Monday, December 29, 2008

Hsp90 again

Several people have asked about the status of heat shock protein 90, inhibition of which was thought of as a new way of treating the most aggressive forms of CLL. Unfortunately the two inhibitors that I described before have proved too toxic to the liver to hold out much hope for them to emerge as anti-CLL drugs. There were 32 papers at ASH which mentioned Hsp90, but most of them were irrelevant to CLL patients. Eloisi Caldas Lopes from Memorial Sloane Kettering described a new inhibitor, PUH-71, which is of a different chemical type to those previously described. This new agent was found to inhibit the growth of human diffuse large B-cell lymphomas in mice without liver toxicity. The agent was preferentially retained in the tumor tissue.

Other Hsp90 inhibitors are in the pipeline. Novartis have two, a pan-Histone deacetylase inhibitor, panobinostat, and a specific Hsp90 inhibitor, AUY, were both tested by Wang et al from MCG Cancer Center, Augusta, Georgia, in a system that stressed the mutant JAK2 status of myeloproliferative disease and both inhibited it through Hsp90 inhibition. In another study workers from Tokyo found that AUY when given with nilotinib could overcome the T315I mutant BCR-ABL that has so far produced a form of imatinib resistance in CML that could not otherwise be overcome. Panobinostat, meanwhile may act synergistically with bortezamib in mantle cell lymphoma (data from MCG Cancer Center, Augusta,H Lee Moffitt Cancer Center, Tampa, and Novartis Institute for Biomedical Research, Cambridge, MA. A phase II study of panobinostat in drug resistant myeloma is being carried out with some beneficial effects.

One of the other difficulties in Hsp90 inhibition is that it tends to upregulate Hsp72 which inhibits apoptosis. According to Emma Davenport and colleagues from the Insitute of Cancer Research, UK, this can be prevented by Hsp72 inhibitors such as KNK437 and triptolide.

John Byrd's group at Colombus, Ohio demonstrated that the Hsp90 inhibitor 17-DMAG represents a novel multi-targeted inhibitor of several critical kinases, transcription factors and anti-apoptosis genes relevant to CLL survival, and not just ZAP70, especially NF-kB. Given its oral formulation, which allows administration of 17-DMAG by continuous dosing and uninterrupted inhibition of Hsp90, initiation of phase II clinical trials in CLL that include detailed pharmacodynamic studies monitoring NF-kB target genes are indicated.

Jamie Cavenagh from Barts reported on a Phase I trial of KW-2478, a novel non-ansamycin, non-purine analogue antagonist for Hsp90. KW-2478 showed a potent anti-tumour activity both in vitro and in vivo in xenograft models, including activity in primary patient samples. The agent retained its activity in primary myeloma cells in the presence of BMSCs, suggesting that KW-2478 can overcome the protective effect of the bone marrow microenvironment. In the phase I trial there was no dose-limiting toxicity and the dose escalation continues.

From MDACC comes the small molecule WP1193, a caffeic acid derivative, which induced apoptosis in all types of drug-resistant CML cells. Treatment of the cells with WP1193 reduced levels of HSP90 transcripts, HSP90 protein and its client proteins, which include Bcr-Abl, Jak2 and Akt.

In conclusion, Hsp90 inhibition remains a promising treatment, not just for CLL, but for a range of different hematological tumors. Its effects are much more complicated that simply down-regulation of Zap-70, and care must be taken that a compensatory up-regulation of protective factors does not take place. The older geldanomycin derivatives may be too toxic for clinical use, but newer, perhaps less toxic inhibitors are in development.

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