The lack of a clear correlation between histone acetylation and response, as well as researchers' intense interest in hsp90 as a target for HDAC inhibitors, highlights a major question in the field: How are these drugs working?
The model has been that deacetylation of the histones exposed their positively charged tails and increased their affinity for the negatively charged DNA backbone. That meant that the DNA became more tightly packed and gene expression was turned off in the affected regions.
Such gene silencing is likely to be part of the story, but only part of it. For example, in the LBH589 study, responders tended to have more genes downregulated than upregulated genes, which is contrary to the gene silencing model. On the other hand, it may not be the number of genes altered that matters as much as whether key genes are re-activated.
Recently, researchers have found that acetylation increases the stability of numerous signaling proteins, in a manner reminiscent of how phosphorylation activates such proteins. That means that HDAC inhibitors could alter signaling in treated cells, potentially affecting processes like proliferation, adhesion, or cell death.
So what is the main mechanism of action? That remains to be seen. While these drugs are considered targeted agents, some investigators think their targets are likely to be relatively widespread throughout the cell.
That uncertainty, however, has not dampened researchers' enthusiasm for the new class of drugs. “I think it is a reflection of the field that there are over a dozen HDAC inhibitors in clinical trials right now,” said Jean-Pierre Issa, MD, of the University of Texas M. D. Anderson Cancer Center.