual MEK/PI3K inhibition. Conclusions: HSP90 inhibition may be a highly effective strategy at managing the diverse array of resistance mechanisms being reported to BRAF inhibitors and appears to be more effective at restoring BIM expression and downregulating Mcl-1 expression than combined MEK/PI3K inhibitor therapy.
Received October 10, 2011. Revision received January 30, 2012. Accepted February 13, 2012.
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